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1. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author: Richard A. Jensen, Denis Rybin, Jaakko Tuomilehto, Reedik Mägi, Inga Prokopenko, Jeffrey R. O'Connell, Marcus E. Kleber, Han Chen, Geoffrey A. Walford, Allan Linnenberg, Anke Tönjes, Francis S. Collins, Sonsoles Morcillo, Gemma Rojo-Martínez, Kenneth Rice, Jose C. Florez, Leif Groop, Manuel Serrano-Ríos, Josée Dupuis, Alisa K. Manning, Peter Kovacs, Torben Jørgensen, Graciela E. Delgado, Alena Stančáková, Hans-Ulrich Häring, Claudia Langenberg, Joshua P. Lewis, Norbert Stefan, Markku Laakso, Torben Hansen, Bruce M. Psaty, Jian'an Luan, Michael Stumvoll, Mark O. Goodarzi, Robert A. Scott, Oluf Pedersen, Ching-Ti Liu, Michael N. Weedon, Michael Boehnke, Ulf Smith, David S. Siscovick, Aaron Leong, Weijia Xie, James B. Meigs, Claes Landenvall, Anne U. Jackson, Joseph M. Zmuda, Mary L. Biggs, Jerome I. Rotter, Federico Soriguer, Winfried März, Zhongyang Zhang, May E. Montasser, Arturo Corbatón-Anchuelo, J M Gómez-Zumaquero, Günther Silbernagel, Kristine Færch, Karen L. Mohlke, Heikki A. Koistinen, Yii-Der Ida Chen, Jaeyoung Hong, Gracia María Martín-Núñez, María Teresa Martínez-Larrad, Emil V. R. Appel, Niels Grarup, Harald Staiger, Johanna Kuusisto, Lars Lind, Nicholas J. Wareham, Andreas Fritsche, Stefan Gustafsson, Andrew P. Morris, Richard N. Bergman, Mark Walker, Cecilia M. Lindgren, Erik Ingelsson, Jorge R. Kizer, Timothy M. Frayling, and Fausto Machicao
Subjects: 0301 basic medicine, Male, Insulin Receptor Substrate Proteins, Endocrinology, Diabetes and Metabolism, Locus (genetics), Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, Endocrinology & Metabolism, Insulin resistance, Genotype, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic association, Genetics, business.industry, Insulin sensitivity, Genetics/Genomes/Proteomics/Metabolomics, 11 Medical And Health Sciences, medicine.disease, IRS1, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, Chemokines, CC, Female, Insulin Resistance, business, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
Published: 2023
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2. Genome-wide association study of body fat distribution traits in Hispanics/Latinos from the HCHS/SOL

Author: Esteban J. Parra, Craig L. Hanis, Lisa Sanchez-Johnsen, Kristin L. Young, Misa Graff, Yujie Wang, Adán Valladares, Lauren E. Petty, Yii-Der Ida Chen, Xiuqing Guo, Mark O. Goodarzi, Miguel Cruz, Kari E. North, Anny H. Xiang, Leslie J. Raffel, Matthew A. Allison, Tamar Sofer, Yann C. Klimentidis, Shelly Ann Love, Anne E. Justice, Stephanie M. Gogarten, Fernando Pires Hartwig, Thomas A. Buchanan, Jennifer E. Below, Jingyi Tan, Jie Yao, Jerome I. Rotter, Willa A. Hsueh, Eli Ipp, Walter Palmas, Kent D. Taylor, Heather M. Highland, and Carmen R. Isasi
Subjects: AcademicSubjects/SCI01140, Waist, Ethnic group, 030209 endocrinology & metabolism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Quantitative Trait, Heritable, 0302 clinical medicine, Genetics, medicine, Body Fat Distribution, Humans, Association Studies Article, Molecular Biology, Alleles, Genetics (clinical), Adiposity, 030304 developmental biology, Body fat distribution, 0303 health sciences, Hispanic latino, Hispanic or Latino, General Medicine, medicine.disease, Hchs sol, Obesity, Body mass index, Genome-Wide Association Study, Demography
Abstract: Author(s): Justice, Anne E; Young, Kristin; Gogarten, Stephanie M; Sofer, Tamar; Graff, Misa; Love, Shelly Ann M; Wang, Yujie; Klimentidis, Yann C; Cruz, Miguel; Guo, Xiuqing; Hartwig, Fernando; Petty, Lauren; Yao, Jie; Allison, Matthew A; Below, Jennifer E; Buchanan, Thomas A; Chen, Yii-Der Ida; Goodarzi, Mark O; Hanis, Craig; Highland, Heather M; Hsueh, Willa A; Ipp, Eli; Parra, Esteban; Palmas, Walter; Raffel, Leslie J; Rotter, Jerome I; Tan, Jingyi; Taylor, Kent D; Valladares, Adan; Xiang, Anny H; Sanchez-Johnsen, Lisa; Isasi, Carmen R; North, Kari E | Abstract: Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC), and hip circumference (HIP) adjusted for body mass index (adjBMI), using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL; and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban, and Dominican) background residing in the US. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for WHRadjBMI, 22 for WCadjBMI, and 28 for HIPadjBMI that reached suggestive significance (P l 1x10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed 4 novel loci (P l 0.05 and consistent direction of effect, and P l 5x10-8 after meta-analysis), including 2 for WHRadjBMI (rs13301996, rs79478137); 1 for WCadjBMI (rs3168072); and 1 for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI; 10 for WCadjBMI; 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity-susceptibility that may be ancestry-specific.
Published: 2021

3. Association of Visceral Adipose Tissue and Insulin Resistance with Incident Metabolic Syndrome Independent of Obesity Status: The IRAS Family Study

Author: Lynne E. Wagenknecht, Carlos Lorenzo, Nicolette D Palmer, Janet A. Tooze, Kristen G. Hairston, Jill M. Norris, Morgana Mongraw-Chaffin, Donald W. Bowden, Yii-Der Ida Chen, and Anthony J. Hanley
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Adipose tissue, 030209 endocrinology & metabolism, Intra-Abdominal Fat, Logistic regression, Article, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Internal medicine, parasitic diseases, medicine, Humans, Obesity, 030212 general & internal medicine, Abdominal obesity, Metabolic Syndrome, Nutrition and Dietetics, business.industry, nutritional and metabolic diseases, Odds ratio, Atherosclerosis, medicine.disease, Homeostatic model assessment, Insulin Resistance, medicine.symptom, Metabolic syndrome, business, tissues, human activities
Abstract: Objective Although increasing evidence suggests that visceral adipose tissue (VAT) is a major underlying cause of metabolic syndrome (MetS), few studies have measured VAT at multiple time points in diverse populations. VAT and insulin resistance were hypothesized to differ by MetS status within BMI category in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study and, further, that baseline VAT and insulin resistance and increases over time are associated with incident MetS. Methods Generalized estimating equations were used for differences in body fat distribution and insulin resistance by MetS status. Mixed effects logistic regression was used for the association of baseline and change in adiposity and insulin resistance with incident MetS across 5 years, adjusted for age, sex, race/ethnicity, and family correlation. Results VAT and insulin sensitivity differed significantly by MetS status and BMI category at baseline. VAT and homeostatic model assessment of insulin resistance (HOMA-IR) at baseline (VAT odds ratio [OR] = 1.16 [95% CI: 1.12-2.31]; HOMA-IR OR = 1.85 [95% CI: 1.32-2.58]) and increases over time (VAT OR = 1.55 [95% CI: 1.22-1.98]; HOMA-IR OR = 3.23 [95% CI: 2.20-4.73]) were associated with incident MetS independent of BMI category. Conclusions Differing levels of VAT may be driving metabolic heterogeneity within BMI categories. Both overall and abdominal obesity (VAT) may play a role in the development of MetS. Increased VAT over time contributed additional risk.
Published: 2021

4. Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer’s disease and myocardial infarction

Author: Vilmundur Gudnason, Solomon K. Musani, Yi-Ping Fu, Albert V. Smith, Yii-Der Ida Chen, Annapurna Kuppa, Xiuqing Guo, Matthew A. Allison, Sharon L.R. Kardia, Donald W. Bowden, Gudny Eirksdottir, Jill M. Norris, Jian Yang, Bratati Kahali, Yanhua Chen, Thomas H. Mosley, Elizabeth K. Speliotes, Lenore J. Launer, James G. Terry, Brian D. Halligan, Jerome I. Rotter, Matthew J. Budoff, Kent D. Taylor, Kathleen A. Ryan, Breland F. Crudup, Adolfo Correa, Lawrence F. Bielak, Jeffrey R. O'Connell, Michael A. Province, Patricia A. Peyser, Nicholette D. Palmer, Christopher J. O'Donnell, Mary F. Feitosa, Lynne E. Wagenknecht, J. Jeffrey Carr, and Xiaomeng Du
Subjects: Liver Cirrhosis, 0301 basic medicine, Apolipoprotein E, Aging, Cirrhosis, Myocardial Infarction, Disease, Neurodegenerative, Alzheimer's Disease, Chronic liver disease, Medical and Health Sciences, Gastroenterology, Oral and gastrointestinal, Hepatitis, Liver disease, 0302 clinical medicine, Gene Frequency, Risk Factors, Non-alcoholic Fatty Liver Disease, Databases, Genetic, Nonalcoholic fatty liver disease, 2.1 Biological and endogenous factors, Exome, Aetiology, Association Studies Article, Genetics (clinical), Genetics & Heredity, Liver Disease, Fatty liver, Alanine Transaminase, Single Nucleotide, General Medicine, Biological Sciences, Prognosis, Phenotype, Liver, Biotechnology, medicine.medical_specialty, Chronic Liver Disease and Cirrhosis, Biology, Polymorphism, Single Nucleotide, Databases, 03 medical and health sciences, Apolipoproteins E, Genetic, Alzheimer Disease, Internal medicine, Acquired Cognitive Impairment, Genetics, medicine, Humans, Obesity, Polymorphism, Molecular Biology, Triglycerides, Alleles, Prevention, Human Genome, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, Brain Disorders, 030104 developmental biology, Dementia, Steatosis, Digestive Diseases, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P
Published: 2021

5. Multi-omics analysis identifies CpGs near G6PC2 mediating the effects of genetic variants on fasting glucose

Author: Thomas Quertermous, I-Shou Chang, I-Te Lee, Yen-Feng Chiu, Chao A. Hsiung, Yii-Der Ida Chen, Chii-Min Hwu, Wen Chang Wang, Yi-Jen Hung, Jerome I. Rotter, Ren-Hua Chung, and Lee-Ming Chuang
Subjects: 0301 basic medicine, Genetics, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, Single-nucleotide polymorphism, Type 2 diabetes, Biology, Quantitative trait locus, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Insulin resistance, DNA methylation, Internal Medicine, medicine, SNP, Genetic association
Abstract: An elevated fasting glucose level in non-diabetic individuals is a key predictor of type 2 diabetes. Genome-wide association studies (GWAS) have identified hundreds of SNPs for fasting glucose but most of their functional roles in influencing the trait are unclear. This study aimed to identify the mediation effects of DNA methylation between SNPs identified as significant from GWAS and fasting glucose using Mendelian randomisation (MR) analyses. We first performed GWAS analyses for three cohorts (Taiwan Biobank with 18,122 individuals, the Healthy Aging Longitudinal Study in Taiwan with 1989 individuals and the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance with 416 individuals) with individuals of Han Chinese ancestry in Taiwan, followed by a meta-analysis for combining the three GWAS analysis results to identify significant and independent SNPs for fasting glucose. We determined whether these SNPs were methylation quantitative trait loci (meQTLs) by testing their associations with DNA methylation levels at nearby CpG sites using a subsample of 1775 individuals from the Taiwan Biobank. The MR analysis was performed to identify DNA methylation with causal effects on fasting glucose using meQTLs as instrumental variables based on the 1775 individuals. We also used a two-sample MR strategy to perform replication analysis for CpG sites with significant MR effects based on literature data. Our meta-analysis identified 18 significant (p
Published: 2021

6. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity

Author: Jack A. Kosmicki, Charles Paulding, Nan Lin, Andrew J. Murphy, Jerome I. Rotter, Brian Zambrowicz, Niek Verweij, Luca A. Lotta, Michal L. Schwartzman, Giusy Della Gatta, Yii-Der Ida Chen, Alexander H. Li, Suganthi Balasubramanian, Jason M. Torres, Hyun Min Kang, Rory Collins, Parsa Akbari, Michael E. Dunn, Gonçalo R. Abecasis, Christian Benner, David J. Carey, Svati H. Shah, Jonathan Marchini, Giovanni Coppola, Marcus B. Jones, Olle Melander, Christopher D. Still, Yi-Ya Fang, Olukayode A. Sosina, Manuel A. R. Ferreira, Roberto Tapia-Conyer, Michael Cantor, Aris N. Economides, Dylan Sun, Adam E. Locke, Jonathan V. Pascale, Daniel J. Rader, Ankit Gilani, Joelle Mbatchou, Jesus Alegre-Díaz, Mark W. Sleeman, Trikaldarshi Persaud, Jeffrey G. Reid, Pablo Kuri-Morales, Jaime Berumen-Campos, John D. Overton, Aris Baras, Ercument Dirice, Sakib Hossain, Alicia Hawes, George D. Yancopoulos, Jonathan Emberson, Victor Garcia, Judith Altarejos, Lori Khrimian, Katia Karalis, William E. Kraus, Tooraj Mirshahi, Kevin Agostinucci, Alan R. Shuldiner, Center, Regeneron Genetics, and Collaboration, DiscovEHR
Subjects: 0301 basic medicine, Genetics, medicine.medical_specialty, Multidisciplinary, Body Weight, Genomics, Organ Size, Biology, medicine.disease, Obesity, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Genetic variation, medicine, Medical genetics, Humans, medicine.symptom, Body mass index, Weight gain, 030217 neurology & neurosurgery, Exome sequencing, Glycemic
Abstract: Introduction Obesity accounts for a substantial and growing burden of disease globally. Body adiposity is highly heritable, and human genetic studies can lead to biological and therapeutic insights. Rationale Whole-exome sequencing of hundreds of thousands of individuals is complementary to approaches used to date in obesity genetics and has the potential to identify rare protein-coding variants with large phenotypic impact. We sequenced the exomes of 645,626 individuals from the UK, the US, and Mexico and estimated associations of rare coding variants with body mass index (BMI), a measure of overall adiposity used to define obesity in clinical practice. We complemented exome sequencing with fine-mapping of common alleles, polygenic score analysis, and in vitro and in vivo modeling work. Results We identified 16 genes for which the burden of rare nonsynonymous variants was associated with BMI at exome-wide statistical significance (inverse-variance weighted meta-analysis P < 3.6 × 10−7), including associations at five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). We observed an overrepresentation of genes highly expressed in the hypothalamus, a key center for the neuroendocrine regulation of energy balance. Protein-truncating variants in GPR75 were found in ~4/10,000 sequenced people and were associated with 1.8 kg/m2 lower BMI, 5.3 kg lower bodyweight, and 54% lower odds of obesity in heterozygous carriers. Knock out of Gpr75 in mice resulted in resistance to weight gain in a high-fat diet model, which was allele-dose dependent (25% and 44% lower weight gain, respectively, for heterozygous Gpr75−/+ mice and knockout Gpr75−/− mice compared with wild type) and accompanied by improved glycemic control and insulin sensitivity. Protein-truncating variants in CALCR were associated with higher BMI and obesity risk, whereas protein-truncating variants in GIPR and two missense alleles [Arg190→Gln (Arg190Gln), Glu288Gly], which we show result in loss of function in vitro, were associated with lower adiposity. Among monogenic obesity genes in the leptin-melanocortin pathway, heterozygous predicted loss-of-function variants in LEP, POMC, PCSK1, and MC4R (but not LEPR) were associated with higher BMI. Rare protein-truncating variants in UBR2, ANO4, and PCSK1 were associated with more than twofold higher odds of obesity in heterozygous carriers, similar to predicted-deleterious nonsynonymous variants in MC4R, which are considered the most common cause of monogenic obesity. Polygenic predisposition due to >2 million common genetic variants influenced the penetrance of obesity in rare variant carriers in an additive fashion. Conclusion These results suggest that inhibition of GPR75 may be a therapeutic strategy for obesity and illustrate the power of massive-scale exome sequencing for the identification of large-effect coding variant associations and drug targets for complex traits.
Published: 2022

7. Rationale, design and baseline characteristics of the Microbiome and Insulin Longitudinal Evaluation Study ( <scp>MILES</scp> )

Author: Zorayr Arzumanyan, Kristi L. Hoffman, Osa L. Crago, Stephen S. Rich, Joseph F. Petrosino, Jerome I. Rotter, Kathryn Roll, Yii-Der Ida Chen, Martin Wu, Mark O. Goodarzi, Alain G. Bertoni, Kevin Sandow, Alexis C. Wood, Elizabeth T. Jensen, and Lok-Sze Kelvin Lam
Subjects: Blood Glucose, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Physiology, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Diabetes mellitus, Internal Medicine, medicine, Humans, Insulin, Microbiome, Family history, business.industry, Glucose Tolerance Test, Anthropometry, medicine.disease, Gastrointestinal Microbiome, Diabetes Mellitus, Type 2, Insulin Resistance, business, Body mass index
Abstract: Aim To investigate the role of the gut microbiome in regulating key insulin homeostasis traits (insulin sensitivity, insulin secretion and insulin clearance) whose dysfunction leads to type 2 diabetes (T2D). Materials and methods The Microbiome and Insulin Longitudinal Evaluation Study (MILES) focuses on African American and non-Hispanic white participants aged 40-80 years without diabetes. Three study visits are planned (at baseline, 15 and 30 months). Baseline measurements include assessment of the stool microbiome and administration of an oral glucose tolerance test, which will yield indexes of insulin sensitivity, insulin secretion and insulin clearance. The gut microbiome profile (composition and function) will be determined using whole metagenome shotgun sequencing along with analyses of plasma short chain fatty acids. Additional data collected include dietary history, sociodemographic factors, health habits, anthropometry, medical history, medications and family history. Most assessments are repeated 15 and 30 months following baseline. Results After screening 875 individuals, 129 African American and 224 non-Hispanic white participants were enrolled. At baseline, African American participants have higher blood pressure, weight, body mass index, waist and hip circumferences but similar waist-hip ratio compared with the non-Hispanic white participants. On average, African American participants are less insulin-sensitive and have higher acute insulin secretion and lower insulin clearance. Conclusions The longitudinal design and robust characterization of potential mediators will allow for the assessment of glucose and insulin homeostasis and gut microbiota as they change over time, improving our ability to discern causal relationships between the microbiome and the insulin homeostasis traits whose deterioration determines T2D, setting the stage for future microbiome-directed therapies to prevent and treat T2D.
Published: 2020

