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1. Regionally enriched rare deleterious exonic variants in the UK and Ireland

Author

Mihail Halachev, Viktoria-Eleni Gountouna, Alison Meynert, Gannie Tzoneva, Alan R. Shuldiner, Colin A. Semple, and James F. Wilson

Subjects
Science
Abstract

Abstract It is unclear how patterns of regional genetic differentiation in the UK and Ireland might impact the protein-coding fraction of the genome. We exploit UK Biobank (UKB) and Viking Genes whole exome sequencing data to study regional genetic differentiation across the UK and Ireland in protein coding genes, encompassing 44,696 unrelated individuals from 20 regions of origin. We demonstrate substantial exonic differentiation among Shetlanders, Orcadians, individuals with full or partial Ashkenazi Jewish ancestry and in several mainland regions (particularly north and south Wales, southeast Scotland and Ireland). With stringent filtering criteria, we find 67 regionally enriched (≥5-fold) variants likely to have adverse biomedical consequences in homozygous individuals. Here, we show that regional genetic variation across the UK and Ireland should be considered in the design of genetic studies and may inform effective genetic screening and counselling.

Published
2024
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2. NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke

Author

Juan Lorenzo Rodriguez-Flores, Shareef Khalid, Neelroop Parikshak, Asif Rasheed, Bin Ye, Manav Kapoor, Joshua Backman, Farshid Sepehrband, Silvio Alessandro Di Gioia, Sahar Gelfman, Tanima De, Nilanjana Banerjee, Deepika Sharma, Hector Martinez, Sofia Castaneda, David D’Ambrosio, Xingmin A. Zhang, Pengcheng Xun, Ellen Tsai, I-Chun Tsai, Regeneron Genetics Center, Maleeha Zaman Khan, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Khalid Mahmood, Tanvir Us Salam, Muhammad Hussain, Javed Iqbal, Faizan Aslam, Michael N. Cantor, Gannie Tzoneva, John Overton, Jonathan Marchini, Jeffrey G. Reid, Aris Baras, Niek Verweij, Luca A. Lotta, Giovanni Coppola, Katia Karalis, Aris Economides, Sergio Fazio, Wolfgang Liedtke, John Danesh, Ayeesha Kamal, Philippe Frossard, Thomas Coleman, Alan R. Shuldiner, and Danish Saleheen

Subjects
Science
Abstract

Abstract The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691 C > T, encoding the missense amino acid substitution p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds ratio (OR) = 3.39, 95% confidence interval (CI) = [2.26, 5.10], p = 3.87 × 10−9), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p = 7.79 × 10−10). NOTCH3 p.Arg231Cys was strongly associated with white matter hyperintensity on MRI in United Kingdom Biobank (UKB) participants (effect [95% CI] in SD units = 1.1 [0.61, 1.5], p = 3.0 × 10−6). The variant is attributable for approximately 2.0% of hemorrhagic strokes and 1.1% of all strokes in South Asians. These findings highlight the value of diversity in genetic studies and have major implications for genomic medicine and therapeutic development in South Asian populations.

Published
2024
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3. Acute pharmacodynamic responses to sitagliptin: Drug‐induced increase in early insulin secretion in oral glucose tolerance test

Author

Amber L. Beitelshees, Elizabeth A. Streeten, Zhinous Shahidzadeh Yazdi, Hilary B. Whitlatch, Braxton D. Mitchell, Alan R. Shuldiner, May E. Montasser, and Simeon I. Taylor

Subjects
Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270
Abstract

Abstract DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses – including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p = 0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from mean ± SEM 0.87 ± 0.05 to 1.62 ± 0.36 mU/L (p = 0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin‐induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90–180 min time points. However, we did not detect significant sex‐associated differences in the magnitude of sitagliptin‐induced changes in T30:T60 ratios for either glucose or insulin. In conclusion, T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.

Published
2024
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4. Missense variants in SORT1 are associated with LDL-C in an Amish population

Author

Kelly A. Mitok, Kathryn L. Schueler, Sarah M. King, Joseph Orr, Kathleen A. Ryan, Mark P. Keller, Ronald M. Krauss, Braxton D. Mitchell, Alan R. Shuldiner, and Alan D. Attie

Subjects
cholesterol/metabolism, dyslipidemias, LDL/metabolism, lipoproteins/metabolism, lipoproteins/receptors, genetic association, Biochemistry, QD415-436
Abstract

Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly associated with low-density lipoprotein cholesterol (LDL-C) in human genome-wide association studies. However, validation studies in mice and cell lines have produced variable results regarding the directionality of the effect of SORT1 on LDL-C. This, together with the fact that the 1p13.3 variants are associated with expression of several genes, has raised the question of whether SORT1 is the causal gene at this locus. Using whole exome sequencing in members of an Amish population, we identified coding variants in SORT1 that are associated with increased (rs141749679, K302E) and decreased (rs149456022, Q225H) LDL-C. Further, analysis of plasma lipoprotein particle subclasses by ion mobility in a subset of rs141749679 (K302E) carriers revealed higher levels of large LDL particles compared to noncarriers. In contrast to the effect of these variants in the Amish, the sortilin K302E mutation introduced into a C57BL/6J mouse via CRISPR/Cas9 resulted in decreased non-high-density lipoprotein cholesterol, and the sortilin Q225H mutation did not alter cholesterol levels in mice. This is indicative of different effects of these mutations on cholesterol metabolism in the two species. To our knowledge, this is the first evidence that naturally occurring coding variants in SORT1 are associated with LDL-C, thus supporting SORT1 as the gene responsible for the association of the 1p13.3 locus with LDL-C.

Published
2023
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5. Associations of genome-wide and regional autozygosity with 96 complex traits in old order Amish

Author

Megan T. Lynch, Kristin A. Maloney, Huichun Xu, James A. Perry, Regeneron Genetics Center, Alan R. Shuldiner, and Braxton D. Mitchell

Subjects
Autozygosity, Runs of Homozygosity, Founder population genetics, Amish, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background: Autozygosity, the proportion of the genome that is homozygous by descent, has been associated with variation in multiple health-related traits impacting evolutionary fitness. Autozygosity (FROH) is typically measured from runs of homozygosity (ROHs) that arise when identical-by-descent (IBD) haplotypes are inherited from each parent. Population isolates with a small set of common founders have elevated autozygosity relative to outbred populations. Methods: In this study, we examined whether degree of autozygosity was associated with variation in 96 cardiometabolic traits among 7221 Old Order Amish individuals residing in Lancaster County, PA. We estimated the average length of an ROH segment to be 6350 KB, with each individual having on average 17.2 segments 1.5 KB or larger. Measurements of genome-wide and regional FROH were used as the primary predictors of trait variation in association analysis. Results: In genome-wide FROH analysis, we did not identify any associations that withstood Bonferroni-correction (p = 0.0005). However, on regional FROH analysis, we identified associations exceeding genome-wide thresholds for two traits: serum bilirubin levels, which were significantly associated with a region on chromosome 2 localized to a region surrounding UGT1A10 (p = 1 × 10− 43), and HbA1c levels, which were significantly associated with a region on chromosome 8 localized near CHRNB3 (p = 8 × 10− 10). Conclusions: These analyses highlight the potential value of autozygosity mapping in founder populations.

Published
2023
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6. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes

Author

Parsa Akbari, Olukayode A. Sosina, Jonas Bovijn, Karl Landheer, Jonas B. Nielsen, Minhee Kim, Senem Aykul, Tanima De, Mary E. Haas, George Hindy, Nan Lin, Ian R. Dinsmore, Jonathan Z. Luo, Stefanie Hectors, Benjamin Geraghty, Mary Germino, Lampros Panagis, Prodromos Parasoglou, Johnathon R. Walls, Gabor Halasz, Gurinder S. Atwal, Regeneron Genetics Center, DiscovEHR Collaboration, Marcus Jones, Michelle G. LeBlanc, Christopher D. Still, David J. Carey, Alice Giontella, Marju Orho-Melander, Jaime Berumen, Pablo Kuri-Morales, Jesus Alegre-Díaz, Jason M. Torres, Jonathan R. Emberson, Rory Collins, Daniel J. Rader, Brian Zambrowicz, Andrew J. Murphy, Suganthi Balasubramanian, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Michael Cantor, Goncalo R. Abecasis, Manuel A. R. Ferreira, Mark W. Sleeman, Viktoria Gusarova, Judith Altarejos, Charles Harris, Aris N. Economides, Vincent Idone, Katia Karalis, Giusy Della Gatta, Tooraj Mirshahi, George D. Yancopoulos, Olle Melander, Jonathan Marchini, Roberto Tapia-Conyer, Adam E. Locke, Aris Baras, Niek Verweij, and Luca A. Lotta

Subjects
Science
Abstract

Fat distribution is associated with cardiometabolic disease, although it has been less well studied than overall obesity. In a multiancestry exome-sequencing study, the authors identified predicted loss-of-function mutations in INHBE associated with favorable fat distribution and protection from type 2 diabetes.

Published
2022
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7. Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program

Author

Daniel DiCorpo, Sheila M. Gaynor, Emily M. Russell, Kenneth E. Westerman, Laura M. Raffield, Timothy D. Majarian, Peitao Wu, Chloé Sarnowski, Heather M. Highland, Anne Jackson, Natalie R. Hasbani, Paul S. de Vries, Jennifer A. Brody, Bertha Hidalgo, Xiuqing Guo, James A. Perry, Jeffrey R. O’Connell, Samantha Lent, May E. Montasser, Brian E. Cade, Deepti Jain, Heming Wang, Ricardo D’Oliveira Albanus, Arushi Varshney, Lisa R. Yanek, Leslie Lange, Nicholette D. Palmer, Marcio Almeida, Juan M. Peralta, Stella Aslibekyan, Abigail S. Baldridge, Alain G. Bertoni, Lawrence F. Bielak, Chung-Shiuan Chen, Yii-Der Ida Chen, Won Jung Choi, Mark O. Goodarzi, James S. Floyd, Marguerite R. Irvin, Rita R. Kalyani, Tanika N. Kelly, Seonwook Lee, Ching-Ti Liu, Douglas Loesch, JoAnn E. Manson, Ryan L. Minster, Take Naseri, James S. Pankow, Laura J. Rasmussen-Torvik, Alexander P. Reiner, Muagututi’a Sefuiva Reupena, Elizabeth Selvin, Jennifer A. Smith, Daniel E. Weeks, Huichun Xu, Jie Yao, Wei Zhao, Stephen Parker, Alvaro Alonso, Donna K. Arnett, John Blangero, Eric Boerwinkle, Adolfo Correa, L. Adrienne Cupples, Joanne E. Curran, Ravindranath Duggirala, Jiang He, Susan R. Heckbert, Sharon L. R. Kardia, Ryan W. Kim, Charles Kooperberg, Simin Liu, Rasika A. Mathias, Stephen T. McGarvey, Braxton D. Mitchell, Alanna C. Morrison, Patricia A. Peyser, Bruce M. Psaty, Susan Redline, Alan R. Shuldiner, Kent D. Taylor, Ramachandran S. Vasan, Karine A. Viaud-Martinez, Jose C. Florez, James G. Wilson, Robert Sladek, Stephen S. Rich, Jerome I. Rotter, Xihong Lin, Josée Dupuis, James B. Meigs, Jennifer Wessel, and Alisa K. Manning

Subjects
Biology (General), QH301-705.5
Abstract

This study of 23,000 non-diabetic individuals highlights loci associated with fasting glucose and fasting insulin in diverse cohorts with whole genome sequence data.

