995 results on '"Willems, A."'
Search Results
2. Diagnosis of pediatric central nervous system tumors using methylation profiling of cfDNA from cerebrospinal fluid
- Author
-
Lotte Cornelli, Ruben Van Paemel, Maísa R. Ferro dos Santos, Sofie Roelandt, Leen Willems, Jelle Vandersteene, Edward Baert, Liselot M. Mus, Nadine Van Roy, Bram De Wilde, and Katleen De Preter
- Subjects
Pediatric oncology ,DNA methylation ,Liquid biopsy ,Central nervous system tumor ,Precision medicine ,Cerebrospinal fluid ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Pediatric central nervous system tumors remain challenging to diagnose. Imaging approaches do not provide sufficient detail to discriminate between different tumor types, while the histopathological examination of tumor tissue shows high inter-observer variability. Recent studies have demonstrated the accurate classification of central nervous system tumors based on the DNA methylation profile of a tumor biopsy. However, a brain biopsy holds significant risk of bleeding and damaging the surrounding tissues. Liquid biopsy approaches analyzing circulating tumor DNA show high potential as an alternative and less invasive tool to study the DNA methylation pattern of tumors. Here, we explore the potential of classifying pediatric brain tumors based on methylation profiling of the circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF). For this proof-of-concept study, we collected cerebrospinal fluid samples from 19 pediatric brain cancer patients via a ventricular drain placed for reasons of increased intracranial pressure. Analyses on the cfDNA showed high variability of cfDNA quantities across patients ranging from levels below the limit of quantification to 40 ng cfDNA per milliliter of CSF. Classification based on methylation profiling of cfDNA from CSF was correct for 7 out of 20 samples in our cohort. Accurate results were mostly observed in samples of high quality, more specifically those with limited high molecular weight DNA contamination. Interestingly, we show that centrifugation of the CSF prior to processing increases the fraction of fragmented cfDNA to high molecular weight DNA. In addition, classification was mostly correct for samples with high tumoral cfDNA fraction as estimated by computational deconvolution (> 40%). In summary, analysis of cfDNA in the CSF shows potential as a tool for diagnosing pediatric nervous system tumors especially in patients with high levels of tumoral cfDNA in the CSF. Further optimization of the collection procedure, experimental workflow and bioinformatic approach is required to also allow classification for patients with low tumoral fractions in the CSF.
- Published
- 2024
- Full Text
- View/download PDF
3. Self-control is associated with health-relevant disparities in buccal DNA-methylation measures of biological aging in older adults
- Author
-
Y. E. Willems, A. deSteiguer, P. T. Tanksley, L. Vinnik, D. Fraemke, A. Okbay, D. Richter, G. G. Wagner, R. Hertwig, P. Koellinger, E. M. Tucker-Drob, K. P. Harden, and Laurel Raffington
- Subjects
Self-control ,DNA-methylation ,Pace of aging ,Biological aging ,Health ,Life span ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Self-control is a personality dimension that is associated with better physical health and a longer lifespan. Here, we examined (1) whether self-control is associated with buccal and saliva DNA-methylation (DNAm) measures of biological aging quantified in children, adolescents, and adults, and (2) whether biological aging measured in buccal DNAm is associated with self-reported health. Following preregistered analyses, we computed two DNAm measures of advanced biological age (principal-component PhenoAge and GrimAge Acceleration) and a DNAm measure of pace of aging (DunedinPACE) in buccal samples from the German Socioeconomic Panel Study (SOEP-G[ene], n = 1058, age range 0–72, M age = 42.65) and saliva samples from the Texas Twin Project (TTP, n = 1327, age range 8–20, M age = 13.50). We found that lower self-control was associated with advanced biological age in older adults (PhenoAge Acceleration β = − .34, [− .51, − .17], p