8. Racial and ethnic differences in the metabolic response of polycystic ovary syndrome

Author: Ricardo Azziz, Uche Ezeh, and Yii-Der Ida Chen
Subjects: Blood Glucose, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Population, 030209 endocrinology & metabolism, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Internal medicine, medicine, Hyperinsulinemia, Humans, Insulin, Prospective Studies, education, education.field_of_study, business.industry, nutritional and metabolic diseases, Glucose Tolerance Test, medicine.disease, Polycystic ovary, Cross-Sectional Studies, Basal (medicine), 030220 oncology & carcinogenesis, Female, Insulin Resistance, business, Body mass index, Polycystic Ovary Syndrome, Compensatory Hyperinsulinemia
Abstract: Context Polycystic ovary syndrome (PCOS) is a highly prevalent disorder associated with insulin resistance (IR) and compensatory hyperinsulinemia. Although variations in cardiometabolic risks across race and ethnicities have been reported in the general population, racial/ethnic disparities in the metabolic dysfunction of PCOS remain relatively unstudied. Objectives To determine whether markers of metabolic function differ in nondiabetic Asian American (AS), African American (AA), Hispanic White (HW), compared to non-Hispanic White (NHW) women with PCOS. Design and setting Prospective cross-sectional study in a tertiary institution. Participants and interventions A total of 259 nondiabetic women with PCOS (by NIH 1990 criteria) who completed a 2-hour 75-g oral glucose tolerance test measuring plasma glucose and insulin levels. Basal IR and insulin secretion, assessed by the homeostasis model assessment (HOMA-IR and HOMA-β%, respectively), and two-hour hyperglycaemia and hyperinsulinemia after an oral glucose load, were compared in 21 AS, 24 AA, 53 HW and 161 NHW consecutive nondiabetic adult PCOS women. Results After adjusting for age and body mass index, HW and AA PCOS women demonstrated higher fasting and post-glucose challenge insulin levels, and higher HOMA-IR and HOMA-β%, than NHW women, although glucose levels were similar. In contrast, AS PCOS women had or tended to have lower HOMA-β% than any other racial/ethnic groups, lower HOMA-IR, and fasting and post-challenge insulin levels than AA or HW, and also had higher (albeit still normal) mean post-challenge glucose levels than NHW women with PCOS despite similar HOMA-IR, and fasting insulin and post-challenge insulin levels. Waist-hip ratio was similar across the four groups. Conclusion Both HW and AA women with PCOS have increased basal state IR and higher β-cell response, and post-challenge hyperinsulinemia compared to NHW and AS subjects. The trend towards a lesser insulin response among Asian women requires further investigation. These findings suggest that the screening and management of metabolic dysfunction in PCOS should consider patients' race/ethnicity.
Published: 2020

9. A Pilot Genome‐Wide Analysis Study Identifies Loci Associated With Response to Obeticholic Acid in Patients With NASH

Author: Samer Gawrieh, Xiuqing Guo, Jingyi Tan, Marie Lauzon, Kent D. Taylor, Rohit Loomba, Oscar W. Cummings, Sreekumar Pillai, Pallav Bhatnagar, Kris V. Kowdley, Katherine Yates, Laura A. Wilson, Yii‐Der Ida Chen, Jerome I. Rotter, Naga Chalasani, and NASH Clinical Research Network
Subjects: medicine.medical_specialty, Clinical Trials and Supportive Activities, Chronic Liver Disease and Cirrhosis, Genome-wide association study, Single-nucleotide polymorphism, Population stratification, Gastroenterology, digestive system, Oral and gastrointestinal, Hepatitis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Clinical Research, Internal medicine, Nonalcoholic fatty liver disease, Genetics, Medicine, SNP, 2.1 Biological and endogenous factors, NASH Clinical Research Network, Allele, Aetiology, lcsh:RC799-869, Genotyping, 030304 developmental biology, 0303 health sciences, Hepatology, business.industry, Liver Disease, Human Genome, Obeticholic acid, nutritional and metabolic diseases, Original Articles, medicine.disease, digestive system diseases, chemistry, 030211 gastroenterology & hepatology, Original Article, lcsh:Diseases of the digestive system. Gastroenterology, business, Digestive Diseases
Abstract: A significantly higher proportion of patients with nonalcoholic steatohepatitis (NASH) who received obeticholic acid (OCA) had histological improvement relative to placebo in the FLINT (farnesoid X nuclear receptor ligand obeticholic acid for noncirrhotic, NASH treatment) trial. However, genetic predictors of response to OCA are unknown. We conducted a genome‐wide association study (GWAS) in FLINT participants to identify variants associated with NASH resolution and fibrosis improvement. Genotyping was performed using the Omni2.5 content GWAS chip. To avoid false positives introduced by population stratification, we focused our GWAS on white participants. Six regions on chromosomes 1, 4, 6, 7, 15, and 17 had multiple single nucleotide polymorphisms (SNPs) with suggestive association (P, We conducted a genome wide association study (GWAS) in FLINT trial participants to identify variants associated with NASH resolution and fibrosis improvement. We identified several variants associated with histological improvement and pruritus in individuals with NASH receiving obeticholic acid (OCA). The rs75508464 variant near CELA3B had the most significant effect on NASH resolution in those receiving OCA.
Published: 2019

10. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

Author: Priyadarshini Kachroo, Julian Hecker, Bo L. Chawes, Tarunveer S. Ahluwalia, Michael H. Cho, Dandi Qiao, Rachel S. Kelly, Su H. Chu, Yamini V. Virkud, Mengna Huang, Kathleen C. Barnes, Esteban G. Burchard, Celeste Eng, Donglei Hu, Juan C. Celedón, Michelle Daya, Albert M. Levin, Hongsheng Gui, L. Keoki Williams, Erick Forno, Angel C.Y. Mak, Lydiana Avila, Manuel E. Soto-Quiros, Michelle M. Cloutier, Edna Acosta-Pérez, Glorisa Canino, Klaus Bønnelykke, Hans Bisgaard, Benjamin A. Raby, Christoph Lange, Scott T. Weiss, Jessica A. Lasky-Su, Namiko Abe, Goncalo Abecasis, Christine Albert, Nicholette (Nichole) Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Terri Beaty, Diane Becker, Lewis Becker, Rebecca Beer, Ferdouse Begum, Amber Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Ingrid Borecki, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Mark Chaffin, Christy Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Patrick Ellinor, Leslie Emery, Charles Farber, Leanna Farnam, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi (Priscilla) Geng, Soren Germer, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, C. Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael Hall, Daniel Harris, Nicola Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, John Hokanson, Kramer Holly, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A. Jhun, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Sekar Kathiresan, Laura Kaufman, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Greg Kinney, Barbara Konkle, Charles Kooperberg, Stephanie Krauter, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, JoAnn Manson, Lauren Margolin, Lisa Martin, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Hao Mei, Deborah A. Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton Mitchell, May E. Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Pradeep Natarajan, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Sam Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dmitry Prokopenko, Bruce Psaty, Pankaj Qasba, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Vasan Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Ken Rice, Stephen Rich, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne Stilp, Elizabeth Streeten, Yun Ju Sung, Jessica Su-Lasky, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Karol Watson, Daniel E. Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, Carla Wilson, James Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael Zody, and Sebastian Zoellner
Subjects: Adult, Costa Rica, Male, Pulmonary and Respiratory Medicine, Adolescent, Vital Capacity, Single-nucleotide polymorphism, Pedigree chart, Critical Care and Intensive Care Medicine, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Polymorphism (computer science), Forced Expiratory Volume, Humans, Medicine, SNP, 030212 general & internal medicine, Child, Asthma, Whole Genome Sequencing, business.industry, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, Minor allele frequency, 030228 respiratory system, Genetic epidemiology, Child, Preschool, Interferon Regulatory Factors, Immunology, Respiratory Physiological Phenomena, Female, Cardiology and Cardiovascular Medicine, business, Cell Adhesion Molecules
Abstract: BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
Published: 2019

11. Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations

Author: Yii-Der Ida Chen, Lindsay M. Reynolds, Robert C. Kaplan, Chaojie Yang, Michael C. Seeds, Martha L. Daviglus, Lyn M. Steffen, Brian Hallmark, Floyd H. Chilton, Michael Y. Tsai, Stephen S. Rich, Alexis C. Wood, Laurel Johnstone, Jin Choul Chai, Chandra Tontsch, Ingo Ruczinski, Timothy D. O’Connor, Lawrence J. Mandarino, Sarah A. Blomquist, Rasika A. Mathias, Rozenn N. Lemaitre, Qibin Qi, Dawn K. Coletta, Amanda M. Fretts, and Ani Manichaikul
Subjects: Fatty Acid Desaturases, 0301 basic medicine, Heredity, QH301-705.5, Genetic genealogy, Medicine (miscellaneous), Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Fatty Acids, Omega-3, Genetic variation, Genotype, medicine, Humans, SNP, Hispanic population, Longitudinal Studies, Biology (General), Genetic association study, Genetics, chemistry.chemical_classification, Genetic Variation, Hispanic or Latino, medicine.disease, United States, 030104 developmental biology, Risk factors, chemistry, Multigene Family, Indians, North American, Heritable quantitative trait, lipids (amino acids, peptides, and proteins), General Agricultural and Biological Sciences, Dyslipidemia, Polyunsaturated fatty acid
Abstract: Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk., Yang et al. examine whether genetic ancestry is associated with genetic variation in fatty acid desaturases and plasma phospholipid levels of long chain polyunsaturated fatty acids (LC-PUFAs) in Hispanic Americans. They find strong associations between Amerind genetic ancestry and LC-PUFA levels; and report that the well-known FADS rs174537 variant was associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides.
Published: 2021

12. A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Author: Rui Xia, Jordana T. Bell, Roby Joehanes, Abbas Dehghan, Sharon L.R. Kardia, Erin B. Ware, Deugi Zhi, Devin Absher, Annette Peters, Martina Müller-Nurasyid, Daniel Levy, Nona Sotoodehnia, Wei Chen, Coleen M. Damcott, Lifang Hou, Donna K. Arnett, Weihua Guan, Jincheng Shen, Steve Horvath, Rory P. Wilson, Kim Valeska Emilie Braun, Lars Lind, Wei Zhao, Myriam Fornage, Shengxu Li, Mina A. Jhun, Paula Singmann, Elena Carnero-Montoro, Michael M. Mendelson, Jennifer A. Smith, Xiaoping Zhao, Marguerite R. Irvin, Bruce M. Psaty, Andrea A. Baccarelli, Jeffrey R. O'Connell, Mohammad Arfan Ikram, Traci M. Bartz, Erik Ingelsson, Klodian Dhana, Melanie Waldenberger, Stefan Gustafsson, Yii-Der Ida Chen, Thomas Meitinger, Themistocles L. Assimes, Elias Salfati, Tao Zhang, Pfeiffer Liliane, Dianjianyi Sun, Rahul Gondalia, Eric Boerwinkle, Philip S. Tsao, Christian Gieger, Eric A. Whitsel, Chen Yao, Tim D. Spector, Alan R. Shuldiner, Åsa K. Hedman, Joyce B. J. van Meurs, May E. Montasser, Anh N. Do, Mohsen Ghanbari, André G. Uitterlinden, Megan L. Grove, Jennifer A. Brody, Epidemiology, and Internal Medicine
Subjects: Adult, Epigenomics, Male, 0301 basic medicine, Science, Concordance, Quantitative Trait Loci, Ethnic group, General Physics and Astronomy, Blood lipids, 030204 cardiovascular system & hematology, Biology, Article, White People, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, Epigenome, 03 medical and health sciences, 0302 clinical medicine, Genetics, Leukocytes, Humans, Dyslipidaemias, Aged, Medicinsk genetik, Genetic association, Multidisciplinary, Carnitine O-Palmitoyltransferase, Hispanic or Latino, General Chemistry, DNA Methylation, Middle Aged, Lipids, Black or African American, 030104 developmental biology, Meta-analysis, DNA methylation, Epigenetics, CpG Islands, Female, Lipoproteins, HDL, Medical Genetics
Abstract: Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups., Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.
Published: 2021

13. A Genome-Wide Association Study Identifies Blood Disorder–Related Variants Influencing Hemoglobin A1c With Implications for Glycemic Status in U.S. Hispanics/Latinos

Author: Robert C. Kaplan, Katherine L. Tucker, Caren E. Smith, Jose M. Ordovas, Ruth J. F. Loos, Tao Wang, Yii-Der Ida Chen, Tin Louie, Jerome I. Rotter, Jee-Young Moon, Lauren E. Petty, Chao-Qiang Lai, Claudia Schurmann, M. Larissa Avilés-Santa, Tamar Sofer, Kent D. Taylor, Martha L. Daviglus, Neil Schneiderman, Craig L. Hanis, Jennifer E. Below, Jianwen Cai, Gregory A. Talavera, Deepti Jain, Erwin P. Bottinger, and Qibin Qi
Subjects: Advanced and Specialized Nursing, Research design, endocrine system diseases, business.industry, Endocrinology, Diabetes and Metabolism, nutritional and metabolic diseases, 030209 endocrinology & metabolism, Genome-wide association study, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Blood Disorder, Diabetes mellitus, Community health, Internal Medicine, Medicine, 030212 general & internal medicine, Hemoglobin, Allele, business, Glycemic, Demography
Abstract: OBJECTIVE We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/Latinos with diverse genetic ancestries. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies. RESULTS Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10−8). In particular, two African ancestry–specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (β = −0.31% [−3.4 mmol/mol]) and −0.35% [−3.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03–0.04% [0.3–0.4 mmol/mol] per allele). A novel Amerindian ancestry–specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28). CONCLUSIONS This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.
Published: 2019

14. Genome‐Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium

Author: Lynne E. Wagenknecht, Tasha E. Fingerlin, Carl D. Langefeld, Richard M. Watanabe, Mark O. Goodarzi, Jill M. Norris, Kendra A. Young, Xiuqing Guo, Leslie J. Raffel, Jerome I. Rotter, Kent D. Taylor, Anny H. Xiang, Adrienne H. Williams, Yii-Der Ida Chen, Nicholette D. Palmer, and Nan Wang
Subjects: Adult, Male, alanine aminotransferase, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, digestive system, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, aspartate aminotransferase, Non-alcoholic Fatty Liver Disease, Mexican Americans, Genetic model, Nonalcoholic fatty liver disease, medicine, Humans, SNP, Aspartate Aminotransferases, 030212 general & internal medicine, Genetics, Nutrition and Dietetics, Mexican-American ancestry, Fatty liver, Membrane Proteins, Alanine Transaminase, Lipase, gamma-Glutamyltransferase, Middle Aged, medicine.disease, digestive system diseases, Liver, Genetic Loci, Linear Models, Female, gamma-glutamyl transferase, genetic variance, Liver function, Genome-Wide Association Study
Abstract: Author(s): Young, Kendra A; Palmer, Nicholette D; Fingerlin, Tasha E; Langefeld, Carl D; Norris, Jill M; Wang, Nan; Xiang, Anny H; Guo, Xiuqing; Williams, Adrienne H; Chen, Yii-Der I; Taylor, Kent D; Rotter, Jerome I; Raffel, Leslie J; Goodarzi, Mark O; Watanabe, Richard M; Wagenknecht, Lynne E | Abstract: ObjectivePopulations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry.MethodsLevels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis.ResultsIn the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2 = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT.ConclusionsPNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry.
Published: 2019

15. Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction

Author: Sekar Kathiresan, Yii-Der Ida Chen, Jennifer A. Mattera, Kent D. Taylor, Harlan M. Krumholz, Stephen S. Rich, Seyedeh M. Zekavat, Rachel P. Dreyer, Mark Chaffin, Gail D'Onofrio, Michael E. Talkowski, John A. Spertus, Jerome I. Rotter, Pradeep Natarajan, Stacey Gabriel, Amit Khera, Namrata Gupta, Ryan L. Collins, Carolina Roselli, Bruce M. Psaty, Wendy S. Post, Judith H. Lichtman, Eric S. Lander, and Broad Institute of MIT and Harvard
Subjects: Male, Multifactorial Inheritance, Myocardial Infarction, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Bioinformatics, Article, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), medicine, Humans, Genetic Predisposition to Disease, In patient, Myocardial infarction, Aged, 030304 developmental biology, Early onset, Whole genome sequencing, 0303 health sciences, Whole Genome Sequencing, Genome, Human, business.industry, Cholesterol, LDL, Middle Aged, medicine.disease, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Background: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual. Methods: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations. Results: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00597922. ©2019, National Institutes of Health (no. TR001100), American Heart Association (no. 17SDG33680041), National Human Genome Research Institute (no. 5UM1HG008895)
Published: 2019

16. Differential gene expression during placentation in pregnancies conceived with different fertility treatments compared with spontaneous pregnancies

Author: Charles R. Farber, Tianyanxin Sun, Seth Guller, Stephen S. Rich, Yii-Der Ida Chen, Alexander F. Koeppel, Tania L Gonzalez, Margareta D. Pisarska, Tejal Ghadiali, Stephen D. Turner, John W Williams, N. Joshi, Erica T. Wang, Mark O. Goodarzi, Tania Basu Serna, Bora Lee, Yayu Lin, Bryna Harwood, Jerome I. Rotter, and Lindsay Kroener
Subjects: Adult, Male, 0301 basic medicine, Infertility, medicine.medical_specialty, Reproductive Techniques, Assisted, Offspring, media_common.quotation_subject, Chorionic villus sampling, Fertility, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Humans, Medicine, reproductive and urinary physiology, media_common, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, business.industry, Obstetrics, Gene Expression Profiling, Gene Expression Regulation, Developmental, Obstetrics and Gynecology, Gestational age, Placentation, Middle Aged, medicine.disease, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Reproductive Medicine, embryonic structures, Chorionic villi, Female, Transcriptome, business, Live Birth
Abstract: Objective To identify differences in the transcriptomic profiles during placentation from pregnancies conceived spontaneously vs. those with infertility using non-in vitro fertilization (IVF) fertility treatment (NIFT) or IVF. Design Cohort study. Setting Academic medical center. Patient(s) Women undergoing chorionic villus sampling at gestational age 11–13 weeks (n = 141), with pregnancies that were conceived spontaneously (n = 74), with NIFT (n = 33), or with IVF (n = 34), resulting in the delivery of viable offspring. Intervention(s) Collection of chorionic villus samples from women who conceived spontaneously, with NIFT, or with IVF for gene expression analysis using RNA sequencing. Main Outcome Measure(s) Baseline maternal, paternal, and fetal demographics, maternal medical conditions, pregnancy complications, and outcomes. Differential gene expression of first-trimester placenta. Result(s) There were few differences in the transcriptome of first-trimester placenta from NIFT, IVF, and spontaneous pregnancies. There was one protein-coding differentially expressed gene (DEG) between the spontaneous and infertility groups, CACNA1I, one protein-coding DEG between the spontaneous and IVF groups, CACNA1I, and five protein-coding DEGs between the NIFT and IVF groups, SLC18A2, CCL21, FXYD2, PAEP, and DNER. Conclusion(s) This is the first and largest study looking at transcriptomic profiles of first-trimester placenta demonstrating similar transcriptomic profiles in pregnancies conceived using NIFT or IVF and spontaneous conceptions. Gene expression differences found to be highest in the NIFT group suggest that the underlying infertility, in addition to treatment-related factors, may contribute to the observed gene expression profiles.
Published: 2019

17. Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Mice and Humans

Author: Nicole Ehrhardt, Helen S. Goodridge, Mark O. Goodarzi, Miklós Péterfy, Thomas A. Buchanan, Xiuqing Guo, Willa A. Hsueh, Yii-Der Ida Chen, Leslie J. Raffel, Louise Lantier, Jason K. Kim, Suchaorn Saengnipanthkul, Jinrui Cui, Jerome I. Rotter, and Sezin Dagdeviren
Subjects: 2. Zero hunger, medicine.medical_specialty, Nutrition and Dietetics, business.industry, Endocrinology, Diabetes and Metabolism, Insulin, medicine.medical_treatment, Medicine (miscellaneous), Insulin sensitivity, 030209 endocrinology & metabolism, Type 2 diabetes, Mexican americans, Carbohydrate metabolism, medicine.disease, Obesity, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Diabetes mellitus, Internal medicine, medicine, 030212 general & internal medicine, business
Abstract: Author(s): Ehrhardt, Nicole; Cui, Jinrui; Dagdeviren, Sezin; Saengnipanthkul, Suchaorn; Goodridge, Helen S; Kim, Jason K; Lantier, Louise; Guo, Xiuqing; Chen, Yii-Der I; Raffel, Leslie J; Buchanan, Thomas A; Hsueh, Willa A; Rotter, Jerome I; Goodarzi, Mark O; Peterfy, Miklos | Abstract: ObjectiveAging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-associated insulin resistance is due to increased adiposity or other age-related factors. To address this question, the impact of aging on insulin sensitivity was investigated independently of changes in body composition.MethodsCohorts of mice aged 4 to 8nmonths ("young") and 18 to 27nmonths ("aged") exhibiting similar body composition were characterized for glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analyses. The relationship between aging and insulin resistance in humans was investigated in 1,250 nondiabetic Mexican Americans who underwent hyperinsulinemic-euglycemic clamps.ResultsIn mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. While aging did not diminish glucose tolerance, hyperinsulinemic-euglycemic clamps demonstrated impaired insulin sensitivity and reduced insulin clearance in aged mice on chow and high-fat diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican American males.ConclusionsThis study demonstrates that in addition to altered body composition, adiposity-independent mechanisms also contribute to aging-associated insulin resistance in mice and humans.
Published: 2019

18. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author: Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center
Subjects: Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract: © The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant
Published: 2019

19. The African Descent and Glaucoma Evaluation Study (ADAGES) III

Author: Lama A. Al-Aswad, Xiuqing Guo, Yii-Der Ida Chen, Linda M. Zangwill, Swapan K Das, Paul A Sidoti, Sung Chul Park, Mark Christopher, Garvin H. Davis, Barry I. Freedman, Maggie C.Y. Ng, Robert N. Weinreb, Luke J. Saunders, Eunice Williams-Steppe, Nicholas P. Bell, Jeffrey M. Liebmann, Harvey Dubiner, Keri Dirkes, Nicholette D. Palmer, Rigby Slight, Daniel A. Auerbach, Kevin Sandow, Robert Ritch, Jasmin Divers, Lauren S. Blieden, Suzanne Vega, Brian C Samuels, Donald W. Bowden, Jeremy Cotliar, Matthew Holmann, Joseph F. Panarelli, Jerome I. Rotter, Kathryn Roll, Radha Ayyagari, African Descent, Robert M. Feldman, John P Mitchell, George A. Cioffi, Christopher A. Girkin, Dana M. Blumberg, Carl D. Langefeld, Naama Hammel, Celso Tello, Felipe A. Medeiros, Kent D. Taylor, and Rajendra Bansal
Subjects: 0301 basic medicine, medicine.medical_specialty, Intraocular pressure, genetic structures, Cross-sectional study, medicine.medical_treatment, Population, Glaucoma, 03 medical and health sciences, 0302 clinical medicine, Ophthalmology, medicine, Glaucoma surgery, education, education.field_of_study, Glaucoma medication, business.industry, Diabetic retinopathy, medicine.disease, eye diseases, 030104 developmental biology, Specimen collection, 030221 ophthalmology & optometry, sense organs, business
Abstract: PURPOSE:To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III. DESIGN:Cross-sectional, case-control study. PARTICIPANTS:Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States. METHODS:Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review. MAIN OUTCOME MEASURES:Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded. RESULTS:The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients. CONCLUSIONS:With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.
Published: 2019

20. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Author: Carly J. van der Heide, Jessica N. Cooke Bailey, Susan Williams, Dan Milea, José Paulo Cabral de Vasconcellos, Sadiq M. Abdullahi, Douglas E. Gaasterland, Ifeoma N. Asimadu, Sayoko E. Moroi, Hasnaa Lamari, Sarah J. Garnai, Janey L. Wiggs, Donald L. Budenz, R. Rand Allingham, Julia E. Richards, Jonathan L. Haines, Jerome I. Rotter, Michael G. Anderson, Xiuqing Guo, Robert M. Feldman, Michael A. Hauser, Yii-Der Ida Chen, Hugo Freire Nunes, Leon W. Herndon, John F. Ervin, Stephen Akafo, Radha Ayyagari, Thomas J. Hoffmann, Rachel W. Kuchtey, Michèle Ramsay, Prisca Biangoup Nyamsi, Zheng Li, Eric Jorgenson, Kar Seng Sim, Ebenezer Obeng-Nyarkoh, William C. Bromley, Christopher A. Girkin, Robert N. Weinreb, Alberta A H J Thiadens, Serge Resnikoff, William E. Sponsel, Maggie C.Y. Ng, Christine M. Hulette, Donald W. Bowden, Saydou Bakayoko, Jeffrey M. Liebmann, Harvey Dubiner, Suhanya Okeke, Abba Hydara, Ruth J. F. Loos, Adeyinka O. Ashaye, Olusegun Olaniyi, Mahmoud B. Alhassan, Khaled K. Abu-Amero, Christopher J Hammond, Tin Aung, John H. Fingert, Robert P. Igo, Shih-Hsiu Wang, Rui Barroso Schimiti, Pratap Challa, Robert F. Mullins, Rodolfo A. Perez-Grossmann, Nouhoum Guirou, Margaret A. Pericak-Vance, Anthony Okeke, Pieter W.M. Bonnemaijer, Paulo Vinicius Svidnicki, Abdoulaye Napo, Louise R. Pasquale, Joyce Kabwe, Chiea Chuen Khor, Mônica Barbosa de Melo, Girish N. Nadkarni, CM Chuka-Okosa, Neil Risch, Nkiru Kizor-Akaraiwe, Miles J. Flamme-Wiese, Cornelia M. van Duijn, N J Uche, Joseph Msosa, Olusola Olawoye, Linda M. Zangwill, Mariana B. Oliveira, Caroline C W Klaver, Allison E. Ashley Koch, Vital Paulino Costa, Ngoy Janvier Kilangalanga, Trevor R. Carmichael, Xue Qin, Kent D. Taylor, Yutao Liu, Dianne A. Cruz, Epidemiology, and Ophthalmology
Subjects: Male, medicine.medical_specialty, Genotype, genetic structures, Open angle glaucoma, Population, Black People, Glaucoma, Genome-wide association study, Polymorphism, Single Nucleotide, 01 natural sciences, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Risk Factors, Interquartile range, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, 0101 mathematics, education, Adaptor Proteins, Signal Transducing, Aged, Original Investigation, education.field_of_study, Amyloid beta-Peptides, business.industry, 010102 general mathematics, Case-control study, General Medicine, Odds ratio, Middle Aged, medicine.disease, Immunohistochemistry, eye diseases, Case-Control Studies, Female, Risk assessment, business, Glaucoma, Open-Angle, Genome-Wide Association Study
Abstract: Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.
Published: 2019

21. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

Author: Mark I. McCarthy, Weihua Meng, Brian L. Yaspan, M Imamura, Mark W. Christiansen, Niina Sandholm, Yii-Der Ida Chen, Sharon G. Adler, Lucia Sobrin, Craig L. Hanis, Valeriya Lyssenko, Shiro Maeda, Yang Hai, Paul Mitchell, Roberta McKean-Cowdin, Xiuqing Guo, John R. Sedor, David S. Siscovick, Sudha K. Iyengar, Heather Hancock, Jane Z. Kuo, Barbara E.K. Klein, David-Alexandre Tregouet, Elisabet Agardh, Kent D. Taylor, Andrew D. Morris, S. Mohsen Hosseini, Andrew D. Paterson, I-Te Lee, Wayne Huey-Herng Sheu, Emma Ahlqvist, Kathryn P. Burdon, Leif Groop, Ayellet V. Segrè, Samy Hadjadj, Samaneh Davoudi, Lynn K. Stanwyck, Emily Y. Chew, Xiaohui Li, Michael A. Grassi, Jie Jin Wang, Samuela Pollack, Albert V. Smith, Kyu Hyung Park, Michiaki Kubo, Mary Frances Cotch, Yucheng Jia, Ching J. Chen, Colin N. A. Palmer, Helen M. Colhoun, Alan D. Penman, R. Varma, Per-Henrik Groop, Tien Yin Wong, Barry I. Freedman, Eli Ipp, Alex S. F. Doney, Gavin Tan, Ronald Klein, Kaanan P. Shah, Jamie E Craig, Donald W. Bowden, Jerome I. Rotter, Robert P. Igo, Darryl Nousome, Ching-Yu Cheng, Michel Marre, Maggie C.Y. Ng, Latchezar Dimitrov, Jeeyun Ahn, Atsushi Takahashi, Richard A. Jensen, Aaron Leong, Jihye Kim, Iiro Toppila, Elizabeth J. Rossin, Alkes L. Price, Diabetes and Obesity Research Program, University of Helsinki, Department of Medicine, Nefrologian yksikkö, Research Programs Unit, Clinicum, HUS Abdominal Center, and Per Henrik Groop / Principal Investigator
Subjects: Blood Glucose, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Endocrinology, Diabetes and Metabolism, LOCI, 030209 endocrinology & metabolism, Genome-wide association study, VARIANTS, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, RESOURCE, Internal medicine, Diabetes mellitus, REVEALS, Genetic variation, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, CHINESE PATIENTS, Allele, METAANALYSIS, POLYMORPHISMS, Glycemic, Glycated Hemoglobin, Diabetic Retinopathy, business.industry, Diabetic retinopathy, medicine.disease, PREVALENCE, 3. Good health, SEVERITY, 030104 developmental biology, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, Multiple comparisons problem, RISK-FACTORS, Medical genetics, Erratum, business, Genome-Wide Association Study, Protein Binding
Abstract: To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value
Published: 2018

22. The trans-ancestral genomic architecture of glycemic traits

Author: Albertine J. Oldehinkel, Wieland Kiess, Xueling Sim, Norihiro Kato, Philippe Froguel, Astrid van Hylckama Vlieg, Josée Dupuis, Nanette R. Lee, Symen Ligthart, Harry Campbell, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Massimo Mangino, Tian Xie, Niek Verweij, James B. Meigs, Chaolong Wang, Michael Y. Tsai, Erik Ingelsson, Colin N. A. Palmer, Erik B. van den Akker, Fumihiko Matsuda, Rainer Rauramaa, Yi-Cheng Chang, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Sven Bergmann, Ya X. Wang, Ching-Ti Liu, Annette Schürmann, Michael Boehnke, David J. Porteous, Kazuya Setoh, Qibin Qi, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Claire J. Steves, Jun Liu, Leslie A. Lange, Noël P. Burtt, Diana Kuh, Cassandra N. Spracklen, Ken K. Ong, Charumathi Sabanayagam, Jost B. Jonas, Ele Ferrannini, Lawrence J. Beilin, Qing Duan, Blair H. Smith, Isobel D. Stewart, Alexander P. Reiner, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Mark I. McCarthy, Anna L. Gloyn, D.I. Boomsma, Dennis Raven, Nicholas J. Timpson, Rona J. Strawbridge, George Dedoussis, Susan Redline, Jaeyoung Hong, Harald Grallert, Jagadish Vangipurapu, Rico Rueedi, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Johannes Waage, Jin Fang Chai, Yii-Der Ida Chen, Graciela E. Delgado, Thibaud S. Boutin, Yang Hai, Yoriko Heianza, Wei Zhao, Andres Metspalu, Tien Yin Wong, Mila Desi Anasanti, Inger Njølstad, Hans Bisgaard, Valeriya Lyssenko, Denis Rybin, Wanqing Wen, Torben Hansen, James F. Wilson, Sameline Grimsgaard, Annette Peters, Michele K. Evans, Damia Noce, Sarah C. Nelson, May E. Montasser, Nan Wang, Geltrude Mingrone, Gudny Eiriksdottir, Nicholas J. Wareham, Fouad Kandeel, Linda S. Adair, Kelvin Lam, Jaana Lindström, Eco J. C. de Geus, Debbie A Lawlor, Sara M. Willems, Xu Lin, Harold Snieder, Matt J. Neville, Naveed Sattar, Chelsea K. Raulerson, Paul M. Ridker, Jer-Yuarn Wu, Weihua Zhang, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Elena Tremoli, Toru Nabika, Jing Hua Zhao, Vilmundur Gudnason, Tao Huang, Robert C. Kaplan, Sohee Han, Mohammad Hadi Zafarmand, Aaron Leong, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Ivana Kolcic, Franco Giulianini, Tao Wang, Lu Qi, Stephan J. L. Bakker, Laura J Corbin, Zoltán Kutalik, Bruna Gigante, Willa A. Hsueh, Peter J. van der Most, Tin Louie, Yujie Wang, Stella Trompet, Fernando Rivideneira, Yasumasa Ohyagi, Lynne E. Wagenknecht, Jerry L. Nadler, Michael Stumvoll, Mark O. Goodarzi, Sahoko Ichihara, Jeffrey R. O'Connell, Tomohiro Katsuya, Giorgio Pistis, Alice Stanton, Sirkka Keinänen-Kiukaanniemi, Momoko Horikoshi, Honglan Li, Tanja G. M. Vrijkotte, Caroline Hayward, Karen L. Mohlke, Carola Marzi, Girish N. Nadkarni, Laura J. Rasmussen-Torvik, Alain G. Bertoni, Andrew R. Wood, Annique Claringbould, Mi Yeong Hwang, Hugh Watkins, Heikki A. Koistinen, Mattias Frånberg, Jani Heikkinen, Elizabeth Selvin, Donald W. Bowden, Abbas Dehghan, Christian Fuchsberger, Audrey Y. Chu, Kent D. Taylor, Katherine A. Kentistou, Johanna Kuusisto, Jingyi Tan, Huaixing Li, Eric Boerwinkle, Catharina A. Hartman, Archie Campbell, Kari E. North, Oluf Pedersen, Sölve Elmståhl, Emil V. R. Appel, Chang-Hsun Hsieh, Dennis O. Mook-Kanamori, Rob M. van Dam, Pontiano Kaleebu, Corri Black, Jennifer A. Brody, Bengt Sennblad, Shaofeng Huo, M. Larissa Avilés-Santa, Ruth J. F. Loos, Patricia B. Munroe, Chien-Hsiun Chen, Liang Sun, Zorayr Arzumanyan, Rebecca Rohde, Yasuharu Tabara, Albert V. Smith, Betina H. Thuesen, Niels Grarup, Jorgen Engmann, Tatijana Zemunik, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Ching-Yu Cheng, Serena Sanna, Damiano Baldassarre, Tarunveer S. Ahluwalia, Mark J. Caulfield, Anne Ndungu, Carl D. Langefeld, Lisa R. Yanek, Luigi Ferrucci, Ananda R. Wickremasinghe, Raymond Noordam, Trevor A. Mori, Tom Wilsgaard, Mika Kivimäki, Rita R. Kalyani, Alan B. Zonderman, Veronique Vitart, Patricia A. Peyser, Shuiqing Lai, Richa Saxena, Li-Ching Chang, Karin Leander, Wei Huang, Peter Vollenweider, Tanya M. Teslovich, Ying Wu, Shufa Du, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Stephen C. J. Parker, Tamar Sofer, Winfried März, Sharon L.R. Kardia, Peter K. Joshi, Neil R. Robertson, Anny H. Xiang, Fumihiko Takeuchi, N. Amin, Jouke-Jan Hottenga, Carol A. Wang, Stefan Gustafsson, Jung Ho Gong, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Gonneke Willemsen, Michael A. Province, Aliki-Eleni Farmaki, Segun Fatumo, Antje Körner, Pim van der Harst, Marie Loh, Kei Hang Katie Chan, Gonçalo R. Abecasis, Nicholette D. Palmer, Simin Liu, Ishminder K. Kooner, Javier Gayán, Arne Astrup, Laura J. Scott, Erwin P. Bottinger, Andrew Wong, Inga Prokopenko, Ping An, Markku Laakso, Matthias Blüher, Susan R. Heckbert, Thomas A. Buchanan, Tatsuaki Matsubara, Andrew P. Morris, Brian H. Chen, Kristi Läll, Teresa Tusie, Timo A. Lakka, Jie Yao, Michael Preuss, Teemu Kuulasmaa, Carlos Lorenzo, Stephen S. Rich, Marie Lauzon, Laura M. Raffield, Pankow S. James, Takahisa Kawaguchi, Kathleen A. Ryan, Wei Zheng, Igor Rudan, Thomas Sparsø, Hugoline G. de Haan, Sandosh Padmanabhan, Richard M. Watanabe, Alicia Huerta-Chagoya, Anette P. Gjesing, Andrew A. Hicks, Richard N. Bergman, Mitsuhiro Yokota, Heather M. Stringham, Bruce M. Psaty, Jian'an Luan, Anuj Goel, Eleanor Wheeler, Masahiro Nakatochi, Young-Jin Kim, Xiao-Ou Shu, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Mari Nelis, Adolfo Correa, Jaspal S. Kooner, Michiya Igase, Anubha Mahajan, Peter E. H. Schwarz, Craig E. Pennell, Claudia Schurmann, Xiaoran Chai, Ji Chen, Lori L. Bonnycastle, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Ilja M. Nolte, Gaëlle Marenne, Timothy M. Frayling, Bong-Jo Kim, Kerrin S. Small, Cecilia M. Lindgren, Bernhard O. Böhm, Shih-Yi Lin, Katharina E. Schraut, Cornelia M. van Duijn, Sanghoon Moon, Mark Walker, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Ko Willems van Dijk, Ozren Polasek, W. Craig Johnson, Dermot F. Reilly, Inês Barroso, Anke Tönjes, Manjinder S. Sandhu, Wen B. Wei, Jose C. Florez, Lorraine Southam, Leif Groop, Lawrence F. Bielak, Peter Kovacs, Jianjun Liu, Jouko Saramies, Helen R. Warren, Man Li, Daniel I. Chasman, Eleftheria Zeggini, Xiaoshuai Zhang, Loic Yengo, Shi Jinxiu, Jirong Long, Xiuqing Guo, Meena Kumari, Leslie J. Raffel, Jill M. Norris, Henrik Vestergaard, Jing He, Peter P. Pramstaller, Diana van Heemst, Kevin Sandow, Marjo-Ritta Jarvelin, Carlos A. Aguilar-Salinas, Peitao Wu, Hortensia Moreno-Macías, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Bernardo L. Horta, Heming Wang, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Rozenn N. Lemaitre, Paul R. H. J. Timmers, Timo Saaristo, Jaakko Tuomilehto, Reedik Mägi, Debashree Ray, J. Wouter Jukema, Claudia Langenberg, Marcus E. Kleber, Francis S. Collins, Klaus Bønnelykke, Lenore J. Launer, Arushi Varshney, Anders Hamsten, European Commission, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanger Institute, Wellcome Trust, Marenne, Gaëlle [0000-0002-4363-7170], Varshney, Arushi [0000-0001-9177-9707], Corbin, Laura J [0000-0002-4032-9500], Parker, Stephen CJ [0000-0001-8122-0117], Langenberg, Claudia [0000-0002-5017-7344], Wheeler, Eleanor [0000-0002-8616-6444], Morris, Andrew P [0000-0002-6805-6014], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Lifelines Cohort Study, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), de Haan, H.G., van den Akker, E., van der Most, P.J., de Geus, EJC, van Dam, R.M., van Heemst, D., van Hylckama Vlieg, A., van Willems van Dijk, K., de Silva, H.J., van der Harst, P., van Duijn, C., Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Helsinki University Hospital Area, University of Helsinki, Clinicum, Department of Public Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Physiology, AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, APH - Mental Health, Nutrition and Health, APH - Methodology, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Public and occupational health, Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Cardiovascular Centre (CVC)
Subjects: Blood Glucose, Disease risk, Multifactorial Inheritance, Glycated Hemoglobin A, [SDV]Life Sciences [q-bio], Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), LOCI, Genome-wide association study, Type 2 diabetes, VARIANTS, GLUCOSE, Epigenesis, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Mechanisms, WIDE ASSOCIATION, genetics, Gene-expression, HEMOGLOBIN, ComputingMilieux_MISCELLANEOUS, 11 Medical and Health Sciences, GENE-EXPRESSION, Genetics, Genetics & Heredity, 0303 health sciences, INSULIN-RESISTANCE, Genome, Loci, 1184 Genetics, developmental biology, physiology, Variants, ALSPAC, Physical Chromosome Mapping, Life Sciences & Biomedicine, Human, Quantitative Trait Loci, Wide association study, Biology, Quantitative trait locus, Article, White People, diseases, MECHANISMS, Quantitative Trait, 03 medical and health sciences, Insulin resistance, Quantitative Trait, Heritable, SDG 3 - Good Health and Well-being, Genetic, Lifelines Cohort Study, Diabetes mellitus, medicine, Humans, Hemoglobin, Heritable, METAANALYSIS, Alleles, 030304 developmental biology, Genetic association, Glycemic, Glycated Hemoglobin, Science & Technology, Genome, Human, Whites, Gene Expression Profiling, DISEASE RISK, Settore MED/13 - ENDOCRINOLOGIA, Insulin-resistance, 06 Biological Sciences, medicine.disease, Glucose, chemistry, Blood Glucose/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Glycated Hemoglobin A/metabolism, Multifactorial Inheritance/genetics, Quantitative Trait Loci/genetics, Glycated hemoglobin, 030217 neurology & neurosurgery, Meta analysis, Epigenesis, Developmental Biology
Abstract: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.
Published: 2021