Published
2022
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8. An Amish founder population reveals rare-population genetic determinants of the human lipidome

Author

May E. Montasser, Stella Aslibekyan, Vinodh Srinivasasainagendra, Hemant K. Tiwari, Amit Patki, Minoo Bagheri, Tobias Kind, Dinesh Kumar Barupal, Sili Fan, James Perry, Kathleen A. Ryan, Alan R. Shuldiner, Donna K. Arnett, Amber L. Beitelshees, Marguerite Ryan Irvin, and Jeffrey R. O’Connell

Subjects
Biology (General), QH301-705.5
Abstract

A GWAS of 355 lipid species in the Old Order Amish founder population reveals associations between Amish-enriched loci and several sphingolipids.

Published
2022
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9. Clinical characterization of familial hypercholesterolemia due to an amish founder mutation in Apolipoprotein B

Author

Katie B. Williams, Michael Horst, Millie Young, Christine Pascua, Erik G. Puffenberger, Karlla W. Brigatti, Claudia Gonzaga-Jauregui, Alan R. Shuldiner, Samuel Gidding, Kevin A. Strauss, and Devyani Chowdhury

Subjects
Familial hypercholesterolemia, Amish, Apolipoprotein, Cholesterol, Carotid initma-media thickness, Pulse wave velocity, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Familial hypercholesterolemia (FH) due to a founder variant in Apolipoprotein B (ApoBR3500Q) is reported in 12% of the Pennsylvania Amish community. By studying a cohort of ApoBR3500Q heterozygotes and homozygotes, we aimed to characterize the biochemical and cardiac imaging features in children and young adults with a common genetic background and similar lifestyle. Methods We employed advanced lipid profile testing, carotid intima media thickness (CIMT), pulse wave velocity (PWV), and peripheral artery tonometry (PAT) to assess atherosclerosis in a cohort of Amish ApoBR3500Q heterozygotes (n = 13), homozygotes (n = 3), and their unaffected, age-matched siblings (n = 9). ApoBR3500Q homozygotes were not included in statistical comparisons. Results LDL cholesterol (LDL-C) was significantly elevated among ApoBR3500Q heterozygotes compared to sibling controls, though several ApoBR3500Q heterozygotes had LDL-C levels in the normal range. LDL particles (LDL-P), small, dense LDL particles, and ApoB were also significantly elevated among subjects with ApoBR3500Q. Despite these differences in serum lipids and particles, CIMT and PWV were not significantly different between ApoBR3500Q heterozygotes and controls in age-adjusted analysis. Conclusions We provide a detailed description of the serum lipids, atherosclerotic plaque burden, vascular stiffness, and endothelial function among children and young adults with FH due to heterozygous ApoBR3500Q. Fasting LDL-C was lower than what is seen with other forms of FH, and even normal in several ApoBR3500Q heterozygotes, emphasizing the importance of cascade genetic testing among related individuals for diagnosis. We found increased number of LDL particles among ApoBR3500Q heterozygotes but an absence of detectable atherosclerosis.

Published
2022
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10. Cerebral blood flow and cardiovascular risk effects on resting brain regional homogeneity

Author

Bhim M. Adhikari, L. Elliot Hong, Zhiwei Zhao, Danny J.J. Wang, Paul M. Thompson, Neda Jahanshad, Alyssa H. Zhu, Stefan Holiga, Jessica A. Turner, Theo G.M. van Erp, Vince D. Calhoun, Kathryn S. Hatch, Heather Bruce, Stephanie M. Hare, Joshua Chiappelli, Eric L. Goldwaser, Mark D. Kvarta, Yizhou Ma, Xiaoming Du, Thomas E. Nichols, Alan R. Shuldiner, Braxton D. Mitchell, Juergen Dukart, Shuo Chen, and Peter Kochunov

Subjects
Arterial-spin labeling, Correlation, Local functional connectivity, Multivariate mediation analysis, Resting state functional MRI, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy volunteers was used for test-retest evaluation of CBF effects on ReHo. Amish Connectome Project (ACP) sample (N = 204, healthy individuals) was used to evaluate association between FCVRS and ReHo and testing if the association diminishes given CBF. The UKBB sample (N = 6,285, healthy participants) was used to replicate the effects of FCVRS on ReHo. We observed strong CBF→ReHo links (p

Published
2022
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11. A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Author

Mina-A Jhun, Michael Mendelson, Rory Wilson, Rahul Gondalia, Roby Joehanes, Elias Salfati, Xiaoping Zhao, Kim Valeska Emilie Braun, Anh Nguyet Do, Åsa K. Hedman, Tao Zhang, Elena Carnero-Montoro, Jincheng Shen, Traci M. Bartz, Jennifer A. Brody, May E. Montasser, Jeff R. O’Connell, Chen Yao, Rui Xia, Eric Boerwinkle, Megan Grove, Weihua Guan, Pfeiffer Liliane, Paula Singmann, Martina Müller-Nurasyid, Thomas Meitinger, Christian Gieger, Annette Peters, Wei Zhao, Erin B. Ware, Jennifer A. Smith, Klodian Dhana, Joyce van Meurs, Andre Uitterlinden, Mohammad Arfan Ikram, Mohsen Ghanbari, Deugi Zhi, Stefan Gustafsson, Lars Lind, Shengxu Li, Dianjianyi Sun, Tim D. Spector, Yii-der Ida Chen, Coleen Damcott, Alan R. Shuldiner, Devin M. Absher, Steve Horvath, Philip S. Tsao, Sharon Kardia, Bruce M. Psaty, Nona Sotoodehnia, Jordana T. Bell, Erik Ingelsson, Wei Chen, Abbas Dehghan, Donna K. Arnett, Melanie Waldenberger, Lifang Hou, Eric A. Whitsel, Andrea Baccarelli, Daniel Levy, Myriam Fornage, Marguerite R. Irvin, and Themistocles L. Assimes

Subjects
Science
Abstract

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
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12. Genome sequencing unveils a regulatory landscape of platelet reactivity

Author

Ali R. Keramati, Ming-Huei Chen, Benjamin A. T. Rodriguez, Lisa R. Yanek, Arunoday Bhan, Brady J. Gaynor, Kathleen Ryan, Jennifer A. Brody, Xue Zhong, Qiang Wei, NHLBI Trans-Omics for Precision (TOPMed) Consortium, Kai Kammers, Kanika Kanchan, Kruthika Iyer, Madeline H. Kowalski, Achilleas N. Pitsillides, L. Adrienne Cupples, Bingshan Li, Thorsten M. Schlaeger, Alan R. Shuldiner, Jeffrey R. O’Connell, Ingo Ruczinski, Braxton D. Mitchell, Nauder Faraday, Margaret A. Taub, Lewis C. Becker, Joshua P. Lewis, Rasika A. Mathias, and Andrew D. Johnson

Subjects
Science
Abstract

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Published
2021
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13. Multiple dimensions of stress vs. genetic effects on depression

Author

Mark D. Kvarta, Heather A. Bruce, Joshua Chiappelli, Stephanie M. Hare, Eric L. Goldwaser, Jessica Sewell, Hemalatha Sampath, Samantha Lightner, Wyatt Marshall, Kathryn Hatch, Elizabeth Humphries, Seth Ament, Alan R. Shuldiner, Braxton D. Mitchell, Francis J. McMahon, Peter Kochunov, and L. Elliot Hong

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Many psychiatric disorders including depression involve complex interactions of genetics and environmental stressors. Environmental influence is challenging to measure objectively and account for in genetic studies because the necessary large population samples in these studies involve individuals with varying cultures and life experiences, clouding genetic findings. In a unique population with relative sociocultural homogeneity and a narrower range of types of stress experiences, we quantitatively assessed multiple stress dimensions and measured their potential influence in biasing the heritability estimate of depression. We quantified depressive symptoms, major lifetime stressors, current perceived stress, and a culturally specific community stress measure in individuals with depression-related diagnoses and community controls in Old Order Amish and Mennonite populations. Results showed that lifetime stressors measured by lifetime stressor inventory (R 2 = 0.06, p = 2 × 10−5) and current stress measured by Perceived Stress Scale (R 2 = 0.13, p

Published
2021
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14. Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

Author

Julie E. Horowitz, Neil Warner, Jeffrey Staples, Eileen Crowley, Nehal Gosalia, Ryan Murchie, Cristopher Van Hout, Karoline Fiedler, Gabriel Welch, Alejandra Klauer King, Jeffrey G. Reid, John D. Overton, Aris Baras, Alan R. Shuldiner, Anne Griffiths, Omri Gottesman, Aleixo M. Muise, and Claudia Gonzaga-Jauregui

Subjects
Medicine, Science
Abstract

Abstract Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.

Published
2021
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15. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Published
2021
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16. Clonal Hematopoiesis Analyses in Clinical, Epidemiologic, and Genetic Aging Studies to Unravel Underlying Mechanisms of Age-Related Dysfunction in Humans

Author

Kenneth Walsh, Nalini Raghavachari, Candace Kerr, Alexander G. Bick, Steven R. Cummings, Todd Druley, Cynthia E. Dunbar, Giulio Genovese, Margaret A. Goodell, Siddhartha Jaiswal, Jaroslaw Maciejewski, Pradeep Natarajan, Anastasia V. Shindyapina, Alan R. Shuldiner, Erik B. Van Den Akker, and Jan Vijg

Subjects
clonal hematopoiesis, aging, CHIP, somatic mutations, longevity, Geriatrics, RC952-954.6
Abstract

Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that expand with age in otherwise normal tissues. In the hematopoietic system, this phenomenon has generally been referred to as “clonal hematopoiesis of indeterminate potential” (CHIP) when it applies to a subset of clones in which mutations in driver genes of hematologic malignancies are found. Other mechanisms of clonal hematopoiesis, including large chromosomal alterations, can also give rise to clonal expansion in the absence of conventional CHIP driver gene mutations. Both types of clonal hematopoiesis (CH) have been observed in studies of animal models and humans in association with altered immune responses, increased mortality, and disease risk. Studies in murine models have found that some of these clonal events are involved in abnormal inflammatory and metabolic changes, altered DNA damage repair and epigenetic changes. Studies in long-lived individuals also show the accumulation of somatic mutations, yet at this advanced age, carriership of somatic mutations is no longer associated with an increased risk of mortality. While it remains to be elucidated what factors modify this genotype-phenotype association, i.e., compensatory germline genetics, cellular context of the mutations, protective effects to diseases at exceptional age, it points out that the exceptionally long-lived are key to understand the phenotypic consequences of CHIP mutations. Assessment of the clinical significance of somatic mutations occurring in blood cell types for age-related outcomes in human populations of varied life and health span, environmental exposures, and germline genetic risk factors will be valuable in the development of personalized strategies tailored to specific somatic mutations for healthy aging.