- Published
- 2024
- Full Text
- View/download PDF
4. No gene by stressful life events interaction on individual differences in adults’ self-control
- Author
-
Yayouk Eva Willems, Laurel Raffington, Lannie Ligthart, Rene Pool, Jouke Jan Hottenga, Catrin Finkenauer, and Meike Bartels
- Subjects
self-control ,genetics ,stress ,gene-environment interaction ,polygenic scores ,Psychiatry ,RC435-571 - Abstract
BackgroundDifficulty with self-control, or the ability to alter impulses and behavior in a goal-directed way, predicts interpersonal conflict, lower socioeconomic attainments, and more adverse health outcomes. Etiological understanding, and intervention for low self-control is, therefore, a public health goal. A prominent developmental theory proposes that individuals with high genetic propensity for low self-control that are also exposed to stressful environments may be most at-risk of low levels of self-control. Here we examine if polygenic measures associated with behaviors marked by low self-control interact with stressful life events in predicting self-control.MethodsLeveraging molecular data from a large population-based Dutch sample (N = 7,090, Mage = 41.2) to test for effects of genetics (i.e., polygenic scores for ADHD and aggression), stressful life events (e.g., traffic accident, violent assault, financial problems), and a gene-by-stress interaction on self-control (measured with the ASEBA Self-Control Scale).ResultsBoth genetics (β =.03 -.04, p
- Published
- 2024
- Full Text
- View/download PDF
5. O’Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum
- Author
-
Velmans, Clara, O'Donnell-Luria, Anne H, Argilli, Emanuela, Mau-them, Frederic Tran, Vitobello, Antonio, Chan, Marcus CY, Fung, Jasmine Lee-Fong, Rech, Megan, Abicht, Angela, Mucca, Marion Aubert, Carmichael, Jason, Chassaing, Nicolas, Clark, Robin, Coubes, Christine, Denommé-Pichon, Anne-Sophie, de Dios, John Karl, England, Eleina, Funalot, Benoit, Gerard, Marion, Joseph, Maries, Kennedy, Colleen, Kumps, Camille, Willems, Marjolaine, van de Laar, Ingrid MBH, Aarts-Tesselaar, Coranne, van Slegtenhorst, Marjon, Lehalle, Daphné, Leppig, Kathleen, Lessmeier, Lennart, Pais, Lynn S, Paterson, Heather, Ramanathan, Subhadra, Rodan, Lance H, Superti-Furga, Andrea, Chung, Brian HY, Sherr, Elliott, Netzer, Christian, Schaaf, Christian P, and Erger, Florian
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Brain Disorders ,Intellectual and Developmental Disabilities (IDD) ,Pediatric ,Human Genome ,Autism ,Mental Health ,Neurosciences ,Clinical Research ,Congenital Structural Anomalies ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Autism Spectrum Disorder ,Child ,Humans ,Intellectual Disability ,Megalencephaly ,Neurodevelopmental Disorders ,Seizures ,Syndrome ,Exome Sequencing ,human genetics ,genetic counselling ,genetics ,behavioural ,mutation ,Medical and Health Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
BackgroundO'Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O'Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.MethodsAffected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.ResultsWe report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.ConclusionOur study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.