23. Early Pregnancy Atherogenic Profile in a First Pregnancy and Hypertension Risk 2 to 7 Years After Delivery

Author: Janet M. Catov, Victoria L. Pemberton, Derek J Marsh, Lisa D. Levine, Judith H. Chung, David M. Haas, Rebecca B. McNeil, Yii-Der Ida Chen, Michelle A. Kominiarek, Brian M. Mercer, Robert M. Silver, Hyagriv N. Simhan, Philip Greenland, LuAnn Polito, C. Noel Bairey Merz, Deborah B. Ehrenthal, Ronald J. Wapner, Samuel Parry, Corette B. Parker, Rolf P. Kreutz, William A. Grobman, Uma M. Reddy, and George R. Saade
Subjects: Adult, Male, medicine.medical_specialty, Time Factors, hypertension, preeclampsia/pregnancy, pregnancy and postpartum, medicine.medical_treatment, Pregnancy Complications, Cardiovascular, Blood Pressure, 030204 cardiovascular system & hematology, Gastroenterology, lipids, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Risk Factors, Cardiovascular Disease, Internal medicine, Humans, Medicine, Women, Retrospective Studies, Original Research, Go Red for Women Spotlight, 030219 obstetrics & reproductive medicine, business.industry, Incidence, Insulin, Infant, Newborn, Pregnancy Outcome, Atherosclerosis, medicine.disease, Obesity, United States, Gestational diabetes, Diabetes, Gestational, Blood pressure, Relative risk, Cohort, Small for gestational age, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, Follow-Up Studies, high blood pressure
Abstract: Background Cardiovascular risk in young adulthood is an important determinant of lifetime cardiovascular disease risk. Women with adverse pregnancy outcomes (APOs) have increased cardiovascular risk, but the relationship of other factors is unknown. Methods and Results Among 4471 primiparous women, we related first‐trimester atherogenic markers to risk of APO (hypertensive disorders of pregnancy, preterm birth, small for gestational age), gestational diabetes mellitus (GDM) and hypertension (130/80 mm Hg or antihypertensive use) 2 to 7 years after delivery. Women with an APO/GDM (n=1102) had more atherogenic characteristics (obesity [34.2 versus 19.5%], higher blood pressure [systolic blood pressure 112.2 versus 108.4, diastolic blood pressure 69.2 versus 66.6 mm Hg], glucose [5.0 versus 4.8 mmol/L], insulin [77.6 versus 60.1 pmol/L], triglycerides [1.4 versus 1.3 mmol/L], and high‐sensitivity C‐reactive protein [5.6 versus 4.0 nmol/L], and lower high‐density lipoprotein cholesterol [1.8 versus 1.9 mmol/L]; P P Conclusions Individual and combined first‐trimester atherogenic characteristics are associated with APO/GDM occurrence and hypertension 2 to 7 years later. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02231398.
Published: 2021

24. Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study

Author: Leon Lenchik, Donald W. Bowden, S. Carrie Smith, Anthony J. Hanley, Jill M. Norris, Corinne D. Engelman, Nicholette D. Palmer, Pamela J. Hicks, Lingyi Lu, Jasmin Divers, Jacob M. Keaton, Yii-Der Ida Chen, Thomas C. Register, Lynne E. Wagenknecht, Carl D. Langefeld, Meijian Guan, Barry I. Freedman, Jianzhao Xu, Maggie C.Y. Ng, Latchezar Dimitrov, and J. Jeffrey Carr
Subjects: Male, 0301 basic medicine, Bone density, Vitamin D-binding protein, Organic chemistry, Genome-wide association study, Type 2 diabetes, Biochemistry, Vascular Medicine, Geographical Locations, Endocrinology, Medical Conditions, 0302 clinical medicine, Bone Density, Medicine and Health Sciences, Ethnicities, Vitamin D, African American people, Musculoskeletal System, Bone mineral, Multidisciplinary, Vitamin D-Binding Protein, Vitamins, Genomics, Middle Aged, Population groupings, Type 2 Diabetes, Physical sciences, Europe, Chemistry, Connective Tissue, Medicine, Female, Anatomy, Research Article, medicine.medical_specialty, Endocrine Disorders, Bone and Mineral Metabolism, Science, 030209 endocrinology & metabolism, Biology, Chemical compounds, 03 medical and health sciences, Insulin resistance, Internal medicine, Diabetes mellitus, Organic compounds, Genome-Wide Association Studies, Genetics, Diabetes Mellitus, medicine, Vitamin D and neurology, Humans, Bone, Skeleton, Aged, Polymorphism, Genetic, Biology and Life Sciences, Computational Biology, Human Genetics, Genome Analysis, Atherosclerosis, medicine.disease, Black or African American, Biological Tissue, Metabolism, 030104 developmental biology, Diabetes Mellitus, Type 2, Metabolic Disorders, People and places, Genome-Wide Association Study
Abstract: Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (β = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (β = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; β = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; β = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; β = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.
Published: 2021

25. Rare coding variants in 35 genes associate with circulating lipid levels – a multi-ancestry analysis of 170,000 exomes

Author: Marju Orho-Melander, Humberto García-Ortiz, Xueling Sim, Amp-T D-Genes, Cheol Joo Park, Gina M. Peloso, Jason Flannick, Brian Tomlinson, Hyun Min Kang, Emilio J. Cordova, Stephen S. Rich, Richard A. Gibbs, Angélica Martínez-Hernández, Lorena Orozco, Harsha Doddapaneni, Lisa R. Yanek, Jiwon Lee, Namrata Gupta, Valeriya Lyssenko, Sohee Han, James B. Meigs, Bong-Jo Kim, Bruce M. Psaty, Leslie S. Emery, Kerrin S. Small, Pradeep Natarajan, May E. Montasser, Christian Gieger, Sharon L.R. Kardia, Sarah C. Nelson, Craig L. Hanis, Heikki A. Koistinen, María Elena González-Villalpando, Edmund Chan, Michael Y. Tsai, Benjamin Glaser, Thomas Meitinger, Matthew J. Bown, Mariaelisa Graff, John Danesh, Sekar Kathiresan, Tiinamaija Tuomi, Ramachandran S. Vasan, Gil Atzmon, Alyna T. Khan, Diego Ardissino, Yii-Der Ida Chen, David Zhang, Rob M. van Dam, Wendy S. Post, Barry I. Freedman, D. C. Rao, Michael Preuss, Donna M. Lehman, L. Adrienne Cupples, Colin N. A. Palmer, Claudia H. T. Tam, Hortensia Moreno-Macías, Markku Laakso, Peter Dornbos, Teresa Tusié-Luna, Stella Aslibekyan, Marguerite R. Irvin, Daniel J. Rader, Jee-Young Moon, Eimear E. Kenny, Lisa W. Martin, Jennifer A. Brody, Amit Khera, Erwin P. Bottinger, Sarah E. Graham, Myriam Fornage, Ruth McPherson, Nancy L. Heard-Costa, Michael Boehnke, Clicerio Gonzalez, Ryan W. Kim, Yi-Cheng Chang, Peter M. Nilsson, Yik Ying Teo, Robert Sladek, Cristen J. Willer, Fei Fei Wang, Donna K. Arnett, Mark Chaffin, Karine A. Viaud Martinez, Alanna C. Morrison, Leslie A. Lange, Ravindranath Duggirala, Donna M. Muzny, Kent D. Taylor, Niels Grarup, Soren Germer, Patricia A. Peyser, Brian E. Cade, Lewis C. Becker, Steven A. Lubitz, Nicholette D. Palmer, Susan K. Dutcher, Ronald C.W. Ma, Xuenan Mi, Xiuqing Guo, Hugh Watkins, Eric Boerwinkle, Qibin Qi, Johanna Kuusisto, Christie M. Ballantyne, Tanika N. Kelly, Rajiv Chowdhury, Elvia Mendoza-Caamal, Wing-Yee So, Tien Yin Wong, Torben Hansen, Cecilia Contreras-Cubas, Jeong-Sun Seo, Mi Yeong Hwang, Daekwan Seo, Dajiang J. Liu, Cristina Revilla-Monsalve, Paul S. de Vries, Daniel R. Witte, Yi-Jen Hung, Olle Melander, Karen L. Mohlke, Lucinda Antonacci-Fulton, Francisco Barajas-Olmos, Soo Heon Kwak, Daniel E. Weeks, Claudia Schurmann, Ginger A. Metcalf, Young-Jin Kim, Adrienne M. Stilp, Lori L. Bonnycastle, John Blangero, Ralph A. DeFronzo, Donald W. Bowden, Rasika A. Mathias, Oluf Pedersen, Rozenn N. Lemaitre, Stephen T. McGarvey, Heribert Schunkert, Jaakko Tuomilehto, Farook Thameem, Valentin Fuster, Joshua C. Bis, George Hindy, Allan Linneberg, James G. Wilson, Kyong Soo Park, Sergio A. Islas-Andrade, Ching-Yu Cheng, Won Jung Choi, Minxian X. Wang, Xuzhi Wang, Adolfo Correa, Jai G. Broome, Gail P. Jarvik, Alexander P. Reiner, E. Shyong Tai, Juyoung Lee, Mark I. McCarthy, Nilesh J. Samani, Susan Redline, Carlos A. Aguilar-Salinas, Jerome I. Rotter, Ma. Eugenia Garay-Sevilla, Jiang He, Patrick T. Ellinor, Joseph Park, Joanne E. Curran, Nir Barzilai, Federico Centeno-Cruz, Seonwook Lee, Lawrence F. Bielak, Jianjun Liu, Charles Kooperberg, Juan M. Peralta, Jose C. Florez, Leif Groop, Noël P. Burtt, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, and Ruth J. F. Loos
Subjects: Genetics, 0303 health sciences, education.field_of_study, Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, DNA sequencing, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, SNP, education, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
Published: 2020

26. Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Author: Daniel I. Chasman, Torben Hansen, Rebecca S. Fine, Kari E. North, Harald Grallert, Jeffrey Haesser, Jie Yao, Arund D. Pradhan, Peter Kovacs, Mariaelisa Graff, Rebecca D. Jackson, Zoltán Kutalik, James G. Wilson, Neil Robertson, Mika Kähönen, Linda S. Adair, Jennifer Kriebel, Ruth J. F. Loos, Massimo Mangino, Jayne F. Martin Carli, Yiying Zhang, M. Arfan Ikram, Paraskevi Christofidou, Linda Broer, Paul M. Ridker, Barbara McKnight, Satu Männistö, Sophia Metz, Tea Skaaby, Jette Bork-Jensen, Craig E. Pennell, Sophie Molnos, Michael A. Province, Xiuqing Guo, Laura B. L. Wittemans, Stephen J. Lye, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Tim Kacprowski, America A. Sandoval-Zárate, Hermina Jakupović, Tuomas O. Kilpeläinen, Michael Preuss, Jaeyoung Hong, Cristina Venturini, Ying Wu, Germán D. Carrasquilla, Ivana Prokic, Mary F. Feitosa, Melissa E. Garcia, Paul L. Auer, Leslie A. Lange, Leo-Pekka Lyytikäinen, Kristin L. Young, Tugce Karaderi, Alexander P. Reiner, Tim D. Spector, Anubha Mahajan, Claudia Schurmann, Jerome I. Rotter, Rudolph L. Leibel, Georg Homuth, Claudia A. Doege, Hakon Hakonarson, Nicholas J. Wareham, Najaf Amin, Shuai Wang, Matthias Blüher, Ayse Demirkan, Andrew P. Morris, Charles A. LeDuc, Claudia Langenberg, Hanieh Yaghootkar, Mike A. Nalls, Erik Ingelsson, Dennis O. Mook-Kanamori, Jorge R. Kizer, Carolina Medina-Gomez, Timothy M. Frayling, Colleen M. Sitlani, David A. Mackey, Bruce M. Psaty, Matthias Nauck, Struan F.A. Grant, Konstantin Strauch, Olli T. Raitakari, Alexander Teumer, Mark Walker, Jonathan P. Bradfield, Judith B. Borja, Karen L. Mohlke, Lars Lind, André G. Uitterlinden, Renée de Mutsert, Ruifang Li-Gao, Cassandra N. Spracklen, Jin Li, Anne E. Justice, Cecilia M. Lindgren, Kaiying Guo, Terho Lehtimäki, Pekka Jousilahti, Yingchang Lu, Yii-Der Ida Chen, Sara M. Willems, Tamara B. Harris, Matthew A. Allison, Carol A. Wang, Niels Grarup, Lam Opal Huang, Veikko Salomaa, Jian'an Luan, Robert A. Scott, Kent D. Taylor, James B. Meigs, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, Department of Organisation and Personnel Management, Health Services Management & Organisation (HSMO), Yaghootkar, Hanieh [0000-0001-9672-9477], Kilpeläinen, Tuomas O [0000-0002-8349-3028], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Leptin, Models, Molecular, medicine.medical_specialty, Genotype, Protein Conformation, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, KLF14, Biology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Missense mutation, Humans, Allele, Exome, Adiposity, 2. Zero hunger, Racial Groups, digestive, oral, and skin physiology, Gene Expression Regulation, Developmental, Genetic Variation, Genetics/Genomes/Proteomics/Metabolomics, medicine.disease, Obesity, 030104 developmental biology, Endocrinology, hormones, hormone substitutes, and hormone antagonists
Abstract: Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10-16, n=3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.
Published: 2020

27. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author: Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris
Subjects: 0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.
Published: 2020

28. Genetic variants modulate gene expression statin response in human lymphoblastoid cell lines

Author: Yii-Der Ida Chen, Jerome I. Rotter, Elizabeth Theusch, Marisa W. Medina, and Ronald M. Krauss
Subjects: 0106 biological sciences, Simvastatin, Gene Expression, Disease, Bioinformatics, Cardiovascular, 01 natural sciences, Medical and Health Sciences, Gene expression, 2.1 Biological and endogenous factors, Aetiology, Expression quantitative trait locus, 0303 health sciences, Chitinases, Biological Sciences, Heart Disease, Cholesterol, lipids (amino acids, peptides, and proteins), DNA microarray, medicine.drug, Biotechnology, Research Article, Statin, lcsh:QH426-470, medicine.drug_class, lcsh:Biotechnology, RNA-sequencing, Biology, Cell Line, 03 medical and health sciences, Clinical Research, lcsh:TP248.13-248.65, Information and Computing Sciences, medicine, Genetics, Humans, Expression quantitative trait locus (eQTL), Lymphoblastoid cell line, Gene, Serpins, 030304 developmental biology, Phosphotransferases (Phosphate Group Acceptor), Human Genome, Atherosclerosis, Gene-environment interaction, lcsh:Genetics, Good Health and Well Being, Expression quantitative trait loci, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, 010606 plant biology & botany
Abstract: Background Statins are widely prescribed to lower plasma low-density lipoprotein cholesterol levels. Though statins reduce cardiovascular disease risk overall, statin efficacy varies, and some people experience adverse side effects while on statin treatment. Statins also have pleiotropic effects not directly related to their cholesterol-lowering properties, but the mechanisms are not well understood. To identify potential genetic modulators of clinical statin response, we looked for genetic variants associated with statin-induced changes in gene expression (differential eQTLs or deQTLs) in lymphoblastoid cell lines (LCLs) derived from participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial. We exposed CAP LCLs to 2 μM simvastatin or control buffer for 24 h and performed polyA-selected, strand-specific RNA-seq. Statin-induced changes in gene expression from 259 European ancestry or 153 African American ancestry LCLs were adjusted for potential confounders prior to association with genotyped and imputed genetic variants within 1 Mb of each gene’s transcription start site. Results From the deQTL meta-analysis of the two ancestral populations, we identified significant cis-deQTLs for 15 genes (TBC1D4, MDGA1, CHI3L2, OAS1, GATM, ASNSD1, GLUL, TDRD12, PPIP5K2, OAS3, SERPINB1, ANKDD1A, DTD1, CYFIP2, and GSDME), eight of which were significant in at least one of the ancestry subsets alone. We also conducted eQTL analyses of the endogenous (control-treated), statin-treated, and average of endogenous and statin-treated LCL gene expression levels. We identified eQTLs for approximately 6000 genes in each of the three (endogenous, statin-treated, and average) eQTL meta-analyses, with smaller numbers identified in the ancestral subsets alone. Conclusions Several of the genes in which we identified deQTLs have functions in human health and disease, such as defense from viruses, glucose regulation, and response to chemotherapy drugs. This suggests that DNA variation may play a role in statin effects on various health outcomes. These findings could prove useful to future studies aiming to assess benefit versus risk of statin treatment using individual genetic profiles.
Published: 2020

29. Physical Activity Associations with Bone Mineral Density and Modification by Metabolic Traits

Author: Jerome I. Rotter, Willa A. Hsueh, Jinrui Cui, Mark O. Goodarzi, Xiuqing Guo, Yii-Der Ida Chen, and Anshu Buttan
Subjects: medicine.medical_specialty, Bone density, Endocrinology, Diabetes and Metabolism, Physical activity, PAI-1, 030209 endocrinology & metabolism, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Internal medicine, medicine, insulin sensitivity, 030212 general & internal medicine, Obesity, Clinical Research Articles, Metabolic and endocrine, Bone mineral, Univariate analysis, Adiponectin, adiponectin, exercise, business.industry, Insulin sensitivity, bone density, Endocrinology, Cohort, Osteoporosis, business, CRP, Body mass index, AcademicSubjects/MED00250
Abstract: Objective To assess the relationship of physical activity with bone mineral density (BMD) at various sites and examine potential modifying metabolic factors. Methods Responses from physical activity questionnaires were used to determine total physical activity (PA), moderate physical activity (mod-PA), and sedentary time. Regression analyses were performed to evaluate association of activity traits with insulin sensitivity by euglycemic clamp, adiponectin, C-reactive protein (CRP), and plasminogen activator inhibitor-1 (PAI-1) in 741 healthy subjects. Results The cohort was relatively sedentary. Activity level was associated with arm, pelvis, and leg BMD in univariate analyses. In multivariate association analyses of arm BMD, only female sex (β = -0.73, P < 0.0001) and adiponectin (β = -0.076, P = 0.0091) were significant. Multivariate analyses of pelvis BMD found independent associations with body mass index (BMI) (β = 0.33, P < 0.0001), adiponectin (β = -0.10, P = 0.013), female sex (β = -0.18, P < 0.0001), sedentary time (β = -0.088, P = 0.034), PA (β = 0.11, P = 0.01), and mod-PA (β = 0.11, P = 0.014). Age (β = -0.10, P = 0.0087), female sex (β = -0.63, P < 0.0001), BMI (β = 0.24, P < 0.0001), and mod-PA (β = 0.10, P = 0.0024) were independently associated with leg BMD. Conclusions These results suggest that BMD increases with physical activity in the arms, legs, and pelvis and is inversely related to sedentary time in the pelvis and legs; these associations may be modified by age, sex, BMI, and adiponectin, depending on the site, with physical activity being more important to pelvis and leg BMD than arm BMD and sedentary time being important for pelvis BMD. Moreover, we demonstrated that CRP, PAI-1, and insulin sensitivity play a minor role in BMD.
Published: 2020