Published
2022
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17. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author

Ioanna Ntalla, Lu-Chen Weng, James H. Cartwright, Amelia Weber Hall, Gardar Sveinbjornsson, Nathan R. Tucker, Seung Hoan Choi, Mark D. Chaffin, Carolina Roselli, Michael R. Barnes, Borbala Mifsud, Helen R. Warren, Caroline Hayward, Jonathan Marten, James J. Cranley, Maria Pina Concas, Paolo Gasparini, Thibaud Boutin, Ivana Kolcic, Ozren Polasek, Igor Rudan, Nathalia M. Araujo, Maria Fernanda Lima-Costa, Antonio Luiz P. Ribeiro, Renan P. Souza, Eduardo Tarazona-Santos, Vilmantas Giedraitis, Erik Ingelsson, Anubha Mahajan, Andrew P. Morris, Fabiola Del Greco M, Luisa Foco, Martin Gögele, Andrew A. Hicks, James P. Cook, Lars Lind, Cecilia M. Lindgren, Johan Sundström, Christopher P. Nelson, Muhammad B. Riaz, Nilesh J. Samani, Gianfranco Sinagra, Sheila Ulivi, Mika Kähönen, Pashupati P. Mishra, Nina Mononen, Kjell Nikus, Mark J. Caulfield, Anna Dominiczak, Sandosh Padmanabhan, May E. Montasser, Jeff R. O’Connell, Kathleen Ryan, Alan R. Shuldiner, Stefanie Aeschbacher, David Conen, Lorenz Risch, Sébastien Thériault, Nina Hutri-Kähönen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Olli T. Raitakari, Catriona L. K. Barnes, Harry Campbell, Peter K. Joshi, James F. Wilson, Aaron Isaacs, Jan A. Kors, Cornelia M. van Duijn, Paul L. Huang, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Erwin P. Bottinger, Ruth J. F. Loos, Girish N. Nadkarni, Michael H. Preuss, Adolfo Correa, Hao Mei, James Wilson, Thomas Meitinger, Martina Müller-Nurasyid, Annette Peters, Melanie Waldenberger, Massimo Mangino, Timothy D. Spector, Michiel Rienstra, Yordi J. van de Vegte, Pim van der Harst, Niek Verweij, Stefan Kääb, Katharina Schramm, Moritz F. Sinner, Konstantin Strauch, Michael J. Cutler, Diane Fatkin, Barry London, Morten Olesen, Dan M. Roden, M. Benjamin Shoemaker, J. Gustav Smith, Mary L. Biggs, Joshua C. Bis, Jennifer A. Brody, Bruce M. Psaty, Kenneth Rice, Nona Sotoodehnia, Alessandro De Grandi, Christian Fuchsberger, Cristian Pattaro, Peter P. Pramstaller, Ian Ford, J. Wouter Jukema, Peter W. Macfarlane, Stella Trompet, Marcus Dörr, Stephan B. Felix, Uwe Völker, Stefan Weiss, Aki S. Havulinna, Antti Jula, Katri Sääksjärvi, Veikko Salomaa, Xiuqing Guo, Susan R. Heckbert, Henry J. Lin, Jerome I. Rotter, Kent D. Taylor, Jie Yao, Renée de Mutsert, Arie C. Maan, Dennis O. Mook-Kanamori, Raymond Noordam, Francesco Cucca, Jun Ding, Edward G. Lakatta, Yong Qian, Kirill V. Tarasov, Daniel Levy, Honghuang Lin, Christopher H. Newton-Cheh, Kathryn L. Lunetta, Alison D. Murray, David J. Porteous, Blair H. Smith, Bruno H. Stricker, André Uitterlinden, Marten E. van den Berg, Jeffrey Haessler, Rebecca D. Jackson, Charles Kooperberg, Ulrike Peters, Alexander P. Reiner, Eric A. Whitsel, Alvaro Alonso, Dan E. Arking, Eric Boerwinkle, Georg B. Ehret, Elsayed Z. Soliman, Christy L. Avery, Stephanie M. Gogarten, Kathleen F. Kerr, Cathy C. Laurie, Amanda A. Seyerle, Adrienne Stilp, Solmaz Assa, M. Abdullah Said, M. Yldau van der Ende, Pier D. Lambiase, Michele Orini, Julia Ramirez, Stefan Van Duijvenboden, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Patrick Sulem, Gudmar Thorleifsson, Rosa B. Thorolfsdottir, Unnur Thorsteinsdottir, Emelia J. Benjamin, Andrew Tinker, Kari Stefansson, Patrick T. Ellinor, Yalda Jamshidi, Steven A. Lubitz, and Patricia B. Munroe

Subjects
Science
Abstract

On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

Published
2020
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18. Genome-wide survey of parent-of-origin-specific associations across clinical traits derived from electronic health records

Author

Hye In Kim, Bin Ye, Jeffrey Staples, Anthony Marcketta, Chuan Gao, Alan R. Shuldiner, and Cristopher V. Van Hout

Subjects
parent-of-origin effect, imprinting, familial relationship, GWAS, electronic health record, Genetics, QH426-470
Abstract

Summary: Parent-of-origin (PoO) effects refer to the differential phenotypic impacts of genetic variants dependent on their parental inheritance due to imprinting. While PoO effects can influence complex traits, they may be poorly captured by models that do not differentiate the parental origin of the variant. The aim of this study was to conduct a genome-wide screen for PoO effects on a broad range of clinical traits derived from electronic health records (EHR) in the DiscovEHR study enriched with familial relationships. Using pairwise kinship estimates from genetic data and demographic data, we identified 22,051 offspring among 134,049 individuals in the DiscovEHR study. PoO of ~9 million variants was assigned in the offspring by comparing offspring and parental genotypes and haplotypes. We then performed genome-wide PoO association analyses across 154 quantitative and 611 binary traits extracted from EHR. Of the 732 significant PoO associations identified (p < 5 × 10−8), we attempted to replicate 274 PoO associations in the UK Biobank study with 5,015 offspring and replicated 9 PoO associations (p < 0.05). In summary, our study implements a bioinformatic and statistical approach to examine PoO effects genome-wide in a large population study enriched with familial relationships and systematically characterizes PoO effects on hundreds of clinical traits derived from EHR. Our results suggest that, while the statistical power to detect PoO effects remains modest yet, accurately modeling PoO effects has the potential to find new associations that may have been missed by the standard additive model, further enhancing the mechanistic understanding of genetic influence on complex traits.

Published
2021
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19. Associations of autozygosity with a broad range of human phenotypes

Author

David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson

Subjects
Science
Abstract

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Published
2019
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20. Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation

Author

Ming-Huei Chen, Lisa R. Yanek, Joshua D. Backman, John D. Eicher, Jennifer E. Huffman, Yoav Ben-Shlomo, Andrew D. Beswick, Laura M. Yerges-Armstrong, Alan R. Shuldiner, Jeffrey R. O’Connell, Rasika A. Mathias, Diane M. Becker, Lewis C. Becker, Joshua P. Lewis, Andrew D. Johnson, and Nauder Faraday

Subjects
platelets, platelet aggregation, snp, genetic association, exome, platelet reactivity, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10–7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20–50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.

Published
2019
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21. Polyherbal dietary supplementation for prediabetic adults: study protocol for a randomized controlled trial

Author

Termeh Feinberg, L. Susan Wieland, Larry E. Miller, Kashif Munir, Toni I. Pollin, Alan R. Shuldiner, Steve Amoils, Lisa Gallagher, Mary Bahr-Robertson, and Christopher R. D’Adamo

Subjects
Prediabetes, Botanical, Berberine, Fenugreek, American ginseng, Gymnema, Medicine (General), R5-920
Abstract

Abstract Background Prediabetes describes a state of hyperglycemia outside of normal limits that does not meet the criteria for diabetes diagnosis, is generally symptomless, and affects an estimated 38% of adults in the United States. Prediabetes typically precedes the diagnosis of type 2 diabetes, which accounts for increased morbidity and mortality. Although the use of dietary and herbal supplements is popular worldwide, and a variety of single herbal medicines have been examined for glycemic management, the potential of increasingly common polyherbal formulations to return glycemic parameters to normal ranges among adults with prediabetes remains largely unexplored. The purpose of this study is to evaluate the efficacy of a commercially available, polyherbal dietary supplement on glycemic and lipid parameters in prediabetic individuals. Methods In this multi-site, double-blinded, randomized controlled clinical trial, 40 participants with prediabetes will be randomized to either a daily oral polyherbal dietary supplement (GlucoSupreme™ Herbal; Designs for Health®, Suffield, CT, USA; containing cinnamon bark (Cinnamomum cassia), banaba leaf (Lagerstroemia speciosa standardized to 1% corosolic acid), kudzu root (Pueraria lobata standardized to 40% isoflavones), fenugreek seed (Trigonella foenum-graceum standardized to 60% saponins), gymnema leaf (Gymnema sylvestre standardized to 25% gymnemic acid), American ginseng root (Panax quinquefolius standardized to 5% ginsenosides), and berberine HCl derived from bark (Berberis aristata)) or placebo for 12 weeks. Short-, medium-, and comparatively long-term markers of glycemic control (blood glucose and fasting insulin, fructosamine, and glycated hemoglobin/A1c, respectively), and other glycemic parameters (GlycoMark, β-cell function, and insulin sensitivity/resistance) will be obtained. Lipid profile (total cholesterol, LDL, HDL, and triglycerides), inflammation (hs-CRP), progression to type 2 diabetes mellitus, as well as safety indices (ALT, AST) will be obtained. An intention-to-treat analysis will be used to assess changes in study outcomes. Discussion Treatment options for adults with prediabetes are currently limited. This study aims to evaluate the safety and efficacy of a commercially available dietary supplement in the popular, but as yet insufficiently studied, category of polyherbal formulas for the management of glycemic parameters and other biomarkers associated with prediabetes. Trial registration ClinicalTrials.gov, ID: NCT03388762. Retrospectively registered on 4 January 2018.