- Published
- 2022
6. Type 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes in 454,193 Individuals Across 13 Cohorts
- Author
-
DiCorpo, Daniel, LeClair, Jessica, Cole, Joanne B, Sarnowski, Chloé, Ahmadizar, Fariba, Bielak, Lawrence F, Blokstra, Anneke, Bottinger, Erwin P, Chaker, Layal, Chen, Yii-Der I, Chen, Ye, de Vries, Paul S, Faquih, Tariq, Ghanbari, Mohsen, Gudmundsdottir, Valborg, Guo, Xiuqing, Hasbani, Natalie R, Ibi, Dorina, Ikram, M Arfan, Kavousi, Maryam, Leonard, Hampton L, Leong, Aaron, Mercader, Josep M, Morrison, Alanna C, Nadkarni, Girish N, Nalls, Mike A, Noordam, Raymond, Preuss, Michael, Smith, Jennifer A, Trompet, Stella, Vissink, Petra, Yao, Jie, Zhao, Wei, Boerwinkle, Eric, Goodarzi, Mark O, Gudnason, Vilmundur, Jukema, J Wouter, Kardia, Sharon LR, Loos, Ruth JF, Liu, Ching-Ti, Manning, Alisa K, Mook-Kanamori, Dennis, Pankow, James S, Picavet, H Susan J, Sattar, Naveed, Simonsick, Eleanor M, Verschuren, WM Monique, van Dijk, Ko Willems, Florez, Jose C, Rotter, Jerome I, Meigs, James B, Dupuis, Josée, and Udler, Miriam S
- Subjects
Epidemiology ,Biomedical and Clinical Sciences ,Health Sciences ,Genetics ,Obesity ,Heart Disease - Coronary Heart Disease ,Liver Disease ,Heart Disease ,Cardiovascular ,Digestive Diseases ,Diabetes ,Nutrition ,Prevention ,Aetiology ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Good Health and Well Being ,Alleles ,Cross-Sectional Studies ,Diabetes Mellitus ,Type 2 ,Genetic Loci ,Humans ,Pharmaceutical Preparations ,Medical and Health Sciences ,Endocrinology & Metabolism ,Biomedical and clinical sciences ,Health sciences - Abstract
ObjectiveType 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed.Research design and methodsHere we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD).ResultsDespite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway.ConclusionsOur findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.
- Published
- 2022
7. Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism
- Author
-
Padhi, Evin M, Hayeck, Tristan J, Cheng, Zhang, Chatterjee, Sumantra, Mannion, Brandon J, Byrska-Bishop, Marta, Willems, Marjolaine, Pinson, Lucile, Redon, Sylvia, Benech, Caroline, Uguen, Kevin, Audebert-Bellanger, Séverine, Le Marechal, Cédric, Férec, Claude, Efthymiou, Stephanie, Rahman, Fatima, Maqbool, Shazia, Maroofian, Reza, Houlden, Henry, Musunuri, Rajeeva, Narzisi, Giuseppe, Abhyankar, Avinash, Hunter, Riana D, Akiyama, Jennifer, Fries, Lauren E, Ng, Jeffrey K, Mehinovic, Elvisa, Stong, Nick, Allen, Andrew S, Dickel, Diane E, Bernier, Raphael A, Gorkin, David U, Pennacchio, Len A, Zody, Michael C, and Turner, Tychele N
- Subjects
Biological Sciences ,Genetics ,Mental Health ,Human Genome ,Intellectual and Developmental Disabilities (IDD) ,Autism ,Pediatric ,Neurosciences ,Clinical Research ,Brain Disorders ,1.1 Normal biological development and functioning ,Underpinning research ,Aetiology ,2.1 Biological and endogenous factors ,Mental health ,Neurological ,Autistic Disorder ,Enhancer Elements ,Genetic ,Exome ,Female ,Gene Regulatory Networks ,Genetic Predisposition to Disease ,Humans ,Male ,Muscle Hypotonia ,Mutation ,Neurodevelopmental Disorders ,Neurons ,Transcription Factors ,Neurodevelopmental disorder ,Enhancer ,Gene regulatory network ,EBF3 ,hs737 ,Genome ,Variant ,De novo ,Genetics & Heredity ,Biochemistry and cell biology - Abstract
BackgroundPrevious research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737.ResultsWe adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10-3), and combined dataset (p = 1.1 × 10-4). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10-35, loss-of-function p = 2.26 × 10-13) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10-6, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia.ConclusionsIn this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.