30. Multi-Ethnic Genome-Wide Association Study of Decomposed Cardioelectric Phenotypes Illustrates Strategies to Identify and Characterize Evidence of Shared Genetic Effects for Complex Traits

Author: Colleen M. Sitlani, Eimear E. Kenny, Yii-Der Ida Chen, Chani J. Hodonsky, Jerome I. Rotter, Rahul Gondalia, Xiuqing Guo, Lucia A. Hindorff, Alex P. Reiner, Heather M. Highland, Charles Kooperberg, Elsayed Z. Soliman, Nona Sotoodehnia, Susan R. Heckbert, Ulrike Peters, Wendy Post, Ralph V. Shohet, Ran Tao, Kari E. North, Amanda A. Seyerle, Dan E. Arking, Genevieve L. Wojcik, Kent D. Taylor, Eric A. Whitsel, Antoine R Baldassari, Jie Yao, Robert C. Kaplan, Henry J. Lin, Mariaelisa Graff, Steven Buyske, Christy L. Avery, and Dawood Darbar
Subjects: 0301 basic medicine, CD36 Antigens, population, Genome-wide association study, 030204 cardiovascular system & hematology, Electrocardiography, 0302 clinical medicine, Gene Frequency, Chinese americans, education.field_of_study, Membrane Glycoproteins, General Medicine, Single Nucleotide, Hispanic or Latino, Phenotype, Cardiovascular Diseases, Trait, epidemiology, Genotype, Population, Locus (genetics), Biology, Polymorphism, Single Nucleotide, QT interval, Article, White People, 03 medical and health sciences, Clinical Research, Genetics, Humans, 1000 Genomes Project, PR interval, Polymorphism, education, Genetic association, Homeodomain Proteins, genome-wide association study, Human Genome, Univariate, electrophysiology, cardiovascular diseases, Minor allele frequency, Black or African American, 030104 developmental biology, Sample size determination, Evolutionary biology, Genetic Loci, Genome-Wide Association Study, Molecular Chaperones, Transcription Factors
Abstract: Background: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci. Methods: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test. Results: We identified 6 novels ( CD36, PITX2, EMB, ZNF592, YPEL2 , and BC043580 ) and 87 known loci (adaptive sum of powered score test P −9 ). Lead single-nucleotide polymorphism rs3211938 at CD36 was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci. Conclusions: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.
Published: 2020

31. The Trans-Ancestral Genomic Architecture of Glycaemic Traits

Author: Hugoline G. de Haan, Andrew A. Hicks, Achilleas Pitsilides, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Anders Hamsten, Dennis O. Mook-Kanamori, Zorayr Arzumanyan, Betina H. Thuesen, Karin Leander, Fernando Rivideneira, Lynne E. Wagenknecht, Andrew R. Wood, Annique Claringbould, Ele Ferranni, Sölve Elmståhl, Eleanor Wheeler, Sharon L.R. Kardia, Richa Saxena, Tatijana Zemunik, Cassandra N. Spracklen, Ken K. Ong, Xiao-Ou Shu, Johannes Waage, Blair H. Smith, Rozenn N. Lemaitre, Torben Hansen, Peter K. Joshi, Lisa R. Yanek, Neil R. Robertson, Sven Bergmann, Mila Desi Anasanti, Inger Njølstad, Ananda R. Wickremasinghe, Xu Lin, Harold Snieder, Wanqing Wen, Veronique Vitart, Paul R. H. J. Timmers, Timo Saaristo, James F. Wilson, Tian Xie, Tao Huang, Rainer Rauramaa, Kei Hang, Rebecca Rohde, Li-Ching Chang, Jing Hua Zhao, Kazuya Setoh, Yasuharu Tabara, Michael Stumvoll, Mark O. Goodarzi, Igor Rudan, James B. Meigs, Jaakko Tuomilehto, Richard M. Watanabe, Ruth J. F. Loos, Reedik Mägi, Jouke-Jan Hottenga, Ozren Polasek, Michael Y. Tsai, Donald W. Bowden, Diana Kuh, Erik B. van den Akker, Yii-Der Ida Chen, Daniel I. Chasman, Weihua Zhang, Nicholette D. Palmer, Marcus E. Kleber, Anny H. Xiang, Chang-Hsun Hsieh, Alan B. Zonderman, Stefan Gustafsson, Timo A. Lakka, Brian H. Chen, Dermot F. Reilly, Francis S. Collins, Oluf Pedersen, Corri Black, Yang Hai, Zoltán Kutalik, Yoriko Heianza, Willa A. Hsueh, Vilmundur Gudnason, Robert C. Kaplan, Jun Liu, Michael A. Province, Aliki-Eleni Farmaki, Stephen S. Rich, Jian'an Luan, Erik Ingelsson, Marie Loh, Michael Preuss, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Colin N. A. Palmer, Fumihiko Matsuda, Takahisa Kawaguchi, Sohee Han, Ching-Ti Liu, Young-Jin Kim, L. Southam, Sara M. Willems, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Stephan J. L. Bakker, Momoko Horikoshi, Tarunveer S. Ahluwalia, Annette Schürmann, Graciela E. Delgado, Thibaud S. Boutin, Thomas Sparsø, Sandosh Padmanabhan, Fouad Kandeel, Eco J. C. de Geus, Anubha Mahajan, Claudia Schurmann, Klaus Bønnelykke, Leslie A. Lange, Qing Duan, Rona J. Strawbridge, Dennis Raven, Gonçalo R. Abecasis, Mitsuhiro Yokota, Jani Heikkinen, Elizabeth Selvin, Audrey Y. Chu, Anke Tönjes, Marta E. Alarcón-Riquelme, Hans Bisgaard, P. Eline Slagboom, Eric Boerwinkle, Massimo Mangino, Catharina A. Hartman, Geltrude Mingrone, Lenore J. Launer, Michael Boehnke, Emil V. R. Appel, Niels Grarup, Arushi Varshney, Archie Campbell, Kari E. North, W. Craig Johnson, Inês Barroso, Ya X. Wang, Carola Marzi, Anuj Goel, Eleftheria Zeggini, Lu Qi, Yasumasa Ohyagi, Tien Yin Wong, Tanja G. M. Vrijkotte, Gudny Eiriksdottir, Harald Grallert, Ishminder K. Kooner, Trevor A. Mori, Jagadish Vangipurapu, Laura J Corbin, Tomohiro Katsuya, Wen B. Wei, Segun Fatumo, Debashree Ray, Annette Peters, Lori L. Bonnycastle, Ilja M. Nolte, M. Arfan Ikram, Manjinder S. Sandhu, Marit E. Jørgensen, Christian Herder, Damia Noce, Sarah C. Nelson, Chien-Hsiun Chen, Heather M. Stringham, Yong-Bing Xiang, Bruce M. Psaty, Alain G. Bertoni, Gaëlle Marenne, Timothy M. Frayling, Jose C. Florez, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Damiano Baldassarre, J. Wouter Jukema, Wei Huang, Yi-Cheng Chang, Albertine J. Oldehinkel, Xiaoshuai Zhang, Yujie Wang, Shaofeng Huo, Xueling Sim, Norihiro Kato, Bernhard O. Böhm, Lorraine Southam, Mari Nelis, Gonneke Willemsen, Laura J. Rasmussen-Torvik, Philippe Froguel, Charumathi Sabanayagam, Leif Groop, Loic Yengo, Shi Jinxiu, Adolfo Correa, Serena Sanna, Arne Astrup, Teemu Kuulasmaa, Symen Ligthart, Shih-Yi Lin, David J. Porteous, Harry Campbell, Peter Vollenweider, Mark J. Caulfield, Kristi Läll, Anne Ndungu, Carl D. Langefeld, Tanya M. Teslovich, Heikki A. Koistinen, Ying Wu, Mattias Frånberg, D.I. Boomsma, Lawrence F. Bielak, Diana van Heemst, Peter Kovacs, Markku Laakso, Leslie J. Raffel, Katharina E. Schraut, Noël P. Burtt, Michiya Igase, Craig E. Pennell, Claudia Langenberg, Huaixing Li, Teresa Tusie, Laura M. Raffield, Jorgen Engmann, Stephen C. J. Parker, Michele K. Evans, Chaolong Wang, Rico Rueedi, Jianjun Liu, Pankow S. James, Hortensia Moreno-Macías, Fumihiko Takeuchi, Cornelia M. van Duijn, Sanghoon Moon, Susan R. Heckbert, Thomas A. Buchanan, Ko Willems van Dijk, Toru Nabika, May E. Montasser, Caroline Hayward, Jie Yao, Aaron Leong, Antje Körner, Jouko Saramies, Jost B. Jonas, Pim van der Harst, Naveed Sattar, Helen R. Warren, Alice Stanton, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Mi Yeong Hwang, Jin Fang Chai, Alicia Huerta-Chagoya, Anette P. Gjesing, Ching-Yu Cheng, Debbie A Lawlor, Simin Liu, Man Li, Ivana Kolcic, Erwin P. Bottinger, Andrew Wong, Stella Trompet, Heming Wang, Jirong Long, Xiuqing Guo, Jeffrey R. O'Connell, Meena Kumari, Sirkka Keinänen-Kiukaanniemi, Rita R. Kalyani, Bengt Sennblad, Mohammad Hadi Zafarmand, Kent D. Taylor, Katherine A. Kentistou, Carol A. Wang, Shuiqing Lai, Patricia B. Munroe, Patricia A. Peyser, Lawrence J. Beilin, Niek Verweij, Inga Prokopenko, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Ping An, Matthias Blüher, Isobel D. Stewart, Alexander P. Reiner, Anna L. Gloyn, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, Wei Zhao, Andres Metspalu, Wieland Kiess, Kathleen A. Ryan, Astrid van Hylckama Vlieg, Jaana Lindström, Wei Zheng, E. Shyong Tai, Josée Dupuis, Nanette R. Lee, Laura J. Scott, Nicholas J. Timpson, George Dedoussis, Mark I. McCarthy, Tatsuaki Matsubara, Carlos Lorenzo, Denis Rybin, Luigi Ferruci, Chelsea K. Raulerson, Mika Kivimäki, Paul M. Ridker, Jer-Yuarn Wu, Shufa Du, Jaeyoung Hong, Linda S. Adair, Tin Louie, Valeriya Lyssenko, Susan Redline, Kelvin Lam, Qibin Qi, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Peter J. van der Most, Sahoko Ichihara, Nicholas J. Wareham, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Rob M. van Dam, Claire J. Steves, Liang Sun, Albert V. Smith, Raymond Noordam, Tom Wilsgaard, Winfried März, Jung Ho Gong, Matt J. Neville, Jerry L. Nadler, Giorgio Pistis, Karen L. Mohlke, Bruna Gigante, Jennifer A. Brody, Andrew P. Morris, Marie Lauzon, Peter E. H. Schwarz, Bernardo L. Horta, Xiaoran Chai, Ji Chen, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Javier Gayán, Elena Tremoli, Girish N. Nadkarni, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Jingyi Tan, Sameline Grimsgaard, Bong-Jo Kim, Kerrin S. Small, Jill M. Norris, Cecilia M. Lindgren, Richard N. Bergman, Mark Walker, Henrik Vestergaard, Larissa Aviles-Santa, Jing He, Masahiro Nakatochi, Peter P. Pramstaller, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Kevin Sandow, Jaspal S. Kooner, Carlos A. Aguilar-Salinas, Peitao Wu, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Nan Wang, Franco Giulianini, Tao Wang, Honglan Li, Abbas Dehghan, Christian Fuchsberger, and Pontiano Kaleebu
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Type 2 diabetes, medicine.disease, Fasting insulin, Fasting glucose, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Diabetes mellitus, medicine, Genomic architecture, business, Glycated haemoglobin, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.
Published: 2020

32. Genome-wide association study identifying novel variant for fasting insulin and allelic heterogeneity in known glycemic loci in Chilean adolescents: The Santiago Longitudinal Study

Author: Mariaelisa Graff, Xiuqing Guo, Bárbara Angel, Kari E. North, Kent D. Taylor, Yii-Der Ida Chen, Cecilia Albala, Venkata Saroja Voruganti, Jie Yao, Victoria L. Buchanan, Heather M. Highland, Estela Blanco, Jingyi Tan, Raquel Burrows, Sheila Gahagan, Anne E. Justice, José Luis Santos, Yujie Wang, Betsy Lozoff, and Carolina Downie
Subjects: 0301 basic medicine, Blood Glucose, medicine.medical_specialty, Longitudinal study, Adolescent, 030209 endocrinology & metabolism, Genome-wide association study, Polymorphism, Single Nucleotide, Fasting insulin, Article, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, medicine, Humans, Insulin, Longitudinal Studies, Chile, Human services, Glycemic, 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, Health Policy, Tumor Suppressor Proteins, Public Health, Environmental and Occupational Health, Membrane Proteins, Fasting, Human development (humanity), Health equity, Minority health, Family medicine, Pediatrics, Perinatology and Child Health, business, Genome-Wide Association Study
Abstract: BACKGROUND: The genetic underpinnings of glycemic traits have been understudied in adolescent and Hispanic/Latino (H/L) populations in comparison to adults and populations of European ancestry. OBJECTIVE: To identify genetic factors underlying glycemic traits in an adolescent H/L population. METHODS: We conducted a genome-wide association study (GWAS) of fasting glucose (FG) and fasting insulin (FI) in H/L adolescents from the Santiago Longitudinal Study. RESULTS: We identified one novel variant positioned in the CSMD1 gene on chromosome 8 (rs77465890, effect allele frequency=0.10) that was associated with FI (β=−0.299, SE=0.054, p=2.72×10(−8)) and was only slightly attenuated after adjusting for body mass index z-scores (β=−0.252, SE=0.047, p=1.03×10(−7)). We demonstrated directionally consistent, but not statistically significant results in African and Hispanic adults of the Population Architecture Using Genomics and Epidemiology Consortium. We also identified secondary signals for two FG loci after conditioning on known variants, which demonstrate allelic heterogeneity in well-known glucose loci. CONCLUSION: Our results exemplify the importance of including populations with diverse ancestral origin and adolescent participants in GWAS of glycemic traits to uncover novel risk loci and expand our understanding of disease etiology.
Published: 2020

33. Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure

Author: Lisa W. Martin, Tuomas O. Kilpeläinen, Xiuqing Guo, Kurt Lohman, Ching-Ti Liu, Jerome I. Rotter, Pirjo Komulainen, Lili Milani, Ilja M. Nolte, Yuri Milaneschi, Andres Metspalu, Yii-Der Ida Chen, Tõnu Esko, Jovia L. Nierenberg, Mika Kähönen, Marjan Ilkov, Dennis O. Mook-Kanamori, Karen Schwander, W. James Gauderman, Hanfei Xu, Vilmundur Gudnason, Alisa K. Manning, Gudny Eiriksdottir, David R. Hillman, Elise Lim, Hugues Aschard, John M. Starr, Michael R. Brown, Alanna C. Morrison, Eric Boerwinkle, Stefan Weiss, Maris Alver, Konstantin Strauch, Thomas Meitinger, Tuomo Rankinen, Timo A. Lakka, Harold Snieder, Stephen S. Rich, Yun Ju Sung, Diana van Heemst, Wanqing Wen, Marcus Dörr, Peter J. van der Most, Terho Lehtimäki, Nora Franceschini, Treva Rice, Amy R. Bentley, Dan E. Arking, Susan Redline, Nienke R. Biermasz, Sarah E. Harris, Melanie Waldenberger, Claude Bouchard, M. Arfan Ikram, Walter Palmas, Lynne E. Wagenknecht, Bruce M. Psaty, Daniel Levy, Cornelia M. van Duijn, Joshua C. Bis, Kelly A. Hall, José Eduardo Krieger, Tanika N. Kelly, Kari E. North, Brigitte Kühnel, Phyllis C. Zee, Melissa A. Richard, Lyle J. Palmer, Till Roenneberg, Alexandre C. Pereira, Yongmei Liu, Andrea R. V. R. Horimoto, Jie Yao, Han Chen, Jiang He, Pamela J. Schreiner, Patricia B. Munroe, Wei Zheng, Charles Kooperberg, Paul S. de Vries, Ana Barac, Rainer Rauramaa, Leo-Pekka Lyytikäinen, James M. Shikany, Brian E. Cade, Christian Gieger, Stephen Sidney, Alan B. Zonderman, Tamar Sofer, Chuan Gao, Thomas W. Winkler, Xiao-Ou Shu, Ian J. Deary, Uwe Völker, RJ Waken, Heming Wang, Myriam Fornage, Brenda W.J.H. Penninx, Gregory P. Wilson, Dina Vojinovic, Robert B. Wallace, Kenneth Rice, Ervin R. Fox, Jeffrey R. O'Connell, Annemarie I. Luik, Traci M. Bartz, Xiaofeng Zhu, Najaf Amin, Nicholette D. Palmer, Sami Heikkinen, Kumaraswamynaidu Chitrala, Raymond Noordam, Jiwon Lee, André G. Uitterlinden, Sutapa Mukherjee, Hans J. Grabe, Mario Sims, Sina A. Gharib, Daniel J. Gottlieb, Dabeeru C. Rao, Annette Peters, Reedik Mägi, Solomon K. Musani, Michele K. Evans, Lenore J. Launer, Harvard Medical School [Boston] (HMS), Broad Institute [Cambridge], Harvard University-Massachusetts Institute of Technology (MIT), Hallym University, Department of Educational Psychology and Counseling, National Taiwan Normal University (NTNU), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Leiden University Medical Center (LUMC), Universiteit Leiden, This project was supported by the US National Heart, Lung, and Blood Institute (NHLBI) R01HL118305. HW and SR were supported by NHLBI R35HL135818. BEC was supported by NHLBI K01HL135405. ARB was supported by the Intramural Research Program of the National Institutes of Health in the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (1ZIAHG200362). D.v.H. was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). The CHARGE cohorts were supported in part by NHLBI infrastructure grant HL105756. Study-specific acknowledgments can be found in the Supplementary Notes., European Project: 602757,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,HUMAN(2013), Life Course Epidemiology (LCE), Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Massachusetts Institute of Technology (MIT)-Harvard University [Cambridge], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Tampere University, Department of Clinical Chemistry, Clinical Medicine, and Department of Clinical Physiology and Nuclear Medicine
Subjects: 0301 basic medicine, Mean arterial pressure, Diastole, Blood Pressure, Biology, 3121 Internal medicine, Genome, Polymorphism, Single Nucleotide, Elevated blood, 3124 Neurology and psychiatry, Article, Cellular and Molecular Neuroscience, 03 medical and health sciences, TRPC3, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Humans, Molecular Biology, Gene, 030304 developmental biology, Genetics, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], Short sleep, Sleep in non-human animals, Pulse pressure, Psychiatry and Mental health, 030104 developmental biology, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Hypertension, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Sleep, [STAT.ME]Statistics [stat]/Methodology [stat.ME], 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups using 1 degree of freedom (1df) interaction and 2df joint tests. Primary multi-ancestry analyses in 62,969 individuals in stage 1 identified 3 novel loci that were replicated in an additional 59,296 individuals in stage 2, including rs7955964 (FIGNL2/ANKRD33) showing significant 1df interactions with long sleep duration and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) showing significant 1df interactions with short sleep duration (Pint < 5×10−8). Secondary ancestry-specific two-stage analyses and combined stage 1 and 2 analyses additionally identified 23 novel loci that need external replication, including 3 and 5 loci showing significant 1df interactions with long and short sleep duration, respectively (Pint < 5×10−8). Multiple genes mapped to our 26 novel loci have known functions in sleep-wake regulation, nervous and cardiometabolic systems. We also identified new gene by long sleep interactions near five known BP loci (≤1Mb) including NME7, FAM208A, MKLN1, CEP164, and RGL3/ELAVL3 (Pint < 5×10−8). This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
Published: 2020

34. Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry

Author: Mariaelisa Graff, Zhaoming Wang, David R. Weir, Ann W. Hsing, Joel N. Hirschhorn, Rebecca S. Fine, Wei Zheng, William Maixner, Adebowale Adeyemo, Rick A. Kittles, Rebecca Rohde, Krista A. Zanetti, Elizabeth K. Speliotes, Keri L. Monda, Ingrid B. Borecki, Yaming Shao, Suhn K. Rhie, Sanjay R. Patel, Richard S. Cooper, Jerome I. Rotter, Michael J. Thun, William J. Blot, Brendan J. Keating, Michèle M. Sale, Scott M. Williams, Yingchang Lu, Margaret A. Tucker, Eric A. Klein, Uma Nayak, Curtis A. Pettaway, Yii-Der Ida Chen, Sailaja Vedantam, Pamela J. Schreiner, Phyllis J. Goodman, Babatunde L. Salako, Christine Neslund-Dudas, Andrew B. Singleton, Michael F. Press, Neil E. Caporaso, Maureen Sanderson, Diane M. Becker, Michele K. Evans, Margaret R. Spitz, Christopher I. Amos, Susan Redline, Kurt Lohman, Ching-Ti Liu, Hampton L. Leonard, Kris Monroe, Sun J. Kang, David Van Den Berg, Janet L. Stanford, Lewis H. Kuller, Traci M. Bartz, J. M. Zmuda, Christopher S. Carlson, Ruth J. F. Loos, Joanne M. Jordan, Guillaume Lettre, Youfang Liu, Lara Sucheston, Mike A. Nalls, Shad B. Smith, Suzanne Kolb, Lisa B. Signorello, Daniel Shriner, Tamara B. Harris, Larry D. Atwood, Wei-Min Chen, Oladosu Ojengbede, Kristin A. Rand, Claudia Schurmann, Guanjie Chen, Sharon L.R. Kardia, Graham Casey, Lawrence F. Bielak, Dena G. Hernandez, Talin Haritunians, Rajiv Nadukuru, Elisa V. Bandera, Matthew A. Allison, Amidou N'Diaye, Donna K. Arnett, Olufunmilayo I. Olopade, Ellen W. Demerath, Babette S. Zemel, Margaret Wrensch, Myriam Fornage, John K. Wiencke, George J. Papanicolaou, Sara S. Strom, Temidayo O. Ogundiran, Gregory L. Burke, Erin B. Ware, Marian L. Neuhouser, James G. Wilson, Dhananjay Vaidya, Nicholette D. Palmer, Marguerite R. Irvin, JoAnn E. Manson, Benjamin A. Rybicki, Laurence N. Kolonel, Chad D. Huff, Jennifer J. Hu, Jennifer A. Brody, L. Keoki Williams, Leslie A. Lange, Qing Duan, David S. Siscovick, Yongmei Liu, Leslie Bernstein, Jennifer A. Smith, Latchezar Dimitrov, Sarah J. Nyante, Sue A. Ingles, Yu Han H. Hsu, Xifeng Wu, Heather M. Ochs-Balcom, Jingzhong Ding, David V. Conti, L. Adrienne Cupples, Gerry A. Coetzee, Thomas H. Mosley, Kristin L. Young, Donald W. Bowden, Edmond K. Kabagambe, Christine B. Ambrosone, Karen C. Johnson, Patricia A. Peyser, Stefan Ambs, Victoria L. Stevens, Minhui Chen, Carl D. Langefeld, Sonja I. Berndt, Andrew F. Olshan, Qiuyin Cai, Jessica D. Faul, Mary F. Feitosa, Brian E. Cade, Esther M. John, Ann G. Schwartz, Yan V. Sun, Xinruo Zhang, Stephen J. Chanock, Jason H. Moore, Alexander P. Reiner, Caroline S. Fox, Charles Kooperberg, Anne E. Justice, Jin Li, Lorna H. McNeill, Alex Stram, Jie Yao, Xiuqing Guo, Mara Z. Vitolins, Edward A. Ruiz-Narváez, Abdullah Kutlar, Charleston W. K. Chiang, Jing Hua Zhao, Lisa R. Yanek, Poorva Mudgal, John D. Carpten, Barbara V. Howard, Anselm Hennis, Charles N. Rotimi, Ulrich Broeckel, Albert M. Levin, Jonathan P. Bradfield, Curtis C. Harris, Regina G. Ziegler, Brian E. Henderson, Bruce M. Psaty, Adeyinka G. Falusi, Katherine L. Nathanson, Barbara McKnight, Melinda C. Aldrich, Herman A. Taylor, Melissa Garcia, Degui Zhi, Dezheng Huo, Barry I. Freedman, D. C. Rao, Sylvia Wassertheil-Smoller, Jie Zhou, Adam B. Murphy, Eric E. Schadt, Sandra L. Deming, John S. Witte, Julie R. Palmer, Neil A. Zakai, Adesola Ogunniyi, Yun Li, Mary Cushman, Victoria L. Buchanan, Jorge L. Rodriguez-Gil, Struan F.A. Grant, Timothy D. Howard, Omri Gottesman, Wei Zhao, Kira C. Taylor, Yan Meng, Hayrettin Okut, Hakon Hakonarson, Xiaofeng Zhu, Elizabeth M. Gillanders, Alan B. Zonderman, Lisa Chu, Badri Padhukasahasram, Vaneet Lotay, W. Ryan Diver, Mary K. Wojczynski, Simin Liu, Erwin P. Bottinger, Cameron D. Palmer, Alessandra Chesi, Elise Lim, Laura J. Rasmussen-Torvik, Eirini Marouli, Kari E. North, Salman M. Tajuddin, Christopher A. Haiman, Barbara Nemesure, Loic Le Marchand, Bamidele O. Tayo, and Maggie C.Y. Ng
Subjects: Male, 0303 health sciences, 030305 genetics & heredity, High density, Black People, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Body Height, Article, Minor allele frequency, Black or African American, Europe, 03 medical and health sciences, Evolutionary biology, Africa, Genetics, Humans, Female, Genotyping, Genetics (clinical), Imputation (genetics), 030304 developmental biology, Genome-Wide Association Study
Abstract: Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
Published: 2020

35. A structural variation reference for medical and population genetics

Author: Harold Z. Wang, Yii-Der Ida Chen, Elise Valkanas, Michael E. Talkowski, Kent D. Taylor, Xuefang Zhao, Henry J. Lin, Konrad J. Karczewski, Ryan L. Collins, Eric Banks, Benjamin M. Neale, Lauren Margolin, Christopher W. Whelan, Valentin Ruano-Rubio, Laura D. Gauthier, Stacey Gabriel, Harrison Brand, Namrata Gupta, Jessica Alföldi, Ruchi Munshi, Yongqing Huang, Daniel G. MacArthur, Laurent C. Francioli, Chad Nusbaum, Eric S. Lander, Mark J. Daly, Nicholas A. Watts, Anthony A. Philippakis, Matthew Solomonson, Sekar Kathiresan, Genome Aggregation Database Production Team, Wendy S. Post, Jack Fu, Alexander Baumann, Kristen M. Laricchia, Amit Khera, Ted Brookings, Anne H. O’Donnell-Luria, Jerome I. Rotter, Matthew R. Stone, Chelsea Lowther, Christine Stevens, Caroline N. Cusick, Ted Sharpe, Grace Tiao, Stephen S. Rich, Mark Walker, Tampere University, Clinical Medicine, Department of Clinical Chemistry, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Institute for Molecular Medicine Finland, HUS Psychiatry, Department of Psychiatry, Department of Public Health, Helsinki Institute of Life Science HiLIFE, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Biosciences, HUS Neurocenter, Department of Neurosciences, and Neurologian yksikkö
Subjects: 0301 basic medicine, Male, Genotyping Techniques, IMPACT, Population genetics, VARIANTS, Genome informatics, Genome, 0302 clinical medicine, Disease, Copy-number variation, education.field_of_study, Multidisciplinary, Continental Population Groups, REARRANGEMENTS, 1184 Genetics, developmental biology, physiology, Genome Aggregation Database Production Team, Genomics, Single Nucleotide, Reference Standards, Middle Aged, 3. Good health, GENOME, Female, Biotechnology, Human, General Science & Technology, Population, Computational biology, Biology, Article, Structural variation, 03 medical and health sciences, Genetic, Medical, Genetics, Humans, Genetic Testing, Polymorphism, education, Selection, COPY NUMBER VARIATION, Whole genome sequencing, Whole Genome Sequencing, DELETION, Racial Groups, Human Genome, Genetic Variation, Chromosome abnormality, EVOLUTION, Human genetics, 030104 developmental biology, Genome Aggregation Database Consortium, Mutation, PATTERNS, Generic health relevance, 3111 Biomedicine, 030217 neurology & neurosurgery
Abstract: Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25–29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening., A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.
Published: 2020

36. X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity

Author: Yii-Der Ida Chen, Matthew A. Allison, Jenny C. Link, Jie Yao, Emilio Ronquillo, Matteo Pellegrini, Arthur P. Arnold, Jerome I. Rotter, Karen Reue, Laurent Vergnes, Xuqi Chen, Rozeta Avetisyan, Carrie B. Wiese, Xiuqing Guo, Julia S. El-Sayed Moustafa, Shigeki Iwase, Feiyang Ma, and Kerrin S. Small
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, X Chromosome, Gene Dosage, Adipose tissue, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Adipocyte, Internal medicine, Gene expression, medicine, Adipocytes, Animals, Humans, Gene, X chromosome, Adiposity, Histone Demethylases, Sex Characteristics, biology, Chromosome, General Medicine, Chromatin Assembly and Disassembly, Mice, Mutant Strains, 030104 developmental biology, Endocrinology, Histone, chemistry, 030220 oncology & carcinogenesis, biology.protein, Demethylase, Female, Research Article
Abstract: Males and females differ in body composition and fat distribution. Using a mouse model that segregates gonadal sex (ovaries and testes) from chromosomal sex (XX and XY), we showed that XX chromosome complement in combination with a high-fat diet led to enhanced weight gain in the presence of male or female gonads. We identified the genomic dosage of Kdm5c, an X chromosome gene that escapes X chromosome inactivation, as a determinant of the X chromosome effect on adiposity. Modulating Kdm5c gene dosage in XX female mice to levels that are normally present in males resulted in reduced body weight, fat content, and food intake to a degree similar to that seen with altering the entire X chromosome dosage. In cultured preadipocytes, the levels of KDM5C histone demethylase influenced chromatin accessibility (ATAC-Seq), gene expression (RNA-Seq), and adipocyte differentiation. Both in vitro and in vivo, Kdm5c dosage influenced gene expression involved in extracellular matrix remodeling, which is critical for adipocyte differentiation and adipose tissue expansion. In humans, adipose tissue KDM5C mRNA levels and KDM5C genetic variants were associated with body mass. These studies demonstrate that the sex-dependent dosage of Kdm5c contributes to male/female differences in adipocyte biology and highlight X-escape genes as a critical component of female physiology.
Published: 2020

37. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Author: Yongmei Liu, Tuomas O. Kilpeläinen, Kenneth Rice, Ching-Ti Liu, Jin-Fang Chai, Donna K. Arnett, Dhananjay Vaidya, Nicholette D. Palmer, Lili Milani, Yuri Milaneschi, Leo-Pekka Lyytikäinen, Colleen M. Sitlani, Richard S. Cooper, Gudny Eiriksdottir, Daniel Levy, Jerome I. Rotter, Lihua Wang, Sven Bergmann, Yih Chung Tham, Thomas Meitinger, Lynne E. Wagenknecht, Virginia Fisher, Babatunde L. Salako, Vilmundur Gudnason, Bamidele O. Tayo, Caizheng Yu, Barry I. Freedman, Muhammad Riaz, Kaare Christensen, Ulrich Broeckel, W. James Gauderman, Massimiliano Cocca, Eric Boerwinkle, Meian He, Rob M. van Dam, M. Arfan Ikram, Lisa de las Fuentes, Jiang He, Aldi T. Kraja, Nancy L. Pedersen, Albert V. Smith, Woon-Puay Koh, Bernardo L. Horta, He Gao, Traci M. Bartz, Mike A. Nalls, Federica Laguzzi, Raymond Noordam, Paul M. Ridker, Tien Yin Wong, Patricia B. Munroe, Paul S. de Vries, Adolfo Correa, Maris Alver, Dan E. Arking, Colin A. McKenzie, John M. Starr, Chi Charles Gu, Dongfeng Gu, Stefan Weiss, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Jill M. Norris, Patrik K. E. Magnusson, Tamar Sofer, Ioanna Ntalla, Xiuqing Guo, Paul Elliott, Lawrence F. Bielak, Konstantin Strauch, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Ilja M. Nolte, Steven C. Hunt, Mario Sims, Giorgia Girotto, Chuan Gao, Pamela J. Schreiner, Philippe Froguel, Archie Campbell, Xiao-Ou Shu, Claude Bouchard, Kurt Lohman, David R. Weir, José Eduardo Krieger, Yii-Der Ida Chen, Rainer Rauramaa, Walter Palmas, Cornelia M. van Duijn, James M. Shikany, Michael M. Province, Jennifer A. Smith, Wei Zheng, Xiaofeng Zhu, Jianjun Liu, Ozren Polasek, Alexandre C. Pereira, Diane M. Becker, Kari E. North, Salman M. Tajuddin, Deng Xuan, Leslie J. Raffel, Jie Yao, Astrid Petersmann, Ervin F. Fox, Mark J. Caulfield, Daniel I. Chasman, Jasmin Divers, Claudia P. Cabrera, Rico Rueedi, M. Yldau van der Ende, Carl D. Langefeld, Mika Kähönen, Terrence Forrester, Tangchun Wu, Harold Snieder, Caroline Hayward, Tamara B. Harris, Fang-Chi Hsu, Helen R. Warren, Brenda W.J.H. Penninx, Chiea Chuen Khor, Ruifang Li-Gao, Changwei Li, Sami Heikkinen, Jeffrey R. O'Connell, Christian Gieger, Michele K. Evans, Ching-Yu Cheng, Jingjing Liang, Stephen B. Kritchevsky, Gregory L. Burke, Donald W. Bowden, Alexander Teumer, Marcus Dörr, Alanna C. Morrison, Jian-Min Yuan, Annette Peters, Dennis O. Mook-Kanamori, Pedro Marques-Vidal, Pirjo Komulainen, Lisa R. Yanek, Melanie Waldenberger, Alisa K. Manning, Charles N. Rotimi, Chew-Kiat Heng, Tõnu Esko, Franco Giulianini, Miao Li Chee, Treva Rice, David J. Porteous, Yechiel Friedlander, Bing Yu, Myriam Fornage, Karin Leander, Dina Vojinovic, Sharon L.R. Kardia, Xiaoyin Li, Najaf Amin, Karen Schwander, Thomas T. Perls, Oscar Leonel Rueda-Ochoa, Erin B. Ware, Ya Xing Wang, Sandosh Padmanabhan, H. Janaka de Silva, André G. Uitterlinden, Rajkumar Dorajoo, Bruna Gigante, Jennifer A. Brody, Paolo Gasparini, Maryam Kavousi, Wanqing Wen, Stephen Sidney, Alan B. Zonderman, Michael R. Brown, Tuomo Rankinen, Timo A. Lakka, Yun Ju Sung, Alaitz Poveda, Bruce M. Psaty, Terho Lehtimäki, Tanika N. Kelly, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, John M. C. Connell, Mickaël Canouil, Niek Verweij, Thomas W. Winkler, Ian J. Deary, Marco Brumat, Yize Li, Fumihiko Takeuchi, Wei Zhao, Andres Metspalu, Marguerite R. Irvin, David C. Liewald, Pim van der Harst, Hugues Aschard, Candace M. Kammerer, Melissa A. Richard, Adesola Ogunniyi, Wen Bin Wei, Morris A. Swertz, Fernando Pires Hartwig, Dabeeru C. Rao, Reedik Mägi, Solomon K. Musani, Mathilde Boissel, Jonathan Marten, Nilesh J. Samani, Amy R. Bentley, Sarah E. Harris, Charumathi Sabanayagam, Mary F. Feitosa, Jost B. Jonas, Andrea R. V. R. Horimoto, Paul W. Franks, E. Shyong Tai, Medical Research Council (MRC), de las Fuentes, L., Sung, Y. J., Noordam, R., Winkler, T., Feitosa, M. F., Schwander, K., Bentley, A. R., Brown, M. R., Guo, X., Manning, A., Chasman, D. I., Aschard, H., Bartz, T. M., Bielak, L. F., Campbell, A., Cheng, C. -Y., Dorajoo, R., Hartwig, F. P., Horimoto, A. R. V. R., Li, C., Li-Gao, R., Liu, Y., Marten, J., Musani, S. K., Ntalla, I., Rankinen, T., Richard, M., Sim, X., Smith, A. V., Tajuddin, S. M., Tayo, B. O., Vojinovic, D., Warren, H. R., Xuan, D., Alver, M., Boissel, M., Chai, J. -F., Chen, X., Christensen, K., Divers, J., Evangelou, E., Gao, C., Girotto, G., Harris, S. E., He, M., Hsu, F. -C., Kuhnel, B., Laguzzi, F., Li, X., Lyytikainen, L. -P., Nolte, I. M., Poveda, A., Rauramaa, R., Riaz, M., Rueedi, R., Shu, X. -O., Snieder, H., Sofer, T., Takeuchi, F., Verweij, N., Ware, E. B., Weiss, S., Yanek, L. R., Amin, N., Arking, D. E., Arnett, D. K., Bergmann, S., Boerwinkle, E., Brody, J. A., Broeckel, U., Brumat, M., Burke, G., Cabrera, C. P., Canouil, M., Chee, M. L., Chen, Y. -D. I., Cocca, M., Connell, J., de Silva, H. J., de Vries, P. S., Eiriksdottir, G., Faul, J. D., Fisher, V., Forrester, T., Fox, E. F., Friedlander, Y., Gao, H., Gigante, B., Giulianini, F., Gu, C. C., Gu, D., Harris, T. B., He, J., Heikkinen, S., Heng, C. -K., Hunt, S., Ikram, M. A., Irvin, M. R., Kahonen, M., Kavousi, M., Khor, C. C., Kilpelainen, T. O., Koh, W. -P., Komulainen, P., Kraja, A. T., Krieger, J. E., Langefeld, C. D., Li, Y., Liang, J., Liewald, D. C. M., Liu, C. -T., Liu, J., Lohman, K. K., Magi, R., Mckenzie, C. A., Meitinger, T., Metspalu, A., Milaneschi, Y., Milani, L., Mook-Kanamori, D. O., Nalls, M. A., Nelson, C. P., Norris, J. M., O'Connell, J., Ogunniyi, A., Padmanabhan, S., Palmer, N. D., Pedersen, N. L., Perls, T., Peters, A., Petersmann, A., Peyser, P. A., Polasek, O., Porteous, D. J., Raffel, L. J., Rice, T. K., Rotter, J. I., Rudan, I., Rueda-Ochoa, O. -L., Sabanayagam, C., Salako, B. L., Schreiner, P. J., Shikany, J. M., Sidney, S. S., Sims, M., Sitlani, C. M., Smith, J. A., Starr, J. M., Strauch, K., Swertz, M. A., Teumer, A., Tham, Y. C., Uitterlinden, A. G., Vaidya, D., van der Ende, M. Y., Waldenberger, M., Wang, L., Wang, Y. -X., Wei, W. -B., Weir, D. R., Wen, W., Yao, J., Yu, B., Yu, C., Yuan, J. -M., Zhao, W., Zonderman, A. B., Becker, D. M., Bowden, D. W., Deary, I. J., Dorr, M., Esko, T., Freedman, B. I., Froguel, P., Gasparini, P., Gieger, C., Jonas, J. B., Kammerer, C. M., Kato, N., Lakka, T. A., Leander, K., Lehtimaki, T., Magnusson, P. K. E., Marques-Vidal, P., Penninx, B. W. J. H., Samani, N. J., van der Harst, P., Wagenknecht, L. E., Wu, T., Zheng, W., Zhu, X., Bouchard, C., Cooper, R. S., Correa, A., Evans, M. K., Gudnason, V., Hayward, C., Horta, B. L., Kelly, T. N., Kritchevsky, S. B., Levy, D., Palmas, W. R., Pereira, A. C., Province, M. M., Psaty, B. M., Ridker, P. M., Rotimi, C. N., Tai, E. S., van Dam, R. M., van Duijn, C. M., Wong, T. Y., Rice, K., Gauderman, W. J., Morrison, A. C., North, K. E., Kardia, S. L. R., Caulfield, M. J., Elliott, P., Munroe, P. B., Franks, P. W., Rao, D. C., Fornage, M., Washington University in Saint Louis (WUSTL), Leiden University Medical Center (LUMC), University of Regensburg, Washington University School of Medicine in St. Louis, National Institutes of Health [Bethesda] (NIH), Harbor UCLA Medical Center [Torrance, Ca.], Massachusetts General Hospital [Boston], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Lifelines Cohort Study, Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Cardiovascular Centre (CVC)
Subjects: 0301 basic medicine, CORONARY-HEART-DISEASE, SOCIOECONOMIC-STATUS, RISK-FACTORS, CARDIOVASCULAR-DISEASE, ESSENTIAL-HYPERTENSION, C825T POLYMORPHISM, SOCIAL-CLASS, ASSOCIATION, EXPRESSION, VARIANTS, Blood Pressure, Genome, 0302 clinical medicine, 11 Medical and Health Sciences, Genetics, Psychiatry, [STAT.AP]Statistics [stat]/Applications [stat.AP], 17 Psychology and Cognitive Sciences, Psychiatry and Mental health, Meta-analysis, Hypertension, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, GNB3, Biochemistry & Molecular Biology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Lifelines Cohort Study, SDG 3 - Good Health and Well-being, Humans, Risk factor, Molecular Biology, Gene, Science & Technology, Neurosciences, Epistasis, Genetic, 06 Biological Sciences, Genetic architecture, Educational attainment, 030104 developmental biology, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurosciences & Neurology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Blood Pressure/genetics, Genome-Wide Association Study, Hypertension/genetics, 030217 neurology & neurosurgery
Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Published: 2020