Published
2019
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22. Clinical case study meets population cohort: identification of a BRCA1 pathogenic founder variant in Orcadians

Author

Shona M. Kerr, Emma Cowan, Lucija Klaric, Christine Bell, Dawn O’Sullivan, David Buchanan, Joseph J. Grzymski, Cristopher V. van Hout, Gannie Tzoneva, Alan R. Shuldiner, James F. Wilson, and Zosia Miedzybrodzka

Subjects
Scotland/epidemiology, Breast Neoplasms/genetics, BRCA2 Protein/genetics, State Medicine, Gene Frequency, Haplotypes, Genetics, BRCA1 Protein/genetics, Humans, Female, Genetic Predisposition to Disease, Genetic Testing, Ovarian Neoplasms/epidemiology, Genetics (clinical)
Abstract

We multiply ascertained the BRCA1 pathogenic missense variant c.5207T > C; p.Val1736Ala (V1736A) in clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. We sought to investigate the frequency and clinical relevance of this variant in those of Orcadian ancestry as an exemplar of the value of population cohorts in clinical care, especially in isolated populations. Oral history and birth, marriage and death registrations indicated genealogical linkage of the clinical cases to ancestors from the Isle of Westray, Orkney. Further clinical cases were identified through targeted testing for V1736A in women of Orcadian ancestry attending National Health Service (NHS) genetic clinics for breast and ovarian cancer family risk assessments. The variant segregates with female breast and ovarian cancer in clinically ascertained cases. Separately, exome sequence data from 2088 volunteer participants with three or more Orcadian grandparents, in the ORCADES research cohort, was interrogated to estimate the population prevalence of V1736A in Orcadians. The effects of the variant were assessed using Electronic Health Record (EHR) linkage. Twenty out of 2088 ORCADES research volunteers (~1%) carry V1736A, with a common haplotype around the variant. This allele frequency is ~480-fold higher than in UK Biobank participants. Cost-effectiveness of population screening for BRCA1 founder pathogenic variants has been demonstrated at a carrier frequency below the ~1% observed here. Thus we suggest that Orcadian women should be offered testing for the BRCA1 V1736A founder pathogenic variant, starting with those with known Westray ancestry.

Published
2023

23. Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium

Author

Bridget M Lin, Kelsey E Grinde, Jennifer A Brody, Charles E Breeze, Laura M Raffield, Josyf C Mychaleckyj, Timothy A Thornton, James A Perry, Leslie J Baier, Lisa de las Fuentes, Xiuqing Guo, Benjamin D Heavner, Robert L Hanson, Yi-Jen Hung, Huijun Qian, Chao A Hsiung, Shih-Jen Hwang, Margaret R Irvin, Deepti Jain, Tanika N Kelly, Sayuko Kobes, Leslie Lange, James P Lash, Yun Li, Xiaoming Liu, Xuenan Mi, Solomon K Musani, George J Papanicolaou, Afshin Parsa, Alex P Reiner, Shabnam Salimi, Wayne H-H Sheu, Alan R Shuldiner, Kent D Taylor, Albert V Smith, Jennifer A Smith, Adrienne Tin, Dhananjay Vaidya, Robert B Wallace, Kenichi Yamamoto, Saori Sakaue, Koichi Matsuda, Yoichiro Kamatani, Yukihide Momozawa, Lisa R Yanek, Betsi A Young, Wei Zhao, Yukinori Okada, Gonzalo Abecasis, Bruce M Psaty, Donna K Arnett, Eric Boerwinkle, Jianwen Cai, Ida Yii-Der Chen, Adolfo Correa, L Adrienne Cupples, Jiang He, Sharon LR Kardia, Charles Kooperberg, Rasika A Mathias, Braxton D Mitchell, Deborah A Nickerson, Steve T Turner, Vasan S Ramachandran, Jerome I Rotter, Daniel Levy, Holly J Kramer, Anna Köttgen, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Kidney Working Group, Stephen S Rich, Dan-Yu Lin, Sharon R Browning, and Nora Franceschini

Subjects
Whole genome sequencing, Kidney traits, Rare variants, Ancestry-specific variants, Medicine, Medicine (General), R5-920
Abstract

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10−11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10−9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10−9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10−9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10−9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

Published
2021
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24. Circulating sex hormone binding globulin levels are modified with intensive lifestyle intervention, but their changes did not independently predict diabetes risk in the Diabetes Prevention Program

Author

Mike Reidy, Christine Lee, Michael Brändle, Sherita Hill Golden, Samuel Dagogo-Jack, David Kessler, Elizabeth Barrett-Connor, Steve Jones, Ling Chen, Judith Wylie-Rosett, Ping Zhang, Paula Williamson, Carlos Lorenzo, Leigh Perreault, Dana Dabelea, Santica Marcovina, Rachel Williams, Marie Smith, Carmen Pal, Patricia Katz, William H. Herman, Sharon L Edelstein, Yong Ma, Vanita R Aroda, Costas A Christophi, Catherine Kim, Sherita H Golden, Edward Horton, Kieren J Mather, George A. Bray, Kishore Gadde, Iris W. Culbert, Jennifer Arceneaux, Annie Chatellier, Amber Dragg, Catherine M. Champagne, Crystal Duncan, Barbara Eberhardt, Frank Greenway, Fonda G. Guillory, April A. Herbert, Michael L. Jeffirs, Betty M. Kennedy, Erma Levy, Monica Lockett, Jennifer C. Lovejoy, Laura H. Morris, Lee E. Melancon, Donna H. Ryan, Deborah A. Sanford, Kenneth G. Smith, Lisa L. Smith, Julia A. St, Richard T. Tulley Amant, Paula C. Vicknair, Donald Williamson, Jeffery J. Zachwieja, Kenneth S. Polonsky, Janet Tobian, David A. Ehrmann, Margaret J. Matulik, Bart Clark, Kirsten Czech, Catherine DeSandre, Ruthanne Hilbrich, Wylie McNabb, Ann R. Semenske, Jose F. Caro, Kevin Furlong, Barry J. Goldstein, Pamela G. Watson, Kellie A. Smith, Jewel Mendoza, Wendi Wildman, Renee Liberoni, John Spandorfer, Constance Pepe, Richard P. Donahue, Ronald B. Goldberg, Ronald Prineas, Jeanette Calles, Juliet Ojito, Patricia Rowe, Paul Cassanova-Romero, Sumaya Castillo-Florez, Hermes J. Florez, Anna Giannella, Lascelles Kirby, Carmen Larreal, Olga Lara, Valerie McLymont, Jadell Mendez, Arlette Perry, Patrice Saab, Beth Veciana, Steven M. Haffner, Helen P. Hazuda, Maria G. Montez, Kathy Hattaway, Arlene Martinez, Tatiana Walker, Richard F. Hamman, Patricia V. Nash, Sheila C. Steinke, Lisa Testaverde, Denise R. Anderson, Larry B. Ballonoff, Alexis Bouffard, Brian Bucca, B. Ned Calonge, Lynne Delve, Martha Farago, James O. Hill, Shelley R. Hoyer, Tonya Jenkins, Bonnie T. Jortberg, Dione Lenz, Marsha Miller, David W. Price, Judith G. Regensteiner, Helen Seagle, Carissa M. Smith, Brent VanDorsten, Edward S. Horton, Kathleen E. Lawton, Catherine S. Poirier, Kati Swift, Ronald A. Arky, Marybeth Bryant, Jacqueline P. Burke, Enrique Caballero, Karen M. Callaphan, Barbara Fargnoli, Therese Franklin, Om P. Ganda, Ashley Guidi, Mathew Guido, Sharon D. Jackson, Alan M. Jacobsen, Lori Lambert, Sarah Ledbury, Margaret Kocal, Lyn M. Kula, Maureen A. Malloy, Maryanne Nicosia, Cathryn F. Oldmixon, Jocelyn Pan, Marizel Quitingon, Stacy Rubtchinsky, Jessica Sansoucy, Dana Schweizer, Ellen W. Seely, Donald Simonson, Fannie Smith, Caren G. Solomon, Jeanne Spellman, James Warram, Steven E. Kahn, Brenda K. Montgomery, Wilfred Fujimoto, Robert H. Knopp, Edward W. Lipkin, Michelle Marr, Ivy Morgan-Taggart, Anne Murillo, Dace Trence, Lonnese Taylor, April Thomas, Elaine C. Tsai, Abbas E. Kitabchi, Mary E. Murphy, Laura Taylor, Jennifer Dolgoff, William B. Applegate, Michael Bryer-Ash, Debra Clark, Sandra L. Frieson, Uzoma Ibebuogu, Raed Imseis, Helen Lambeth, Lynne C. Lichtermann, Hooman Oktaei, Harriet Ricks, Lily M.K. Rutledge, Amy R. Sherman, Clara M. Smith, Judith E. Soberman, Beverly Williams-Cleaves, Boyd E. Metzger, Mark E. Molitch, Mariana K. Johnson, Daphne T. Adelman, Catherine Behrends, Michelle Cook, Marian Fitzgibbon, Mimi M. Giles, Deloris Heard, Cheryl K.H. Johnson, Diane Larsen, Anne Lowe, Megan Lyman, David McPherson, Samsam C. Penn, Thomas Pitts, Renee Reinhart, Susan Roston, Pamela A. Schinleber, David M. Nathan, Charles McKitrick, Heather Turgeon, Mary Larkin, Kathy Abbott, Ellen Anderson, Laurie Bissett, Kristy Bondi, Enrico Cagliero, Jose C. Florez, Kali D’Anna, Linda Delahanty, Valerie Goldman, Peter Lou, Alexandra Poulos, Elyse Raymond, Christine Stevens, Beverly Tseng, Jerrold M. Olefsky, Mary Lou Carrion-Petersen, Madeline Beltran, Lauren N. Claravall, Jonalle M. Dowden, Steven V. Edelman, Robert R. Henry, Javiva Horne, Marycie Lamkin, Simona Szerdi Janesch, Diana Leos, Sunder Mudaliar, William Polonsky, Jean Smith, Jennifer Torio-Hurley, Karen Vejvoda, F. Xavier Pi-Sunyer, Jane E. Lee, David B. Allison, Nnenna Agharanya, Nancy J. Aronoff, Maria Baldo, Jill P. Crandall, Sandra T. Foo, Susan Hagamen, Jose A. Luchsinger, Kathy Parkes, Mary Beth Pena, Ellen S. Rooney, Gretchen E.H. Van Wye, Kristine A. Viscovich, David G. Marrero, Kieren J. Mather, Melvin J. Prince, Susie M. Kelly, Marcia A. Jackson, Gina McAtee, Paula Putenney, Ronald T. Ackermann, Carolyn M. Cantrell, Yolanda F. Dotson, Edwin S. Fineberg, Megan Fultz, John C. Guare, Angela Hadden, James M. Ignaut, Marion S. Kirkman, Erin O’Kelly Phillips, Beverly D. Porter, Paris J. Roach, Nancy D. Rowland, Madelyn L. Wheeler, Vanita Aroda, Robert E. Ratner, Gretchen Youssef, Sue Shapiro, Catherine Bavido-Arrage, Geraldine Boggs, Marjorie Bronsord, Ernestine Brown, Wayman W. Cheatham, Susan Cola, Cindy Evans, Peggy Gibbs, Tracy Kellum, Renee Wiggins, Milvia Lagarda, Lilia Leon, Claresa Levatan, Milajurine Lindsay, Asha K. Nair, Maureen Passaro, Angela Silverman, Gabriel Uwaifo, Debra Wells-Thayer, Mohammed F. Saad, Karol Watson, Maria Budget, Sujata Jinagouda, Medhat Botrous, Khan Akbar, Claudia Conzues, Perpetua Magpuri, Kathy Ngo, Amer Rassam, Debra Waters, Kathy Xapthalamous, Julio V. Santiago, Neil H. White, Angela L. Brown, Samia Das, Prajakta Khare-Ranade, Tamara Stich, Ana Santiago, Edwin Fisher, Emma Hurt, Tracy Jones, Michelle Kerr, Lucy Ryder, Cormarie Wernimont, Christopher D. Saudek, Vanessa Bradley, Emily Sullivan, Tracy Whittington, Caroline Abbas, Adrienne Allen, Frederick L. Brancati, Sharon Cappelli, Jeanne M. Clark, Jeanne B. Charleston, Janice Freel, Katherine Horak, Alicia Greene, Dawn Jiggetts, Deloris Johnson, Hope Joseph, Kimberly Loman, Henry Mosley, John Reusing, Richard R. Rubin, Alafia Samuels, Thomas Shields, Shawne Stephens, Kerry J. Stewart, LeeLana Thomas, Evonne Utsey, David S. Schade, Karwyn S. Adams, Janene L. Canady, Carolyn Johannes, Claire Hemphill, Penny Hyde, Leslie F. Atler, Patrick J. Boyle, Mark R. Burge, Lisa Chai, Kathleen Colleran, Ysela Gonzales, Doris A. Hernandez-McGinnis, Carolyn King, Sofya Rubinchik, Willette Senter, Jill Crandall, Harry Shamoon, Janet O. Brown, Gilda Trandafirescu, Elsie Adorno, Liane Cox, Helena Duffy, Samuel Engel, Allison Friedler, Angela Goldstein, Crystal J. Howard-Century, Jennifer Lukin, Stacey Kloiber, Nadege Longchamp, Helen Martinez, Dorothy Pompi, Jonathan Scheindlin, Elissa Violino, Elizabeth A. Walker, Elise Zimmerman, Joel Zonszein, Trevor Orchard, Rena R. Wing, Susan Jeffries, Gaye Koenning, M. Kaye Kramer, Susan Barr, Catherine Benchoff, Miriam Boraz, Lisa Clifford, Rebecca Culyba, Marlene Frazier, Ryan Gilligan, Stephanie Guimond, Susan Harrier, Louann Harris, Andrea Kriska, Bonny Rockette-Wagner, Qurashia Manjoo, Monica Mullen, Alicia Noel, Amy Otto, Jessica Pettigrew, Debra Rubinstein, Linda Semler, Cheryl F. Smith, Elizabeth Venditti, Valarie Weinzierl, Katherine V. Williams, Tara Wilson, Richard F. Arakaki, Renee W. Latimer, Narleen K. Baker-Ladao, Mae K. Isonaga, Ralph Beddow, Nina E. Bermudez, Lorna Dias, Jillian Inouye, Marjorie K. Mau, John S. Melish, Kathy Mikami, Pharis Mohideen, Sharon K. Odom, Raynette U. Perry, Robin E. Yamamoto, William C. Knowler, Norman Cooeyate, Mary A. Hoskin, Carol A. Percy, Alvera Enote, Camille Natewa, Kelly J. Acton, Vickie L. Andre, Rosalyn Barber, Shandiin Begay, Peter H. Bennett, Mary Beth Benson, Evelyn C. Bird, Brenda A. Broussard, Brian C. Bucca, Marcella Chavez, Sherron Cook, Jeff Curtis, Tara Dacawyma, Matthew S. Doughty, Roberta Duncan, Charlotte Dodge, Cyndy Edgerton, Jacqueline M. Ghahate, Justin Glass, Martia Glass, Dorothy Gohdes, Wendy Grant, Robert L. Hanson, Ellie Horse, Louise E. Ingraham, Merry Jackson, Priscilla Jay, Roylen S. Kaskalla, Kathleen M. Kobus, Jonathan Krakoff, Jason Kurland, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Yolanda Nashboo, Julie A. Nelson, Steven Poirier, Evette Polczynski, Christopher Piromalli, Jeanine Roumain, Debra Rowse, Robert J. Roy, Sandra Sangster, Janet Sewenemewa, Miranda Smart, Darryl Tonemah, Charlton Wilson, Michelle Yazzie, Raymond Bain, Sarah Fowler, Marinella Temprosa, Michael D. Larsen, Tina Brenneman, Sharon L. Edelstein, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezabeh, Nicole Butler, Jackie Callaghan, Caitlin E. Carter, Costas Christophi, Gregory M. Dwyer, Mary Foulkes, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Kristina L. Grimes, Nisha Grover-Fairchild, Lori Haffner, Heather Hoffman, Kathleen Jablonski, Tara L. Jones, Richard Katz, Preethy Kolinjivadi, John M. Lachin, Pamela Mucik, Robert Orlosky, Qing Pan, Susan Reamer, James Rochon, Alla Sapozhnikova, Hanna Sherif, Charlotte Stimpson, Ashley Hogan Tjaden, Fredricka Walker-Murray, Elizabeth M. Venditti, Andrea M. Kriska, Valerie Weinzierl, Jessica Harting, F. Alan Aldrich, John Albers, Greg Strylewicz, R. Eastman, Judith Fradkin, Sanford Garfield, Edward Gregg, Morton B. Brown, David Altshuler, Liana K. Billings, Maegan Harden, Toni I. Pollin, Alan R. Shuldiner, Paul W. Franks, and Marie-France Hivert