- Published
- 2021
8. Genome-wide association analysis of metabolic syndrome quantitative traits in the GENNID multiethnic family study.
- Author
-
Wan, Jia Y, Goodman, Deborah L, Willems, Emileigh L, Freedland, Alexis R, Norden-Krichmar, Trina M, Santorico, Stephanie A, Edwards, Karen L, and American Diabetes GENNID Study Group
- Subjects
American Diabetes GENNID Study Group ,Family studies ,Genetic epidemiology ,Linkage ,Metabolic syndrome ,Quantitative trait loci ,Obesity ,Genetics ,Human Genome ,Diabetes ,Nutrition ,Aetiology ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Medical Biochemistry and Metabolomics ,Clinical Sciences - Abstract
BackgroundTo identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups.MethodsData was collected from GENetics of Noninsulin dependent Diabetes Mellitus (GENNID), a multiethnic resource of Type 2 diabetic families and included 1520 subjects in 259 African-American, European-American, Japanese-Americans, and Mexican-American families. We focused on eight MetS traits: weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein, triglycerides, fasting glucose, and insulin. Using genotyped and imputed data from Illumina's Multiethnic array, we conducted genome-wide association analyses with linear mixed models for all ethnicities, except for the smaller Japanese-American group, where we used additive genetic models with gene-dropping.ResultsFindings included ethnic-specific genetic associations and heterogeneity across ethnicities. Most significant associations were outside our candidate linkage regions and were coincident within a gene or intergenic region, with two exceptions in European-American families: (a) within previously identified linkage region on chromosome 2, two significant GLI2-TFCP2L1 associations with weight, and (b) one chromosome 11 variant near CADM1-LINC00900 with pleiotropic blood pressure effects.ConclusionsThis multiethnic family study found genetic heterogeneity and coincident associations (with one case of pleiotropy), highlighting the importance of including diverse populations in genetic research and illustrating the complex genetic architecture underlying MetS.
- Published
- 2021
9. Data-driven sudden cardiac arrest research in Europe: Experts’ perspectives on ethical challenges and governance strategies
- Author
-
Marieke A.R. Bak, Jelle C.H. Vroonland, Marieke T. Blom, Domagoj Damjanovic, Dick L. Willems, Hanno L. Tan, and M. Corrette Ploem
- Subjects
Research ethics ,Data protection ,Observational studies ,Big data ,Biobank ,Genetics ,Specialties of internal medicine ,RC581-951 - Abstract
Background: Observational studies using large-scale databases and biobanks help improve prevention and treatment of sudden cardiac arrest (SCA) but the lack of guidance on data protection issues in this setting may harm patients’ rights and the research enterprise itself. This qualitative study explored the ethical aspects of observational SCA research, as well as solutions. Methods: European experts in SCA research, medical ethics and health law reflected on this topic through semi-structured interviews (N = 29) and a virtual roundtable conference (N = 18). The ESCAPE-NET project served as a discussion case. Findings were coded and thematically analysed. Results: The first theme concerned the potential benefits and harms (at individual and group level) of observational data-based SCA studies and included the following sub-themes: societal value, scientific validity, data privacy, disclosure of genetic findings, stigma and discrimination, and medicalisation of sudden death. The second theme involved governance through ‘privacy by design’, ‘privacy by policy’ and associated regulation and oversight. Sub-themes were: de-identification of data, informed consent (broad and deferred), ethics review, and harmonisation. Conclusions: Researchers and scientific societies should be aware that ethico-legal issues may arise during data-driven studies in SCA and other emergencies. These can be mitigated by combining technical data protection safeguards with appropriate informed consent policies and proportional ethics oversight. To ensure responsible conduct of data research in emergency medicine, we recommend the establishment of ‘codes of conduct’ which should be developed in interdisciplinary groups and together with patient representatives.