38. Population sequencing data reveal a compendium of mutational processes in human germline

Author: Josyf C. Mychaleckyj, Timothy D. O’Connor, Eric Boerwinkle, Yii-Der Ida Chen, Chii-Min Hwu, John Blangero, D. C. Rao, Patricia A. Peyser, Susan Redline, Shamil R. Sunyaev, Christian Gilissen, Esteban G. Burchard, Jerome I. Rotter, Ryan D. Hernandez, Braxton D. Mitchell, Courtney G. Montgomery, Stephen T. McGarvey, Sharon L.R. Kardia, Jakob M. Goldmann, Kathleen C. Barnes, Lisa de las Fuentes, Lawrence F. Bielak, Jiang He, Patrick T. Ellinor, Jennifer A. Smith, Peter V. Kharchenko, Ani Manichaikul, Wendy S.W. Wong, Adolfo Correa, Vladimir B. Seplyarskiy, Donna K. Arnett, Scott T. Weiss, Ruslan A. Soldatov, Edwin K. Silverman, Nicholette D. Palmer, Ryan J. McGinty, Stephen S. Rich, Leslie S. Emery, Vasan S. Ramachandran, and Jennifer A. Brody
Subjects: Whole genome sequencing, 0303 health sciences, Replication timing, Mutation rate, education.field_of_study, DNA damage, Population, Computational biology, Biology, Genome, Germline, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, education, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage.
Published: 2020

39. Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Author: Marcus Dörr, Vilmundur Gudnason, Brian G. Kral, Xiuqing Guo, Eric Boerwinkle, Stefan Weiss, Stephen S. Rich, Wendy S. Post, Albert V. Smith, Shih-Jen Hwang, Paul S. de Vries, Kent D. Taylor, Daniel I. Chasman, Lisa R. Yanek, Paul M. Ridker, Alanna C. Morrison, Bruce M. Psaty, Traci M. Bartz, Christopher J. O'Donnell, Franco Giulianini, Jie Yao, Nona Sotoodehnia, Mary F. Feitosa, Yi-Ping Fu, Fernando Rivadeneira, Lewis C. Becker, Abbas Dehghan, Joshua C. Bis, Tamara B. Harris, Lenore J. Launer, Rasika A. Mathias, Diane M. Becker, Uwe Völker, Yii-Der Ida Chen, Henry Völzke, Kenneth Rice, Jerome I. Rotter, Marcello Ricardo Paulista Markus, Albert Hofman, Julie Hahn, Oscar H. Franco, André G. Uitterlinden, Megan L. Grove, Jennifer A. Brody, Michael R. Brown, Dubé, Marie-Pierre, Epidemiology, and Internal Medicine
Subjects: 0301 basic medicine, Oncology, Aging, Myocardial Infarction, Social Sciences, Genome-wide association study, Coronary Artery Disease, Disease, Cardiovascular Medicine, 030204 cardiovascular system & hematology, Cardiovascular, Vascular Medicine, Coronary artery disease, Medical Conditions, 0302 clinical medicine, Sociology, Consortia, Epidemiology, Medicine and Health Sciences, Coronary Heart Disease, 2.1 Biological and endogenous factors, Prospective Studies, Myocardial infarction, Aetiology, Prospective cohort study, 0303 health sciences, Multidisciplinary, Genomics, Single Nucleotide, 3. Good health, Europe, Heart Disease, Cardiovascular Diseases, Cohort, Medicine, Research Article, medicine.medical_specialty, General Science & Technology, Science, Cardiology, Locus (genetics), Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Clinical Research, Internal medicine, Genome-Wide Association Studies, Genetics, medicine, Humans, Polymorphism, Alleles, Heart Disease - Coronary Heart Disease, 030304 developmental biology, Genetic association, Whites, business.industry, Human Genome, Biology and Life Sciences, Computational Biology, Human Genetics, Cardiovascular Disease Risk, Genome Analysis, medicine.disease, Minor allele frequency, 030104 developmental biology, Cross-Sectional Studies, Good Health and Well Being, Genetic Loci, business, Genome-Wide Association Study, 2.4 Surveillance and distribution
Abstract: Background Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome. Methods and results Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10−7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event. Conclusion This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
Published: 2020

40. The Genetics of Retinopathy of Prematurity: A Model for Neovascular Retinal Disease

Author: Yii-Der Ida Chen, Ryan Swan, Michael F. Chiang, Sang Jin Kim, R.V. Paul Chan, Kemal Sonmez, Charles F. Simmons, Kent D. Taylor, J. Peter Campbell, Jerome I. Rotter, and Xiaohui Li
Subjects: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Candidate gene, Disease, Low Birth Weight and Health of the Newborn, Eye, Article, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Clinical Research, Preterm, Infant Mortality, Genetics, medicine, 2.1 Biological and endogenous factors, Clinical significance, Aetiology, Eye Disease and Disorders of Vision, Imaging and Informatics in ROP Research Consortium, Genetic association, Pediatric, business.industry, Prevention, Human Genome, Neurosciences, Childhood blindness, Retinopathy of prematurity, Perinatal Period - Conditions Originating in Perinatal Period, medicine.disease, eye diseases, Ophthalmology, Low birth weight, 030104 developmental biology, 030221 ophthalmology & optometry, Familial exudative vitreoretinopathy, medicine.symptom, business, Biotechnology
Abstract: Topic Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease in premature infants and is a major cause of childhood blindness worldwide. In addition to known clinical risk factors such as low birth weight and gestational age, there is a growing body of evidence supporting a genetic basis for ROP. Clinical Relevance Although comorbidities and environmental factors—most notably gestational age and oxygen—have been identified as contributing to ROP outcomes in premature infants, some infants progress to severe disease despite absence of these clinical risk factors. The contribution of genetic factors may explain these differences and allow better detection and treatment of infants at risk for severe ROP. Methods To comprehensively review genetic factors that potentially contribute to the development and severity of ROP, we conducted a literature search focusing on the genetic basis for ROP. Terms related to other heritable retinal vascular diseases such as “familial exudative vitreoretinopathy,” as well as to genes implicated in animal models of ROP, were also used to capture research in diseases with similar pathogenesis to ROP in humans with known genetic components. Results Contributions across several genetic domains are described, including vascular endothelial growth factor, the Wnt signaling pathway, insulin-like growth factor 1, inflammatory mediators, and brain-derived neurotrophic factor. Conclusions Most candidate gene studies of ROP have limitations such as inability to replicate results, conflicting results from various studies, small sample size, and differences in clinical characterization. Additional difficulty arises in separating the contribution of genetic factors such as Wnt signaling to ROP and prematurity. Although studies have implicated involvement of multiple signaling pathways in ROP, the genetics of ROP have not been clearly elucidated. Next-generation sequencing and genome-wide association studies have potential to expand future understanding of underlying genetic risk factors and pathophysiology of ROP.
Published: 2018

41. rs641738C>T near MBOAT7 is positively associated with liver fat, ALT, and histological severity of NAFLD: a meta-analysis

Author: Jesus M. Banales, Jerome I. Rotter, Connor A. Emdin, Leon A. Adams, Sreekumar G. Pillai, Stephan Buch, Yu Ri Im, Thomas Berg, Claudia Langenberg, Kendra A. Young, Felix Stickel, Elizabeth K. Speliotes, Julia Kozlitina, Sonia Caprio, Madison Fairey, Kevin Teo, Hanieh Yaghootkar, Abhijit Chowdhury, Eu-Pnafld Investigators, Yii-Der Ida Chen, Harriet Hunter, Faiza Qayyum, Pavel Strnad, Matthias C. Reichert, Elmar Aigner, Marcin Krawczyk, Dana de Gracia Hahn, Lin Li, Matthew Hickman, Nicholette D. Palmer, Panu K. Luukkonen, Jiawen Dong, Christian Datz, Ali Canbay, Kent D. Taylor, Joel E. Lavine, Philip E. Melton, Nicola Santoro, Richard M. Watanabe, Xiuqing Guo, Giuseppina Rosaria Umano, Lynne E. Wagenknecht, Amedine Duret, Pallav Bhatnagar, Trevor A. Mori, Johanna K. DiStefano, Anne Tybjærg-Hansen, Stefano Romeo, Julia Wattacheril, Jake P. Mann, Luca Valenti, Ankita Chatterjee, Stefan Stender, Jochen Hampe, Rajarshi Banerjee, Glenn S. Gerhard, Frank Lammert, Rohit Loomba, Christian A. Hudert, Kushala W M Abeysekera, L Heintz, Constantinos A. Parisinos, Hong Kai Lim, Christopher D. Still, Matt Kelly, Mrudula Utukuri, Priyadarshi Basu, Nicholas J. Wareham, Hannele Yki-Järvinen, and Clemens Schafmayer
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Insulin, medicine.medical_treatment, Fatty liver, Genome-wide association study, medicine.disease, Gastroenterology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Internal medicine, Genetic model, medicine, Steatosis, Risk factor, business, 030304 developmental biology
Abstract: Background & AimsA common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and characterize its role in the regulation of related metabolic phenotypes through meta-analysis.MethodsWe performed meta-analysis of studies with data on the association between rs641738C>T genotype and: liver fat, NAFLD histology, and serum ALT, lipids, or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed random effects meta-analysis using recessive, additive, and dominant genetic models.ResultsData from 1,047,265 participants (8,303 with liver biopsies) across 42 studies was included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI: 0.02 - 0.05]) and diagnosis of NAFLD (OR 1.22 [95% CI 1.08 - 1.39]) in Caucasian adults. The variant was also positively associated with presence of severe steatosis, NASH, and advanced fibrosis (OR: 1.32 [95% CI: 1.06 - 1.63]) in Caucasian adults using a recessive model of inheritance (CC+CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (Pz=0.002) and lower serum triglycerides (Pz=1.5×10−4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.ConclusionOur study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.
Published: 2019

42. Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Author: Cashell E. Jaquish, Craig P. Hersh, Emily Barron-Casella, Larry Phillips, James S. Pankow, JoAnn E. Manson, Mariza de Andrade, Vivien A. Sheehan, Norann A. Zaghloul, Yongmei Liu, Sergei Nekhai, Russell P. Tracy, Bruce S. Weir, Pankaj Qasba, Adrienne M. Stilp, Tasha E. Fingerlin, Heather M. Ochs-Balcom, L. Adrienne Cupples, Rongze Yang, David A. Schwartz, Shannon Kelly, Scott E. Devine, Tanja Smith, G.L. Kinney, Beverly Snively, Kent D. Taylor, Manolis Kellis, Ruth J. F. Loos, Seth A. Ament, Kathleen C. Barnes, Robert C. Kaplan, Ulrich Broeckel, Hemant K. Tiwari, Karin F. Hoth, Peter Durda, Julie L. Mikulla, Charles B. Eaton, Cotton Seed, Merry Lynn McDonald, Eric Boerwinkle, Josh Smith, Honghuang Lin, Ingrid B. Borecki, Jeffrey L. Curtis, Emelia J. Benjamin, Kenneth Rice, Sharon L.R. Kardia, Nicholas L. Smith, Coleen M. Damcott, Jeffrey Haessler, Kimberly L. Jones, Elaine Cornell, Nona Sotoodehnia, Adolfo Correa, Rich Johnston, C. Charles Gu, Chii Min Hwu, Peter C. Anderson, Lesley F. Tinker, Colleen Davis, R. Graham Barr, Scott T. Weiss, Leanna Farnam, Chao Hsiung, Brian Silver, Patrick F. McArdle, Lisa W. Martin, Yii-Der Ida Chen, John Barnard, Holly Kramer, Sekar Kathiresan, Gonçalo R. Abecasis, Barry Make, Michael C. Mahaney, Marco V Perez, Donna K. Arnett, Mark Chaffin, Xiuqing Guo, Joshua C. Bis, Pamela Russell, Paul L. Auer, James G. Wilson, Marilyn J. Telen, David K. Levine, Jennifer A. Smith, Christopher Scheller, Meher Preethi Boorgula, Aakrosh Ratan, Kari E. North, Dan E. Arking, Elizabeth A. Regan, Margaret G. Parker, Andres Metspalu, Jai G. Broome, Daniel Taliun, Lynette Ekunwe, Alyna T. Khan, Hao Mei, Dhananjay Vaidya, Ellen M. Schmidt, Stanford Mwasongwe, Joshua P. Lewis, Stacey Gabriel, Christine E. Seidman, Margery Gass, Deborah A. Nickerson, Nicola L. Hawley, Rebecca L. Beer, Afshin Parsa, Steven L. Salzberg, Terri H. Beaty, Stella Aslibekyan, Girish N. Nadkarni, Wei Zhao, David L. Tirschwell, Karen Bunting, Dawn L. DeMeo, Laura J. Rasmussen-Torvik, Julia Powers Becker, Dmitry Prokopenko, Karen Schwander, Bruce D. Gelb, Stephanie Krauter, Laura M. Raffield, Michael E. Hall, Frank C. Sciurba, Lauren Margolin, Nora Franceschini, Daniel N. Harris, Seyedeh M. Zekavat, Dawood Darbar, Keng-Han Lin, Haley Huston, Steven A. Lubitz, Andrea Ganna, Carole Sztalryd, Cathy C. Laurie, Christy Chang, James E. Hixson, Steven A. McCarroll, Barbara A. Konkle, Michael D. Kessler, Scott I. Vrieze, Yingze Zhang, Sarah Ruuska, George J. Papanicolaou, Weiniu Gan, Maris Alver, Elizabeth A. Streeten, Fei Fei Wang, Lu-Chen Weng, Braxton D. Mitchell, Lee-Ming Chuang, Sean P. David, Wei-Min Chen, Susan R. Heckbert, Ryan D. Hernandez, Andrew D. Johnson, Cristen J. Willer, Ani Manichaikul, Jonathan M. Bloom, Timothy D. O’Connor, Sylvia Smoller, Marguerite R. Irvin, Seung Hoan Choi, Ida Surakka, Veikko Salomaa, Diane M. Becker, Ron Do, W. Craig Johnson, Cecelia A. Laurie, Meryl S. LeBoff, Aniket Shetty, Tõnu Esko, Michael C. Zody, Xiaoqi Geng, Da Wei Gong, Snow Xueyan Zhao, Esteban G. Burchard, Xiuwen Zheng, Cara L. Carty, Alexander P. Reiner, Tim Assimes, Deborah A. Meyers, Mina K. Chung, Harald H H Göring, Benjamin M. Neale, Pradeep Natarajan, Yan Gao, Stephen S. Rich, Yun Ju Sung, Susan K. Dutcher, Ferdouse Begum, Stephanie M. Gogarten, John Blangero, Jonathan Cardwell, Kayleen Williams, Rakhi P. Naik, Amol C. Shetty, Sayantan Das, Myriam Fornage, May E. Montasser, Michelle Daya, Edwin K. Silverman, Daniel E. Weeks, Laura J. Kaufman, Dimitrios Avramopoulos, Michael Y. Tsai, Christine M. Albert, Vijay G. Sankaran, Jeffrey R. O'Connell, Thomas W. Blackwell, Stephen T. McGarvey, Robert M. Reed, Leslie A. Lange, Qing Duan, Bruce M. Psaty, Leslie S. Emery, Bertha Hidalgo, Jennifer A. Brody, L. Keoki Williams, Soren Germer, Zhaohui S. Qin, Deepti Jain, Deborah Applebaum-Bowden, Carla Wilson, Degui Zhi, Christoph Lange, Elliott Hong, L.F. Bielak, Wen Jane Lee, Yue Guan, Tarik Walker, Rebecca D. Jackson, Charles R. Farber, Mark J. Daly, Stephanie M. Fullerton, John E. Hokanson, Karol E. Watson, James Luo, Richard Casaburi, Seunggeun Lee, Jill M. Johnsen, Margaret A. Taub, Ryan L. Minster, Ravi Duggirala, Susan K. Mathai, Yun Li, Quenna Wong, Matthew Flickinger, Huichun Xu, Susan Redline, Ulrike Peters, Ivana V. Yang, Jesse M. Engreitz, Sanni Ruotsalainen, Sean K. McFarland, Avram D Walts, Patricia A. Peyser, Allison E. Ashley-Koch, Lewis C. Becker, Nicholette Palmer Allred, James A. Perry, Jody S. Sylvia, Tamar Sofer, Vasan S. Ramachandran, Laura Almasy, Matthew J. Budoff, Ranjan Deka, David M. Herrington, Simeon I. Taylor, Daniel Levy, Chaojie Yang, Sameer Chavan, Kathleen A. Ryan, Josyf C. Mychaleckyj, Ingo Ruczinski, Sebastian Zoellner, Michael Preuss, Tim Poterba, Wendy S. Post, Amber L. Beitelshees, Ben Heavner, Carolina Roselli, Namiko Abe, Jonathon LeFaive, Mark T. Gladwin, Brian Custer, Robert B. Wallace, Simin Liu, Michael H. Cho, Robert E. Handsaker, Dabeeru C. Rao, Bo Juen Chen, Wayne Hui Heng Sheu, Xiang Zhou, Marcos Bezerra, Solomon K. Musani, Eimear E. Kenny, James F. Casella, Kathryn L. Lunetta, Nancy Min, Nicholas Rafaels, Lisa R. Yanek, Min A. Jhun, David C. Glahn, Rasika A. Mathias, Mollie A. Minear, Russell P. Bowler, Jason Ernst, Carolyn J. Crandall, Sara Penchev, Alvaro Alonso, Timothy A. Thornton, Toni I. Pollin, Charles Kooperberg, Ethan M. Lange, Juan M. Peralta, Pramod Anugu, Lucinda Fulton, Adam A. Szpiro, Michael R. DeBaun, M. Benjamin Shoemaker, Sam Phillips, Dan M. Roden, Mao Fu, Daniel I. Chasman, James D. Crapo, Hua Tang, Gina M. Peloso, Hyun Min Kang, Samuli Ripatti, Phuwanat Sakornsakolpat, Christopher R. Gignoux, Peter VandeHaar, Jerome I. Rotter, Dandi Qiao, Emily S. Wan, Shabnam Salimi, Kevin Sandow, Jiang He, Patrick T. Ellinor, Joanne E. Curran, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Clinicum, Doctoral Programme in Population Health, Department of Public Health, and Complex Disease Genetics
Subjects: 0301 basic medicine, Apolipoprotein B, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Lipoprotein particle, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, Aetiology, lcsh:Science, African Continental Ancestry Group, Genetics, Multidisciplinary, Genome, biology, CHOLESTEROL, Adaptor Proteins, Lipoprotein(a), Single Nucleotide, NHLBI TOPMed Lipids Working Group, 3142 Public health care science, environmental and occupational health, 3. Good health, Cholesterol, Heart Disease, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, RARE VARIANTS, lipids (amino acids, peptides, and proteins), LOW-FREQUENCY, Human, DNA Copy Number Variations, Science, Quantitative Trait Loci, European Continental Ancestry Group, Black People, POPULATION-SCALE, Quantitative trait locus, Article, White People, General Biochemistry, Genetics and Molecular Biology, LDL, Structural variation, 03 medical and health sciences, COMPONENTS-ANALYSIS, RISK-FACTOR, Humans, CORONARY-HEART-DISEASE, Polymorphism, Whole Genome Sequencing, Prevention, Human Genome, General Chemistry, Atherosclerosis, Vesicular Transport, Good Health and Well Being, 030104 developmental biology, chemistry, biology.protein, lcsh:Q, 3111 Biomedicine, Lipoprotein, Genome-Wide Association Study
Abstract: Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.
Published: 2018