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Introduction Sex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methods This is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.Results ILS resulted in significantly higher increases (postmenopausal women: p

Published
2020
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25. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Author

Viktoria Gusarova, Colm O’Dushlaine, Tanya M. Teslovich, Peter N. Benotti, Tooraj Mirshahi, Omri Gottesman, Cristopher V. Van Hout, Michael F. Murray, Anubha Mahajan, Jonas B. Nielsen, Lars Fritsche, Anders Berg Wulff, Daniel F. Gudbjartsson, Marketa Sjögren, Connor A. Emdin, Robert A. Scott, Wen-Jane Lee, Aeron Small, Lydia C. Kwee, Om Prakash Dwivedi, Rashmi B. Prasad, Shannon Bruse, Alexander E. Lopez, John Penn, Anthony Marcketta, Joseph B. Leader, Christopher D. Still, H. Lester Kirchner, Uyenlinh L. Mirshahi, Amr H. Wardeh, Cassandra M. Hartle, Lukas Habegger, Samantha N. Fetterolf, Teresa Tusie-Luna, Andrew P. Morris, Hilma Holm, Valgerdur Steinthorsdottir, Patrick Sulem, Unnur Thorsteinsdottir, Jerome I. Rotter, Lee-Ming Chuang, Scott Damrauer, David Birtwell, Chad M. Brummett, Amit V. Khera, Pradeep Natarajan, Marju Orho-Melander, Jason Flannick, Luca A. Lotta, Cristen J. Willer, Oddgeir L. Holmen, Marylyn D. Ritchie, David H. Ledbetter, Andrew J. Murphy, Ingrid B. Borecki, Jeffrey G. Reid, John D. Overton, Ola Hansson, Leif Groop, Svati H. Shah, William E. Kraus, Daniel J. Rader, Yii-Der I. Chen, Kristian Hveem, Nicholas J. Wareham, Sekar Kathiresan, Olle Melander, Kari Stefansson, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Goncalo R. Abecasis, David Altshuler, Jose C. Florez, Michael Boehnke, Mark I. McCarthy, George D. Yancopoulos, David J. Carey, Alan R. Shuldiner, Aris Baras, Frederick E. Dewey, and Jesper Gromada

Subjects
Science
Abstract

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
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26. Evaluation of WISP1 as a candidate gene for bone mineral density in the Old Order Amish

Author

Xing Wang, Shabnam Salimi, Zhongliang Deng, James Perry, Kathleen A. Ryan, Zhizhen Li, Dongfang Liu, Elizabeth Streeten, Alan R. Shuldiner, and Mao Fu

Subjects
Medicine, Science
Abstract

Abstract Wnt1-inducible signaling pathway protein-1 (WISP1) is a novel target of the Wnt pathway for modulating osteogenesis and improving bone strength. However, it is not clear if genetic variants in the WISP1 region are associated with bone mineral density (BMD) in human. The aim of this study is to investigate the role of genetic variation in WISP1 gene as a determinant of BMD in 1,510 Old Order Amish (OOA). We performed regional association analysis of 58 tag variants within 5 kb upstream and downstream to WISP1 with BMD and found 5 variants that were associated with BMD at multiple skeletal sites (P values from 2.89 × 10−6 to 1.62 × 10−2), with some significant associations even after adjustment for multiple comparisons. To replicate these results in an independent dataset, we performed a look-up of BMD associations with these variants in European ancestry subjects from the large GEFOS Consortium and observed the nominal associations of two of these variants with BMD (P values: 0.031 to 0.048). In conclusion, we have demonstrated that genetic variants surrounding WISP1 are associated with BMD at multiple skeletal sites in the OOA, thus influencing osteoporosis risk. These results support a role for the WISP1 gene on influencing variation in BMD.