- Published
- 2023
- Full Text
- View/download PDF
10. Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- Author
-
Yaghootkar, Hanieh, Zhang, Yiying, Spracklen, Cassandra N, Karaderi, Tugce, Huang, Lam Opal, Bradfield, Jonathan, Schurmann, Claudia, Fine, Rebecca S, Preuss, Michael H, Kutalik, Zoltan, Wittemans, Laura BL, Lu, Yingchang, Metz, Sophia, Willems, Sara M, Li-Gao, Ruifang, Grarup, Niels, Wang, Shuai, Molnos, Sophie, Sandoval-Zárate, América A, Nalls, Mike A, Lange, Leslie A, Haesser, Jeffrey, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Feitosa, Mary F, Sitlani, Colleen M, Venturini, Cristina, Mahajan, Anubha, Kacprowski, Tim, Wang, Carol A, Chasman, Daniel I, Amin, Najaf, Broer, Linda, Robertson, Neil, Young, Kristin L, Allison, Matthew, Auer, Paul L, Blüher, Matthias, Borja, Judith B, Bork-Jensen, Jette, Carrasquilla, Germán D, Christofidou, Paraskevi, Demirkan, Ayse, Doege, Claudia A, Garcia, Melissa E, Graff, Mariaelisa, Guo, Kaiying, Hakonarson, Hakon, Hong, Jaeyoung, Ida Chen, Yii-Der, Jackson, Rebecca, Jakupović, Hermina, Jousilahti, Pekka, Justice, Anne E, Kähönen, Mika, Kizer, Jorge R, Kriebel, Jennifer, LeDuc, Charles A, Li, Jin, Lind, Lars, Luan, Jian'an, Mackey, David A, Mangino, Massimo, Männistö, Satu, Martin Carli, Jayne F, Medina-Gomez, Carolina, Mook-Kanamori, Dennis O, Morris, Andrew P, de Mutsert, Renée, Nauck, Matthias, Prokic, Ivana, Pennell, Craig E, Pradhan, Arund D, Psaty, Bruce M, Raitakari, Olli T, Scott, Robert A, Skaaby, Tea, Strauch, Konstantin, Taylor, Kent D, Teumer, Alexander, Uitterlinden, Andre G, Wu, Ying, Yao, Jie, Walker, Mark, North, Kari E, Kovacs, Peter, Ikram, M Arfan, van Duijn, Cornelia M, Ridker, Paul M, Lye, Stephen, Homuth, Georg, Ingelsson, Erik, Spector, Tim D, McKnight, Barbara, Province, Michael A, Lehtimäki, Terho, Adair, Linda S, Rotter, Jerome I, Reiner, Alexander P, and Wilson, James G
- Subjects
Genetics ,Nutrition ,Prevention ,Obesity ,Aetiology ,2.1 Biological and endogenous factors ,Oral and gastrointestinal ,Metabolic and endocrine ,Cardiovascular ,Stroke ,Cancer ,Adiposity ,Gene Expression Regulation ,Developmental ,Genetic Variation ,Genotype ,Humans ,Leptin ,Models ,Molecular ,Protein Conformation ,Racial Groups ,Medical and Health Sciences ,Endocrinology & Metabolism - Abstract
Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
- Published
- 2020
11. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
- Author
-
Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso
- Subjects
Cholesterol ,Lipids ,Genetics ,Genome-wide association study ,GWAS ,Biology (General) ,QH301-705.5 ,QH426-470 - Abstract
Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
- Published
- 2022
- Full Text
- View/download PDF
12. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
- Author
-
Spracklen, Cassandra N, Karaderi, Tugce, Yaghootkar, Hanieh, Schurmann, Claudia, Fine, Rebecca S, Kutalik, Zoltan, Preuss, Michael H, Lu, Yingchang, Wittemans, Laura BL, Adair, Linda S, Allison, Matthew, Amin, Najaf, Auer, Paul L, Bartz, Traci M, Blüher, Matthias, Boehnke, Michael, Borja, Judith B, Bork-Jensen, Jette, Broer, Linda, Chasman, Daniel I, Chen, Yii-Der Ida, Chirstofidou, Paraskevi, Demirkan, Ayse, van Duijn, Cornelia M, Feitosa, Mary F, Garcia, Melissa E, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Guo, Xiuqing, Haesser, Jeffrey, Hansen, Torben, Harris, Tamara B, Highland, Heather M, Hong, Jaeyoung, Ikram, M Arfan, Ingelsson, Erik, Jackson, Rebecca, Jousilahti, Pekka, Kähönen, Mika, Kizer, Jorge R, Kovacs, Peter, Kriebel, Jennifer, Laakso, Markku, Lange, Leslie