43. Genetic variation of SORBS1 gene is associated with glucose homeostasis and age at onset of diabetes: A SAPPHIRe Cohort Study

Author: Tien-Jyun Chang, Wen-Chang Wang, Chao A. Hsiung, Chih-Tsueng He, Ming-Wei Lin, Wayne Huey-Herng Sheu, Yi-Cheng Chang, Tom Quertermous, Yii-Der Ida Chen, Jerome I. Rotter, Lee-Ming Chuang, and The SAPPHIRe Study Group
Subjects: Blood Glucose, Male, 0301 basic medicine, SORBS1, medicine.medical_treatment, Physiology, lcsh:Medicine, Prevalence, 2.1 Biological and endogenous factors, Insulin, Glucose homeostasis, Aetiology, Age of Onset, lcsh:Science, Multidisciplinary, biology, Incidence, Incidence (epidemiology), Diabetes, Microfilament Proteins, Single Nucleotide, Middle Aged, Female, Type 2, Adult, China, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Asian People, Diabetes mellitus, Diabetes Mellitus, Genetics, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, Metabolic and endocrine, Nutrition, business.industry, lcsh:R, Glucose Tolerance Test, medicine.disease, Minor allele frequency, Insulin receptor, 030104 developmental biology, SAPPHIRe Study Group, Diabetes Mellitus, Type 2, biology.protein, lcsh:Q, business, Follow-Up Studies
Abstract: The SORBS1 gene plays an important role in insulin signaling. We aimed to examine whether common single-nucleotide polymorphisms (SNPs) of SORBS1 are associated with prevalence and incidence of diabetes, age at onset of diabetes, and the related traits of glucose homeostasis. A total of 1135 siblings from 492 ethnic Chinese families were recruited at baseline, and 630 were followed up for 5.19 ± 0.96 years. Nine SNPs including rs7081076, rs2281939, rs3818540, rs2274490, rs61739184, rs726176, rs2296966, rs17849148, and rs3193970 were genotyped and examined. To deal with correlated data of subjects within the same families, the generalized estimating equations approach was applied throughout all association analyses. The GG genotype of rs2281939 was associated with a higher risk of diabetes at baseline, an earlier onset of diabetes, and higher steady-state plasma glucose levels in the modified insulin suppression test. The minor allele T of rs2296966 was associated with higher prevalence and incidence of diabetes, an earlier onset of diabetes, and higher 2-h glucose during oral glucose tolerance test. These two SNPs revealed independent associations with age of diabetes onset as well as risk of diabetes at baseline. These findings supported that SORBS1 gene participates in the pathogenesis of diabetes.
Published: 2018

44. Associations of autozygosity with a broad range of human phenotypes

Author: Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics
Subjects: 0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract: Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.
Published: 2019

45. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Author: Teresa Tusié-Luna, Svati H. Shah, Wen-Jane Lee, Amit Khera, Gonçalo R. Abecasis, Olle Melander, Alan R. Shuldiner, Connor A. Emdin, Kari Stefansson, Jesper Gromada, Andrew P. Morris, Lee-Ming Chuang, Omri Gottesman, Lars G. Fritsche, Pradeep Natarajan, Marju Orho-Melander, Daniel F. Gudbjartsson, Anubha Mahajan, Marylyn D. Ritchie, William E. Kraus, Tooraj Mirshahi, Colm O'Dushlaine, Jason Flannick, Nicholas J. Wareham, Anne Tybjærg-Hansen, Anders Berg Wulff, Rashmi B. Prasad, Aris Baras, Jonas B. Nielsen, Valgerdur Steinthorsdottir, Yii-Der Ida Chen, Jerome I. Rotter, Lukas Habegger, Samantha N. Fetterolf, David Altshuler, Om Prakash Dwivedi, Tanya M. Teslovich, Cristen J. Willer, Luca A. Lotta, Andrew J. Murphy, Joseph B. Leader, Cristopher V. Van Hout, Christopher D. Still, Ola Hansson, David Birtwell, Alexander Lopez, Daniel J. Rader, John D. Overton, Anthony Marcketta, Patrick Sulem, Peter N. Benotti, Jose C. Florez, Lydia Coulter Kwee, David J. Carey, Oddgeir L. Holmen, Kristian Hveem, Leif Groop, Sekar Kathiresan, Viktoria Gusarova, Unnur Thorsteinsdottir, Cassandra M. Hartle, Uyenlinh L. Mirshahi, H. Lester Kirchner, Shannon Bruse, Robert A. Scott, Michael F. Murray, Marketa Sjögren, Jeffrey G. Reid, Aeron Small, Børge G. Nordestgaard, Amr H. Wardeh, Chad M. Brummett, Mark I. McCarthy, Frederick E. Dewey, David H. Ledbetter, John Penn, Ingrid B. Borecki, Scott M. Damrauer, Hilma Holm, Michael Boehnke, George D. Yancopoulos, Institute for Molecular Medicine Finland, University of Helsinki, Centre of Excellence in Complex Disease Genetics, and HUS Abdominal Center
Subjects: Blood Glucose, Male, 0301 basic medicine, Insulin Resistance/genetics, General Physics and Astronomy, Type 2 diabetes, 030204 cardiovascular system & hematology, Inbred C57BL, Cardiovascular, HAN CHINESE, Whole Exome Sequencing, Mice, 0302 clinical medicine, Risk Factors, ANGPTL4, Homeostasis, Glucose homeostasis, lcsh:Science, Mice, Knockout, Lipoprotein lipase, Multidisciplinary, Diabetes, Lipoprotein Lipase/metabolism, REMNANT CHOLESTEROL, ADIPOSE-TISSUE, Female, Type 2, Heterozygote, medicine.medical_specialty, Knockout, Science, LIPOPROTEIN-LIPASE, HEART-DISEASE, Diabetes Mellitus, Type 2/etiology, Article, General Biochemistry, Genetics and Molecular Biology, Angiopoietin-like 4 Protein/deficiency, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Exome Sequencing, Diabetes Mellitus, Genetics, medicine, Angiopoietin-Like Protein 4, Animals, Humans, Gene Silencing, GENOME-WIDE ASSOCIATION, Metabolic and endocrine, Genetic Association Studies, CHINESE POPULATION, Blood Glucose/metabolism, PLASMA-LIPIDS, business.industry, Case-control study, Genetic Variation, General Chemistry, Odds ratio, Atherosclerosis, medicine.disease, Mice, Inbred C57BL, Lipoprotein Lipase, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Amino Acid Substitution, Case-Control Studies, lcsh:Q, 3111 Biomedicine, ANGIOPOIETIN-LIKE PROTEIN-4, Insulin Resistance, business
Abstract: Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D., Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.
Published: 2018

46. IGF1 Gene Is Associated With Triglyceride Levels In Subjects With Family History Of Hypertension From The SAPPHIRe And TWB Projects

Author: I-Te Lee, Yen-Feng Chiu, Chien-Hsing Lee, Chao A. Hsiung, Thomas Quertermous, Kuan-Yi Hung, Wen Chang Wang, Yi-Cheng Chang, Ren-Hua Chung, Yii-Der Ida Chen, and Chii-Min Hwu
Subjects: Insulin-like growth factor 1, medicine.medical_specialty, Family history of hypertension, 030204 cardiovascular system & hematology, Triglyceride, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, Genetic linkage, Internal medicine, Genetic model, medicine, Family history, Gene, Single-nucleotide polymorphism, business.industry, IGF1, General Medicine, medicine.disease, Large sample, Minor allele frequency, Endocrinology, chemistry, 030220 oncology & carcinogenesis, business, Research Paper
Abstract: Chromosome 12q23-q24 has been linked to triglyceride (TG) levels by previous linkage studies, and it contains the Insulin-like growth factor 1 (IGF1) gene. We investigated the association between IGF1 and TG levels using two independent samples collected in Taiwan. First, based on 954 siblings in 397 families from the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe), we found that rs978458 was associated with TG levels (β = -0.049, p = 0.0043) under a recessive genetic model. Specifically, subjects carrying the homozygous genotype of the minor allele had lower TG levels, compared with other subjects. Then, a series of stratification analyses in a large sample of 13,193 unrelated subjects from the Taiwan biobank (TWB) project showed that this association appeared in subjects with a family history (FH) of hypertension (β = -0.045, p = 0.0000034), but not in subjects without such an FH. A re-examination of the SAPPHIRe sample confirmed that this association appeared in subjects with an FH of hypertension (β = -0.068, p = 0.0025), but not in subjects without an FH. The successful replication in two independent samples indicated that IGF1 is associated with TG levels in subjects with an FH of hypertension in Taiwan.
Published: 2018

47. The GLP-1 response to glucose does not mediate beta and alpha cell dysfunction in Hispanics with abnormal glucose metabolism

Author: Yii-Der Ida Chen, Elizabeth Adams, Pauline Genter, Eli Ipp, Kevin Sandow, Jerome I. Rotter, Emma Keefe, and Virginia Gray
Subjects: Adult, Blood Glucose, Male, 0301 basic medicine, endocrine system, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Glucagon, Article, Alpha cell, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Glucagon-Like Peptide 1, Internal medicine, Diabetes mellitus, Glucose Intolerance, Internal Medicine, medicine, Humans, Glucose homeostasis, business.industry, Insulin, digestive, oral, and skin physiology, nutritional and metabolic diseases, Type 2 Diabetes Mellitus, Hispanic or Latino, General Medicine, Middle Aged, medicine.disease, Abnormal glucose homeostasis, 030104 developmental biology, Diabetes Mellitus, Type 2, Female, business, hormones, hormone substitutes, and hormone antagonists, Hormone
Abstract: Aims Glucagon-like peptide-1 (GLP-1) contributes to insulin secretion after meals. Though Hispanics have increased risk for type 2 diabetes mellitus, it is unknown if impaired GLP-1 secretion contributes to this risk. We therefore studied plasma GLP-1 secretion and action in Hispanic adults. Methods Hispanic (H; n = 31) and non-Hispanic (nH; n = 15) participants underwent an oral glucose tolerance test (OGTT). All participants were categorized by glucose tolerance into four groups: normal glucose tolerant non-Hispanic (NGT-nH; n = 15), normal glucose tolerant Hispanic (NGT-H; n = 12), impaired glucose tolerant Hispanic (IGT-H; n = 11), or newly diagnosed type 2 diabetes mellitus, Hispanic (T2D-H; n = 8). Results Glucose-induced increments in plasma GLP-1 (Δ-GLP-1) were not different in NGT-H and NGT-nH (p = .38), nor amongst Hispanic subgroups with varying degrees of glucose homeostasis (p = .6). In contrast, the insulinogenic index in T2D-H group was lower than the other groups (p = .016). Subjects with abnormal glucose homeostasis (AGH), i.e., T2D-H plus IGT-H, had a diminished glucagon suppression index compared to patients with normal glucose homeostasis (NGT-H plus NGT-nH) (p = .035). Conclusions GLP-1 responses to glucose were similar in Hispanic and Non-Hispanic NGT. Despite similar glucose-induced Δ-GLP-1, insulin and glucagon responses were abnormal in T2D-H and AGH, respectively. Thus, impaired GLP-1 secretion is unlikely to play a role in islet dysfunction in T2D. Although GLP-1 therapeutics enhance insulin secretion and glucagon suppression, it is likely due to pharmacological amplification of the GLP-1 pathways rather than treatment of hormonal deficiency.
Published: 2018

48. Genome-Wide Study of Subcutaneous and Visceral Adipose Tissue Reveals Novel Sex-Specific Adiposity Loci in Mexican Americans

Author: Jerome I. Rotter, Yii-Der Ida Chen, Matthew A. Allison, Elizabeth K. Speliotes, Chuan Gao, Jill M. Norris, Lynne E. Wagenknecht, Kent D. Taylor, Xiuqing Guo, Nicholette D. Palmer, Donald W. Bowden, Jacklyn N. Hellwege, Carl D. Langefeld, and Julie T. Ziegler
Subjects: 0301 basic medicine, 2. Zero hunger, medicine.medical_specialty, Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism, Insulin, medicine.medical_treatment, Medicine (miscellaneous), Adipose tissue, Single-nucleotide polymorphism, Biology, medicine.disease, Obesity, 3. Good health, Minor allele frequency, 03 medical and health sciences, 030104 developmental biology, Endocrinology, Insulin resistance, Internal medicine, medicine, SNP, Risk factor
Abstract: Author(s): Gao, Chuan; Langefeld, Carl D; Ziegler, Julie T; Taylor, Kent D; Norris, Jill M; Chen, Yii-Der I; Hellwege, Jacklyn N; Guo, Xiuqing; Allison, Matthew A; Speliotes, Elizabeth K; Rotter, Jerome I; Bowden, Donald W; Wagenknecht, Lynne E; Palmer, Nicholette D | Abstract: OBJECTIVE:This study aimed to explore the genetic mechanisms of regional fat deposition, which is a strong risk factor for metabolic diseases beyond total adiposity. METHODS:A genome-wide association study of 7,757,139 single-nucleotide polymorphisms (SNPs) in 983 Mexican Americans (nmale = 403; nfemale = 580) from the Insulin Resistance Atherosclerosis Family Study was performed. Association analyses were performed with and without sex stratification for subcutaneous adipose tissue, visceral adipose tissue (VAT), and visceral-subcutaneous ratio (VSR) obtained from computed tomography. RESULTS:The strongest signal identified was SNP rs2185405 (minor allele frequencies [MAF] = 40%; PVAT = 1.98 × 10-8 ) with VAT. It is an intronic variant of the GLIS family zinc finger 3 gene (GLIS3). In addition, SNP rs12657394 (MAF = 19%) was associated with VAT in males (Pmale = 2.39×10-8 ; Pfemale = 2.5 × 10-3 ). It is located intronically in the serum response factor binding protein 1 gene (SRFBP1). On average, male carriers of the variant had 24.6 cm2 increased VAT compared with noncarriers. Subsequently, genome-wide SNP-sex interaction analysis was performed. SNP rs10913233 (MAF = 14%; Pint = 3.07 × 10-8 ) in PAPPA2 and rs10923724 (MAF = 38%; Pint = 2.89 × 10-8 ) upstream of TBX15 were strongly associated with the interaction effect for VSR. CONCLUSIONS:Six loci were identified with genome-wide significant associations with fat deposition and interactive effects. These results provided genetic evidence for a differential basis of fat deposition between genders.
Published: 2017

49. Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)

Author: Alain G. Bertoni, Yii-Der Ida Chen, Mark O. Goodarzi, Gautam Ramesh, Elizabeth T. Jensen, Stephen S. Rich, Alexis C. Wood, and Jerome I. Rotter
Subjects: 0301 basic medicine, insulin secretion, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Sciences, 030209 endocrinology & metabolism, prediabetes, Type 2 diabetes, Microbiology, Biochemistry, Article, Analytical Chemistry, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Clinical Research, Diabetes mellitus, Internal medicine, medicine, insulin sensitivity, Secretion, Microbiome, Prediabetes, Molecular Biology, Metabolic and endocrine, disposition index, diabetes, business.industry, Insulin, medicine.disease, QR1-502, insulin clearance, 030104 developmental biology, Endocrinology, Cohort, Patient Safety, Biochemistry and Cell Biology, business
Abstract: Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia.
Published: 2021

50. Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study

Author: Paul Mitchell, Alan D. Penman, Vilmundur Gudnason, Xiuqing Guo, Mark W. Christiansen, Yii-Der Ida Chen, Yang Hai, Alfred Tau Liang Gan, Yi-Jen Hung, Barbara E.K. Klein, Wen-Ling Liao, Richard A. Jensen, Wen-Jane Lee, Bruce M. Psaty, Kathryn P. Burdon, Ching J. Chen, Albert V. Smith, Lynn K. Stanwyck, Yong He Chong, Jie Jin Wang, Qiao Fan, Yucheng Jia, Georgia Kaidonis, Craig L. Hanis, Ronald Klein, Gavin Tan, Jihye Kim, Jane Kuo, Eli Ipp, Ching-Yu Cheng, Samuela Pollack, Fuu Jen Tsai, Tien Yin Wong, Gerald Liew, Mary Frances Cotch, Alkes L. Price, Jerome I. Rotter, Xiaohui Li, Kevin Sandow, Yu-Chuen Huang, Lucia Sobrin, Jamie E Craig, and Heather Hancock
Subjects: Male, Risk, Endocrinology, Diabetes and Metabolism, Physiology, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Risk factor, Aged, Genetic association, Genetics, Diabetic Retinopathy, business.industry, Genetics/Genomes/Proteomics/Metabolomics, Mendelian Randomization Analysis, Odds ratio, Middle Aged, medicine.disease, Lipids, 3. Good health, 030221 ophthalmology & optometry, Female, business, Dyslipidemia, Genome-Wide Association Study
Abstract: Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
Published: 2017

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