Published
2018
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27. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3

Published
2021
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28. Publisher Correction: A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Author

Min-A Jhun, Michael Mendelson, Rory Wilson, Rahul Gondalia, Roby Joehanes, Elias Salfati, Xiaoping Zhao, Kim Valeska Emilie Braun, Anh Nguyet Do, Åsa K. Hedman, Tao Zhang, Elena Carnero-Montoro, Jincheng Shen, Traci M. Bartz, Jennifer A. Brody, May E. Montasser, Jeff R. O’Connell, Chen Yao, Rui Xia, Eric Boerwinkle, Megan Grove, Weihua Guan, Pfeiffer Liliane, Paula Singmann, Martina Müller-Nurasyid, Thomas Meitinger, Christian Gieger, Annette Peters, Wei Zhao, Erin B. Ware, Jennifer A. Smith, Klodian Dhana, Joyce van Meurs, Andre Uitterlinden, Mohammad Arfan Ikram, Mohsen Ghanbari, Deugi Zhi, Stefan Gustafsson, Lars Lind, Shengxu Li, Dianjianyi Sun, Tim D. Spector, Yii-der Ida Chen, Coleen Damcott, Alan R. Shuldiner, Devin M. Absher, Steve Horvath, Philip S. Tsao, Sharon Kardia, Bruce M. Psaty, Nona Sotoodehnia, Jordana T. Bell, Erik Ingelsson, Wei Chen, Abbas Dehghan, Donna K. Arnett, Melanie Waldenberger, Lifang Hou, Eric A. Whitsel, Andrea Baccarelli, Daniel Levy, Myriam Fornage, Marguerite R. Irvin, and Themistocles L. Assimes

Subjects
Science
Published
2021
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29. A population-specific reference panel empowers genetic studies of Anabaptist populations

Author

Liping Hou, Rachel L. Kember, Jared C. Roach, Jeffrey R. O’Connell, David W. Craig, Maja Bucan, William K. Scott, Margaret Pericak-Vance, Jonathan L. Haines, Michael H. Crawford, Alan R. Shuldiner, and Francis J. McMahon

Subjects
Medicine, Science
Abstract

Abstract Genotype imputation is a powerful strategy for achieving the large sample sizes required for identification of variants underlying complex phenotypes, but imputation of rare variants remains problematic. Genetically isolated populations offer one solution, however population-specific reference panels are needed to assure optimal imputation accuracy and allele frequency estimation. Here we report the Anabaptist Genome Reference Panel (AGRP), the first whole-genome catalogue of variants and phased haplotypes in people of Amish and Mennonite ancestry. Based on high-depth whole-genome sequence (WGS) from 265 individuals, the AGRP contains >12 M high-confidence single nucleotide variants and short indels, of which ~12.5% are novel. These Anabaptist-specific variants were more deleterious than variants with comparable frequencies observed in the 1000 Genomes panel. About 43,000 variants showed enriched allele frequencies in AGRP, consistent with drift. When combined with the 1000 Genomes Project reference panel, the AGRP substantially improved imputation, especially for rarer variants. The AGRP is freely available to researchers through an imputation server.

Published
2017
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30. Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis

Author

Christina G. Tise, Leslie E. Anforth, Albert E. Zhou, James A. Perry, Patrick F. McArdle, Elizabeth A. Streeten, Alan R. Shuldiner, and Laura M. Yerges-Armstrong

Subjects
Serum sulfate, SLC13A1, DHEA, DHEA-S, Sulfation, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Context: Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10−20). Objective: To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis. Design: Retrospective cohort study. Setting: Academic research. Patients: Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study. Main outcome measures: DHEA, DHEA-S, and DHEA-S/DHEA ratio. Results: Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10−13), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03). Conclusions: Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.

Published
2017
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31. Germline Mutations in CIDEB and Protection against Liver Disease

Author

Niek Verweij, Mary E. Haas, Jonas B. Nielsen, Olukayode A. Sosina, Minhee Kim, Parsa Akbari, Tanima De, George Hindy, Jonas Bovijn, Trikaldarshi Persaud, Lawrence Miloscio, Mary Germino, Lampros Panagis, Kyoko Watanabe, Joelle Mbatchou, Marcus Jones, Michelle LeBlanc, Suganthi Balasubramanian, Craig Lammert, Sofia Enhörning, Olle Melander, David J. Carey, Christopher D. Still, Tooraj Mirshahi, Daniel J. Rader, Prodromos Parasoglou, Johnathon R. Walls, John D. Overton, Jeffrey G. Reid, Aris Economides, Michael N. Cantor, Brian Zambrowicz, Andrew J. Murphy, Goncalo R. Abecasis, Manuel A.R. Ferreira, Eriks Smagris, Viktoria Gusarova, Mark Sleeman, George D. Yancopoulos, Jonathan Marchini, Hyun M. Kang, Katia Karalis, Alan R. Shuldiner, Giusy Della Gatta, Adam E. Locke, Aris Baras, and Luca A. Lotta

Subjects
General Medicine
Published
2022

32. Functional characterization of a novel p.Ser76Thr variant in IGFBP4 that associates with body mass index in American Indians

Author

Yunhua L, Muller, Michael, Saporito, Samantha, Day, Khushdeep, Bandesh, Cigdem, Koroglu, Sayuko, Kobes, William C, Knowler, Robert L, Hanson, Cristopher V, Van Hout, Alan R, Shuldiner, Clifton, Bogardus, and Leslie J, Baier

Subjects
Polymorphism, Single Nucleotide, Body Mass Index, PPAR gamma, Mice, Phosphatidylinositol 3-Kinases, Insulin-Like Growth Factor Binding Protein 4, Indians, North American, Genetics, Animals, Humans, Obesity, Proto-Oncogene Proteins c-akt, American Indian or Alaska Native, Genetics (clinical)
Abstract

Insulin-like growth factor binding protein 4 (IGFBP4) is involved in adipogenesis, and IGFBP4 null mice have decreased body fat through decreased PPAR-γ expression. In the current study, we assessed whether variation in the IGFBP4 coding region influences body mass index (BMI) in American Indians who are disproportionately affected by obesity. Whole exome sequence data from a population-based sample of 6779 American Indians with longitudinal measures of BMI were used to identify variation in IGFBP4 that associated with BMI. A novel variant that predicts a p.Ser76Thr in IGFBP4 (Thr-allele frequency = 0.02) was identified which associated with the maximum BMI measured during adulthood (BMI 39.8 kg/m

Published
2022

35. Evidence of Neurovascular Water Exchange and Endothelial Vascular Dysfunction in Schizophrenia: An Exploratory Study

Author

Eric L Goldwaser, Danny J J Wang, Bhim M Adhikari, Joshua Chiappelli, Xingfeng Shao, Jiaao Yu, Tong Lu, Shuo Chen, Wyatt Marshall, Alexa Yuen, Mark Kvarta, Yizhou Ma, Xiaoming Du, Si Gao, Osamah Saeedi, Heather Bruce, Patrick Donnelly, Hugh O’Neill, Alan R Shuldiner, Braxton D Mitchell, Peter Kochunov, and L Elliot Hong

Subjects
Psychiatry and Mental health
Abstract

Background and Hypothesis Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood–brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD. Study Design We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = 32 SSD) is impaired in SSD and associated with clinical symptoms. Peripheral vascular endothelial health was examined by brachial artery flow-mediated dilation (n = 44 HC, n = 37 SSD) to examine whether centrally measured Kw is related to endothelial functions. Study Results Whole-brain average Kw was significantly reduced in SSD (P = .007). Exploratory analyses demonstrated neurovascular water exchange reductions in the right parietal lobe, including the supramarginal gyrus (P = .002) and postcentral gyrus (P = .008). Reduced right superior corona radiata (P = .001) and right angular gyrus Kw (P = .006) was associated with negative symptoms. Peripheral endothelial function was also significantly reduced in SSD (P = .0001). Kw in 94% of brain regions in HC positively associated with peripheral endothelial function, which was not observed in SSD, where the correlation was inversed in 52% of brain regions. Conclusions This study provides initial evidence of neurovascular water exchange abnormalities, which appeared clinically associated, especially with negative symptoms, in schizophrenia.

Published
2023

36. Data from Identification of a Variant in KDR Associated with Serum VEGFR2 and Pharmacodynamics of Pazopanib

Author

Alan R. Shuldiner, Mark J. Ratain, Braxton D. Mitchell, Nancy J. Cox, Jeffrey R. O'Connell, Lini N. Pandite, Lon R. Cardon, Yuan Liu, Nan Bing, Paul A. Wilson, Matthew R. Levine, Vasiliki Thomeas, Eric R. Gamazon, Dara Torgerson, Soma Das, Theodore G. Karrison, Kathleen A. Ryan, Emily Kistner-Griffin, Yu-Ching Cheng, Chun-Fang Xu, and Michael L. Maitland

Abstract

Purpose: VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors.Experimental Design: We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy.Results: rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (P = 2.7 × 10−37). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (P = 0.01).Conclusion: Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors. Clin Cancer Res; 21(2); 365–72. ©2014 AACR.

Published
2023

37. Pharmacogenetics of SGLT2 Inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker

Author

Simeon I. Taylor, Hua-Ren Cherng, Zhinous Shahidzadeh Yazdi, May E. Montasser, Hilary B. Whitlatch, Braxton D. Mitchell, Alan R. Shuldiner, Elizabeth A. Streeten, and Amber L. Beitelshees

Subjects
Article
Abstract

BackgroundSGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes – including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.MethodsCanagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses – including drug-induced increases in urinary excretion of glucose, sodium, and uric acid.ResultsThis pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; p=6×10-5), serum creatinine (+0.05 mg/dL; p=8×10-4), and serum uric acid (-0.90 mg/dL; p=5×10-10). The effects of sex on glucosuria depended upon how data were normalized. Whereas males’ responses were ∼60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73m2.ConclusionsNormalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study (NCT02891954) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function.RegistrationNCT02462421 (clinicaltrials.gov)FundingResearch grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.

Published
2023

38. Genome-wide significant risk loci for mood disorders in the Old Order Amish founder population

Author

Elizabeth M. Humphries, Kwangmi Ahn, Rachel L. Kember, Fabiana L. Lopes, Evelina Mocci, Juan M. Peralta, John Blangero, David C. Glahn, Fernando S. Goes, Peter P. Zandi, Peter Kochunov, Cristopher Van Hout, Alan R. Shuldiner, Toni I. Pollin, Braxton D. Mitchell, Maja Bucan, L. Elliot Hong, Francis J. McMahon, and Seth A. Ament

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, Molecular Biology
Published
2023

39. From Genotype to Phenotype: Nonsense Variants in SLC13A1 Are Associated with Decreased Serum Sulfate and Increased Serum Aminotransferases

Author

Christina G. Tise, James A. Perry, Leslie E. Anforth, Mary A. Pavlovich, Joshua D. Backman, Kathleen A. Ryan, Joshua P. Lewis, Jeffrey R. O’Connell, Laura M. Yerges-Armstrong, and Alan R. Shuldiner

Subjects
SLC13A1, serum sulfate, loss-of-function variants, Old Order Amish, GWAS/ExWAS, Genetics, QH426-470
Abstract

Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10−8) and 27.3% (P = 6.9 × 10−14) decrease in serum sulfate, respectively (P = 8.8 × 10-20 for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10−12). Consistent with sulfate’s role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1. This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity.