A, Lehtimäki, Terho, Li, Jin, Li-Gao, Ruifang, Lind, Lars, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mackey, David A, Mahajan, Anubha, Mangino, Massimo, Männistö, Satu, McCarthy, Mark I, McKnight, Barbara, Medina-Gomez, Carolina, Meigs, James B, Molnos, Sophie, Mook-Kanamori, Dennis, Morris, Andrew P, de Mutsert, Renee, Nalls, Mike A, Nedeljkovic, Ivana, North, Kari E, Pennell, Craig E, Pradhan, Aruna D, Province, Michael A, Raitakari, Olli T, Raulerson, Chelsea K, Reiner, Alex P, Ridker, Paul M, Ripatti, Samuli, Roberston, Neil, Rotter, Jerome I, Salomaa, Veikko, Sandoval-Zárate, America A, Sitlani, Colleen M, Spector, Tim D, Strauch, Konstantin, Stumvoll, Michael, Taylor, Kent D, Thuesen, Betina, Tönjes, Anke, Uitterlinden, Andre G, Venturini, Cristina, Walker, Mark, Wang, Carol A, Wang, Shuai, Wareham, Nicholas J, Willems, Sara M, Willems van Dijk, Ko, Wilson, James G, Wu, Ying, Yao, Jie, Young, Kristin L, Langenberg, Claudia, and Frayling, Timothy M
- Subjects
Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Human Genome ,Nutrition ,Obesity ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Cardiovascular ,Adiponectin ,Adipose Tissue ,Adolescent ,Adult ,Black or African American ,Aged ,Aged ,80 and over ,Exome ,Female ,Genetic Predisposition to Disease ,Hispanic or Latino ,Humans ,Lipids ,Male ,Middle Aged ,Phenotype ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,White People ,Young Adult ,adiponectin ,cardio metabolic traits ,exome ,genetics ,genome-wide association study ,lipids ,obesity ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
- Published
- 2019
13. Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels
- Author
-
Wang, Zhe, Chen, Han, Bartz, Traci M, Bielak, Lawrence F, Chasman, Daniel I, Feitosa, Mary F, Franceschini, Nora, Guo, Xiuqing, Lim, Elise, Noordam, Raymond, Richard, Melissa A, Wang, Heming, Cade, Brian, Cupples, L Adrienne, de Vries, Paul S, Giulanini, Franco, Lee, Jiwon, Lemaitre, Rozenn N, Martin, Lisa W, Reiner, Alex P, Rich, Stephen S, Schreiner, Pamela J, Sidney, Stephen, Sitlani, Colleen M, Smith, Jennifer A, van Dijk, Ko Willems, Yao, Jie, Zhao, Wei, Fornage, Myriam, Kardia, Sharon LR, Kooperberg, Charles, Liu, Ching-Ti, Mook-Kanamori, Dennis O, Province, Michael A, Psaty, Bruce M, Redline, Susan, Ridker, Paul M, Rotter, Jerome I, Boerwinkle, Eric, Morrison, Alanna C, and Group, on behalf of the CHARGE Gene-Lifestyle Interactions Working
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Substance Misuse ,Human Genome ,Genetics ,Cardiovascular ,Heart Disease ,Alcoholism ,Alcohol Use and Health ,Aetiology ,2.1 Biological and endogenous factors ,Stroke ,Cancer ,Oral and gastrointestinal ,Good Health and Well Being ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Alcohol Drinking ,Apolipoproteins E ,Cholesterol ,HDL ,Female ,Gene Frequency ,Genetic Loci ,Genome-Wide Association Study ,Humans ,Lipids ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,Proprotein Convertase 9 ,Triglycerides ,White People ,Young Adult ,exome ,gene-environment interaction ,genome-wide association study ,lipids ,self-report ,CHARGE Gene-Lifestyle Interactions Working Group ,Medical Biotechnology ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology - Abstract
BackgroundAlcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.MethodsIn the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.ResultsWe discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3, and CD300LG) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (P=6.65×10-6 for the interaction test) and replicated at nominal significance level (P=0.013) in SMC5.ConclusionsIn conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
- Published
- 2020
14. Transethnic meta-analysis of metabolic syndrome in a multiethnic study.
- Author
-
Willems, Emileigh L, Wan, Jia Y, Norden-Krichmar, Trina M, Edwards, Karen L, and Santorico, Stephanie A
- Subjects
Humans ,Diabetes Mellitus ,Type 2 ,Phenotype ,Polymorphism ,Single Nucleotide ,Mexican Americans ,Male ,Meta-Analysis as Topic ,Genome-Wide Association Study ,Metabolic Syndrome ,White People ,Black or African American ,Asian ,allelic heterogeneity ,genome-wide association ,meta-analysis ,metabolic syndrome ,transethnic ,Human Genome ,Diabetes ,Genetics ,Nutrition ,Metabolic and endocrine ,African Americans ,Asian Americans ,Whites ,Public Health and Health Services ,Epidemiology - Abstract
Genome-wide association studies (GWAS) have been used to establish thousands of genetic associations across numerous phenotypes. To improve the power of GWAS and generalize associations across ethnic groups, transethnic meta-analysis methods are used to combine the results of several GWAS from diverse ancestries. The goal of this study is to identify genetic associations for eight quantitative metabolic syndrome (MetS) traits through a meta-analysis across four ethnic groups. Traits were measured in the GENetics of Noninsulin dependent Diabetes Mellitus (GENNID) Study which consists of African-American (families = 73, individuals = 288), European-American (families = 79, individuals = 519), Japanese-American (families = 17, individuals = 132), and Mexican-American (families = 113, individuals = 610) samples. Genome-wide association results from these four ethnic groups were combined using four meta-analysis methods: fixed effects, random effects, TransMeta, and MR-MEGA. We provide an empirical comparison of the four meta-analysis methods from the GENNID results, discuss which types of loci (characterized by allelic heterogeneity) appear to be better detected by each of the four meta-analysis methods in the GENNID Study, and validate our results using previous genetic discoveries. We specifically compare the two transethnic methods, TransMeta and MR-MEGA, and discuss how each transethnic method's framework relates to the types of loci best detected by each method.
- Published
- 2020
15. Combining globally search for a regular expression and print matching lines with bibliographic monitoring of genomic database improves diagnosis
- Author
-
Frédéric Tran Mau-Them, Alexis Overs, Ange-Line Bruel, Romain Duquet, Mylene Thareau, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Arthur Sorlin, Hana Safraou, Sophie Nambot, Julian Delanne, Sebastien Moutton, Caroline Racine, Camille Engel, Melchior De Giraud d’Agay, Daphne Lehalle, Alice Goldenberg, Marjolaine Willems, Christine Coubes, David Genevieve, Alain Verloes, Yline Capri, Laurence Perrin, Marie-Line Jacquemont, Laetitia Lambert, Elodie Lacaze, Julien Thevenon, Nadine Hana, Julien Van-Gils, Charlotte Dubucs, Varoona Bizaoui, Marion Gerard-Blanluet, James Lespinasse, Sandra Mercier, Anne-Marie Guerrot, Isabelle Maystadt, Emilie Tisserant, Laurence Faivre, Christophe Philippe, Yannis Duffourd, and Christel Thauvin-Robinet
- Subjects
GREP ,intellectual disability ,developmental anomalies ,genomic database ,diagnostic improvement ,exome sequencing (ES) ,Genetics ,QH426-470 - Abstract
Introduction: Exome sequencing has a diagnostic yield ranging from 25% to 70% in rare diseases and regularly implicates genes in novel disorders. Retrospective data reanalysis has demonstrated strong efficacy in improving diagnosis, but poses organizational difficulties for clinical laboratories.Patients and methods: We applied a reanalysis strategy based on intensive prospective bibliographic monitoring along with direct application of the GREP command-line tool (to “globally search for a regular expression and print matching lines”) in a large ES database. For 18 months, we submitted the same five keywords of interest [(intellectual disability, (neuro)developmental delay, and (neuro)developmental disorder)] to PubMed on a daily basis to identify recently published novel disease–gene associations or new phenotypes