Published
2016
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40. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Yingchang Lu, Felix R. Day, Stefan Gustafsson, Martin L. Buchkovich, Jianbo Na, Veronique Bataille, Diana L. Cousminer, Zari Dastani, Alexander W. Drong, Tõnu Esko, David M. Evans, Mario Falchi, Mary F. Feitosa, Teresa Ferreira, Åsa K. Hedman, Robin Haring, Pirro G. Hysi, Mark M. Iles, Anne E. Justice, Stavroula Kanoni, Vasiliki Lagou, Rui Li, Xin Li, Adam Locke, Chen Lu, Reedik Mägi, John R. B. Perry, Tune H. Pers, Qibin Qi, Marianna Sanna, Ellen M. Schmidt, William R. Scott, Dmitry Shungin, Alexander Teumer, Anna A. E. Vinkhuyzen, Ryan W. Walker, Harm-Jan Westra, Mingfeng Zhang, Weihua Zhang, Jing Hua Zhao, Zhihong Zhu, Uzma Afzal, Tarunveer Singh Ahluwalia, Stephan J. L. Bakker, Claire Bellis, Amélie Bonnefond, Katja Borodulin, Aron S. Buchman, Tommy Cederholm, Audrey C. Choh, Hyung Jin Choi, Joanne E. Curran, Lisette C. P. G. M. de Groot, Philip L. De Jager, Rosalie A. M. Dhonukshe-Rutten, Anke W. Enneman, Elodie Eury, Daniel S. Evans, Tom Forsen, Nele Friedrich, Frédéric Fumeron, Melissa E. Garcia, Simone Gärtner, Bok-Ghee Han, Aki S. Havulinna, Caroline Hayward, Dena Hernandez, Hans Hillege, Till Ittermann, Jack W. Kent, Ivana Kolcic, Tiina Laatikainen, Jari Lahti, Irene Mateo Leach, Christine G. Lee, Jong-Young Lee, Tian Liu, Youfang Liu, Stéphane Lobbens, Marie Loh, Leo-Pekka Lyytikäinen, Carolina Medina-Gomez, Karl Michaëlsson, Mike A. Nalls, Carrie M. Nielson, Laticia Oozageer, Laura Pascoe, Lavinia Paternoster, Ozren Polašek, Samuli Ripatti, Mark A. Sarzynski, Chan Soo Shin, Nina Smolej Narančić, Dominik Spira, Priya Srikanth, Elisabeth Steinhagen-Thiessen, Yun Ju Sung, Karin M. A. Swart, Leena Taittonen, Toshiko Tanaka, Emmi Tikkanen, Nathalie van der Velde, Natasja M. van Schoor, Niek Verweij, Alan F. Wright, Lei Yu, Joseph M. Zmuda, Niina Eklund, Terrence Forrester, Niels Grarup, Anne U. Jackson, Kati Kristiansson, Teemu Kuulasmaa, Johanna Kuusisto, Peter Lichtner, Jian'an Luan, Anubha Mahajan, Satu Männistö, Cameron D. Palmer, Janina S. Ried, Robert A. Scott, Alena Stancáková, Peter J. Wagner, Ayse Demirkan, Angela Döring, Vilmundur Gudnason, Douglas P. Kiel, Brigitte Kühnel, Massimo Mangino, Barbara Mcknight, Cristina Menni, Jeffrey R. O'Connell, Ben A. Oostra, Alan R. Shuldiner, Kijoung Song, Liesbeth Vandenput, Cornelia M. van Duijn, Peter Vollenweider, Charles C. White, Michael Boehnke, Yvonne Boettcher, Richard S. Cooper, Nita G. Forouhi, Christian Gieger, Harald Grallert, Aroon Hingorani, Torben Jørgensen, Pekka Jousilahti, Mika Kivimaki, Meena Kumari, Markku Laakso, Claudia Langenberg, Allan Linneberg, Amy Luke, Colin A. Mckenzie, Aarno Palotie, Oluf Pedersen, Annette Peters, Konstantin Strauch, Bamidele O. Tayo, Nicholas J. Wareham, David A. Bennett, Lars Bertram, John Blangero, Matthias Blüher, Claude Bouchard, Harry Campbell, Nam H. Cho, Steven R. Cummings, Stefan A. Czerwinski, Ilja Demuth, Rahel Eckardt, Johan G. Eriksson, Luigi Ferrucci, Oscar H. Franco, Philippe Froguel, Ron T. Gansevoort, Torben Hansen, Tamara B. Harris, Nicholas Hastie, Markku Heliövaara, Albert Hofman, Joanne M. Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Paul B. Knekt, Seppo Koskinen, Peter Kovacs, Terho Lehtimäki, Lars Lind, Yongmei Liu, Eric S. Orwoll, Clive Osmond, Markus Perola, Louis Pérusse, Olli T. Raitakari, Tuomo Rankinen, D. C. Rao, Treva K. Rice, Fernando Rivadeneira, Igor Rudan, Veikko Salomaa, Thorkild I. A. Sørensen, Michael Stumvoll, Anke Tönjes, Bradford Towne, Gregory J. Tranah, Angelo Tremblay, André G. Uitterlinden, Pim van der Harst, Erkki Vartiainen, Jorma S. Viikari, Veronique Vitart, Marie-Claude Vohl, Henry Völzke, Mark Walker, Henri Wallaschofski, Sarah Wild, James F. Wilson, Loïc Yengo, D. Timothy Bishop, Ingrid B. Borecki, John C. Chambers, L. Adrienne Cupples, Abbas Dehghan, Panos Deloukas, Ghazaleh Fatemifar, Caroline Fox, Terrence S. Furey, Lude Franke, Jiali Han, David J. Hunter, Juha Karjalainen, Fredrik Karpe, Robert C. Kaplan, Jaspal S. Kooner, Mark I. McCarthy, Joanne M. Murabito, Andrew P. Morris, Julia A. N. Bishop, Kari E. North, Claes Ohlsson, Ken K. Ong, Inga Prokopenko, J. Brent Richards, Eric E. Schadt, Tim D. Spector, Elisabeth Widén, Cristen J. Willer, Jian Yang, Erik Ingelsson, Karen L. Mohlke, Joel N. Hirschhorn, John Andrew Pospisilik, M. Carola Zillikens, Cecilia Lindgren, Tuomas Oskari Kilpeläinen, and Ruth J. F. Loos

Subjects
Science
Abstract

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Published
2016
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41. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Cristian Pattaro, Alexander Teumer, Mathias Gorski, Audrey Y. Chu, Man Li, Vladan Mijatovic, Maija Garnaas, Adrienne Tin, Rossella Sorice, Yong Li, Daniel Taliun, Matthias Olden, Meredith Foster, Qiong Yang, Ming-Huei Chen, Tune H. Pers, Andrew D. Johnson, Yi-An Ko, Christian Fuchsberger, Bamidele Tayo, Michael Nalls, Mary F. Feitosa, Aaron Isaacs, Abbas Dehghan, Pio d’Adamo, Adebowale Adeyemo, Aida Karina Dieffenbach, Alan B. Zonderman, Ilja M. Nolte, Peter J. van der Most, Alan F. Wright, Alan R. Shuldiner, Alanna C. Morrison, Albert Hofman, Albert V. Smith, Albert W. Dreisbach, Andre Franke, Andre G. Uitterlinden, Andres Metspalu, Anke Tonjes, Antonio Lupo, Antonietta Robino, Åsa Johansson, Ayse Demirkan, Barbara Kollerits, Barry I. Freedman, Belen Ponte, Ben A. Oostra, Bernhard Paulweber, Bernhard K. Krämer, Braxton D. Mitchell, Brendan M. Buckley, Carmen A. Peralta, Caroline Hayward, Catherine Helmer, Charles N. Rotimi, Christian M. Shaffer, Christian Müller, Cinzia Sala, Cornelia M. van Duijn, Aude Saint-Pierre, Daniel Ackermann, Daniel Shriner, Daniela Ruggiero, Daniela Toniolo, Yingchang Lu, Daniele Cusi, Darina Czamara, David Ellinghaus, David S. Siscovick, Douglas Ruderfer, Christian Gieger, Harald Grallert, Elena Rochtchina, Elizabeth J. Atkinson, Elizabeth G. Holliday, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, Federico Murgia, Fernando Rivadeneira, Florian Ernst, Florian Kronenberg, Frank B. Hu, Gerjan J. Navis, Gary C. Curhan, George B. Ehret, Georg Homuth, Stefan Coassin, Gian-Andri Thun, Giorgio Pistis, Giovanni Gambaro, Giovanni Malerba, Grant W. Montgomery, Gudny Eiriksdottir, Gunnar Jacobs, Guo Li, H-Erich Wichmann, Harry Campbell, Helena Schmidt, Henri Wallaschofski, Henry Völzke, Hermann Brenner, Heyo K. Kroemer, Holly Kramer, Honghuang Lin, I. Mateo Leach, Ian Ford, Idris Guessous, Igor Rudan, Inga Prokopenko, Ingrid Borecki, Iris M. Heid, Ivana Kolcic, Ivana Persico, J. Wouter Jukema, James F. Wilson, Janine F. Felix, Jasmin Divers, Jean-Charles Lambert, Jeanette M. Stafford, Jean-Michel Gaspoz, Jennifer A. Smith, Jessica D. Faul, Jie Jin Wang, Jingzhong Ding, Joel N. Hirschhorn, John Attia, John B. Whitfield, John Chalmers, Jorma Viikari, Josef Coresh, Joshua C. Denny, Juha Karjalainen, Jyotika K. Fernandes, Karlhans Endlich, Katja Butterbach, Keith L. Keene, Kurt Lohman, Laura Portas, Lenore J. Launer, Leo-Pekka Lyytikäinen, Loic Yengo, Lude Franke, Luigi Ferrucci, Lynda M. Rose, Lyudmyla Kedenko, Madhumathi Rao, Maksim Struchalin, Marcus E. Kleber, Margherita Cavalieri, Margot Haun, Marilyn C. Cornelis, Marina Ciullo, Mario Pirastu, Mariza de Andrade, Mark A. McEvoy, Mark Woodward, Martin Adam, Massimiliano Cocca, Matthias Nauck, Medea Imboden, Melanie Waldenberger, Menno Pruijm, Marie Metzger, Michael Stumvoll, Michele K. Evans, Michele M. Sale, Mika Kähönen, Mladen Boban, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nabila Bouatia-Naji, Nicholas G. Martin, Nick Hastie, Nicole Probst-Hensch, Nicole Soranzo, Olivier Devuyst, Olli Raitakari, Omri Gottesman, Oscar H. Franco, Ozren Polasek, Paolo Gasparini, Patricia B. Munroe, Paul M. Ridker, Paul Mitchell, Paul Muntner, Christa Meisinger, Johannes H. Smit, ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, Peter Kovacs, Philipp S. Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, Rita P. S. Middelberg, Robert J. Carroll, Brenda W. Penninx, Rodney J. Scott, Ronit Katz, Sanaz Sedaghat, Sarah H. Wild, Sharon L. R. Kardia, Sheila Ulivi, Shih-Jen Hwang, Stefan Enroth, Stefan Kloiber, Stella Trompet, Benedicte Stengel, Stephen J. Hancock, Stephen T. Turner, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanja Zeller, Tatijana Zemunik, Terho Lehtimäki, Thomas Illig, Thor Aspelund, Tiit Nikopensius, Tonu Esko, Toshiko Tanaka, Ulf Gyllensten, Uwe Völker, Valur Emilsson, Veronique Vitart, Ville Aalto, Vilmundur Gudnason, Vincent Chouraki, Wei-Min Chen, Wilmar Igl, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Ruth J. F. Loos, Yongmei Liu, Harold Snieder, Peter P. Pramstaller, Afshin Parsa, Jeffrey R. O’Connell, Katalin Susztak, Pavel Hamet, Johanne Tremblay, Ian H. de Boer, Carsten A. Böger, Wolfram Goessling, Daniel I. Chasman, Anna Köttgen, W. H. Linda Kao, and Caroline S. Fox

Subjects
Science
Abstract

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Published
2016
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42. UGT1A1 genetic variants are associated with increases in bilirubin levels in rheumatoid arthritis patients treated with sarilumab

Author

Nan Lin, Amy Damask, Anita Boyapati, Jennifer D. Hamilton, Sara Hamon, Nils Ternes, Michael C. Nivens, John Penn, Alexander Lopez, Jeffrey G. Reid, John Overton, Alan R. Shuldiner, Goncalo Abecasis, Aris Baras, and Charles Paulding

Subjects
Adult, Arthritis, Rheumatoid, Pharmacology, Treatment Outcome, Antirheumatic Agents, Genetics, Humans, Molecular Medicine, Bilirubin, Glucuronosyltransferase, Antibodies, Monoclonal, Humanized, Genome-Wide Association Study
Abstract

Sarilumab is a human monoclonal antibody against interleukin (IL)-6Rα that has been approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Mild liver function test abnormalities have been observed in patients treated with sarilumab. We describe a genome-wide association study of bilirubin elevations in RA patients treated with sarilumab. Array genotyping and exome sequencing were performed on DNA samples from 1075 patients. Variants in the UGT1A1 gene were strongly associated with maximum bilirubin elevations in sarilumab-treated patients (rs4148325; p = 2.88 × 10−41) but were not associated with aminotransferase elevations. No other independent loci showed evidence of association with bilirubin elevations after sarilumab treatment. These findings suggest that most bilirubin increases during sarilumab treatment are related to genetic variation in UGT1A1 rather than underlying liver injury.

Published
2022

43. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update

Author

Craig R. Lee, Jasmine A. Luzum, Katrin Sangkuhl, Roseann S. Gammal, Marc S. Sabatine, Charles Michael Stein, David F. Kisor, Nita A. Limdi, Yee Ming Lee, Stuart A. Scott, Jean‐Sébastien Hulot, Dan M. Roden, Andrea Gaedigk, Kelly E. Caudle, Teri E. Klein, Julie A. Johnson, and Alan R. Shuldiner

Subjects
Cytochrome P-450 CYP2C19, Pharmacology, Ticlopidine, Genotype, Pharmacogenetics, Prodrugs, Pharmacology (medical), Platelet Aggregation Inhibitors, Clopidogrel
Abstract

CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype-guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org).

Published
2022

44. The prevalence of prenatal sonographic findings in postnatal diagnostic exome sequencing performed for neurocognitive phenotypes: A cohort study

Author

Rivka, Sukenik-Halevy, Sharon, Perlman, Noa, Ruhrman-Shahar, Offra, Engel, Naama, Orenstein, Claudia, Gonzaga-Jauregui, Alan R, Shuldiner, Nurit, Magal, Ofir, Hagari, Noy, Azulay, Gabriel Arie, Lidzbarsky, Lily, Bazak, and Lina, Basel-Salmon

Subjects
Cohort Studies, Polyhydramnios, Fetal Growth Retardation, Phenotype, Pregnancy, Prenatal Diagnosis, Prevalence, Humans, Obstetrics and Gynecology, Exome, Female, Ultrasonography, Prenatal, Genetics (clinical)
Abstract

Prenatal exome sequencing (ES) is currently indicated for fetal malformations. Some neurocognitive genetic disorders may not have a prenatal phenotype. We assessed the prevalence of prenatally detectable phenotypes among patients with neurocognitive syndromes diagnosed postnatally by ES.The medical files of a cohort of 138 patients diagnosed postnatally with a neurocognitive disorder using ES were reviewed for prenatal sonographic data. The Online Mendelian Inheritance in Man (OMIM) database was searched for prenatally detectable phenotypes for all genes identified.Prenatal imaging data were available for 122 cases. Of these, 29 (23.75%) had fetal structural abnormalities and another 29 had other ultrasound abnormalities (fetal growth restriction, polyhydramnios, elevated nuchal translucency). In 30 patients, structural aberrations that were not diagnosed prenatally were detected at birth; in 21 (17.2%), the abnormalities could theoretically be detected prenatally by third-trimester/targeted scans. According to OMIM, 55.9% of the diagnosed genes were not associated with structural anomalies.Most patients (52.5%) with postnatally diagnosed neurocognitive disorders did not have prenatal sonographic findings indicating prenatal ES should be considered. The prevalence of specific prenatal phenotypes such as fetal growth restriction and polyhydramnios in our cohort suggests that additional prenatal findings should be assessed as possible indications for prenatal ES.

Published
2022

45. Depression, stress, and regional cerebral blood flow

Author

Joshua Chiappelli, Bhim M Adhikari, Mark D Kvarta, Heather A Bruce, Eric L Goldwaser, Yizhou Ma, Shuo Chen, Seth Ament, Alan R Shuldiner, Braxton D Mitchell, Peter Kochunov, Danny JJ Wang, and L Elliot Hong

Subjects
Neurology, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Decreased cerebral blood flow (CBF) may be an important mechanism associated with depression. In this study we aimed to determine if the association of CBF and depression is dependent on current level of depression or the tendency to experience depression over time (trait depression), and if CBF is influenced by depression-related factors such as stressful life experiences and antidepressant medication use. CBF was measured in 254 participants from the Amish Connectome Project (age 18–76, 99 men and 154 women) using arterial spin labeling. All participants underwent assessment of symptoms of depression measured with the Beck Depression Inventory and Maryland Trait and State Depression scales. Individuals diagnosed with a unipolar depressive disorder had significantly lower average gray matter CBF compared to individuals with no history of depression or to individuals with a history of depression that was in remission at time of study. Trait depression was significantly associated with lower CBF, with the associations strongest in cingulate gyrus and frontal white matter. Use of antidepressant medication and more stressful life experiences were also associated with significantly lower CBF. Resting CBF in specific brain regions is associated with trait depression, experience of stressful life events, and current antidepressant use, and may provide a valuable biomarker for further studies.

Published
2023

47. The Association between Factor XI Deficiency and the Risk of Bleeding, Cardiovascular, and Venous Thromboembolic Events

Author

Alan R. Shuldiner, Chalothorn Dan, Sarah Sharman Moser, Morton Lori C, Ming-Dauh Wang, Gabriel Chodick, Yan G. Ni, Ophira Salomon, and Jessica J. Jalbert

Subjects
Adult, Male, Venous Thrombosis, medicine.medical_specialty, Factor XI Deficiency, business.industry, MEDLINE, Hemorrhage, Retrospective cohort study, Venous Thromboembolism, Hematology, medicine.disease, Internal medicine, Humans, Medicine, Female, business, Factor XI, Stroke, Retrospective Studies
Abstract

The objective of this study was to assess the relationship between factor XI (FXI) deficiency and the risks of bleeding and cardiovascular (CV) events. We conducted a retrospective cohort study using data from Maccabi Healthcare Services (MHS). We identified adults with FXI deficiency (severe

Published
2021

48. Rare genetic coding variants associated with human longevity and protection against age-related diseases

Author

Vera Gorbunova, Joydeep Mitra, Tina Gao, M. Reza Jabalameli, Almut Nebel, Matthias Laudes, Paul D. Robbins, Siegfried Görg, Quanwei Zhang, Alan R. Shuldiner, Valerio Napolioni, Kenny Ye, Nir Barzilai, Gil Atzmon, Warren C. Ladiges, Sofiya Milman, Yousin Suh, Guillermo G. Torres, Nha Nguyen, Zhengdong Zhang, Michael D. Greicius, Zhen Wang, Jhih Rong Lin, Jan Vijg, Patrick Sin-Chan, Andre Franke, and Laura J. Niedernhofer

Subjects
Genetics, Aging, ved/biology, media_common.quotation_subject, ved/biology.organism_classification_rank.species, Neuroscience (miscellaneous), Wnt signaling pathway, Longevity, Biology, Genetic code, Human longevity, Genetic variation, Geriatrics and Gerontology, Signal transduction, Centenarian, Model organism, media_common
Abstract

Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on individuals harboring the known common risk allele APOE4. The genetic component of extreme human longevity constitutes, at least in part, rare coding variants in pathways that protect against aging, including those that control longevity in model organisms. In this whole-exome sequencing study of the largest centenarian cohort to date, Lin et al. demonstrate that conserved pathways—for example, IIS and AMPK signaling—are as relevant to human longevity and healthy aging as they are in worms, flies and mice.

Published
2021

49. 'Assessing the Impact of Individual Autozygosity on Complex Traits'

Author

Megan T. Lynch, Kristin A. Maloney, Huichun Xu, James A. Perry, Alan R. Shuldiner, Braxton D. Mitchell, and Regeneron Genetics Center N/A

Abstract

Autozygosity, the proportion of the genome that is homozygous by descent, has been associated with variation in multiple health-related traits impacting evolutionary fitness. Autozygosity (FROH) is typically measured from runs of homozygosity (ROHs) that arise when identical-by-descent (IBD) haplotypes are inherited from each parent. Population isolates with a small set of common founders have elevated autozygosity relative to outbred populations. In this study, we examined whether degree of autozygosity was associated with variation in 96 cardiometabolic traits among 7221 Old Order Amish individuals residing in Lancaster County, PA. We estimated the average length of an ROH segment to be 6350 KB, with each individual having on average 17.2 segments 1.5 KB or larger, which in aggregate span ~ 3.7% of the genome. Measurements of genome-wide and regional FROH were used as the primary predictors of trait variation in association analysis. In genome-wide FROH analysis, we did not identify any associations that withstood Bonferroni-correction (p = 0.0005). However, on regional FROH analysis, we identified associations exceeding genome-wide thresholds for two traits: serum bilirubin levels, which were significantly associated with a region on chromosome 2 localized to a region surrounding UGT1A10 (p = 1x10− 43), and HbA1c levels, which were significantly associated with a region on chromosome 8 localized near CHRNB3 (p = 8x10− 10). These analyses highlight the potential value of autozygosity mapping in founder populations.

Published
2022

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