in genes already implicated in human pathology. We used the Linux GREP tool and an in-house script to collect all variants of these genes from our 5,459 exome database.Results: After GREP queries and variant filtration, we identified 128 genes of interest and collected 56 candidate variants from 53 individuals. We confirmed causal diagnosis for 19/128 genes (15%) in 21 individuals and identified variants of unknown significance for 19/128 genes (15%) in 23 individuals. Altogether, GREP queries for only 128 genes over a period of 18 months permitted a causal diagnosis to be established in 21/2875 undiagnosed affected probands (0.7%).Conclusion: The GREP query strategy is efficient and less tedious than complete periodic reanalysis. It is an interesting reanalysis strategy to improve diagnosis.
- Published
- 2023
- Full Text
- View/download PDF
16. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
- Author
-
Kanoni, Stavroula, Graham, Sarah E., Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L., Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W., Locke, Adam E., Marouli, Eirini, Zajac, Greg J. M., Wu, Kuan-Han H., Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T., Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F., Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M., Rasheed, Humaira, Havulinna, Aki S., Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A., Lingren, Todd, Feng, QiPing, Kullo, Iftikhar J., Narita, Akira, Takayama, Jun, Martin, Hilary C., Hunt, Karen A., Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E., Campbell, Archie, Lin, Kuang, Millwood, Iona Y., Rasheed, Asif, Hindy, George, Faul, Jessica D., Zhao, Wei, Weir, David R., Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R., Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M., Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Wood, Andrew R., Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A., Mitchell, Ruth E., Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A., Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R., Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L., Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Floris, McDaid, Aaron F., Marques-Vidal, Pedro, Wielscher, Matthias, Trompet, Stella, Sattar, Naveed, Møllehave, Line T., Munz, Matthias, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Lukas, Scholz, Markus, Galesloot, Tessel E., Bradfield, Jonathan P., Ruotsalainen, Sanni E., Daw, EWarwick, Zmuda, Joseph M., Mitchell, Jonathan S., Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A., Vazquez-Moreno, Miguel, Feitosa, Mary F., Wojczynski, Mary K., Wang, Zhe, Preuss, Michael H., Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W., Engmann, Jorgen, Tsao, Noah L., Verma, Anurag, Slieker, Roderick C., Lo, Ken Sin, Zilhao, Nuno R., Le, Phuong, Kleber, Marcus E., Delgado, Graciela E., Huo, Shaofeng, Ikeda, Daisuke D., Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L., Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J., Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlos, Lyssenko, Valeriya, Nongmaithem, Suraj S., Bayyana, Swati, Stringham, Heather M., Irvin, Marguerite R., Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R. H. J., Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A., Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N., Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C., Wang, Ya Xing, Wei, Wen B., Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A., Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F., Smith, Jennifer A., Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J., Pitkänen, Niina, Cade, Brian E., van der Laan, Sander W., Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R., Doumatey, Ayo P., Adeyemo, Adebowale A., Lee, Jong Young, Petersen, Eva R. B., Nielsen, Aneta A., Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W., Wang, Carol A., Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O., van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D., Reiner, Alexander P., Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C., Launer, Lenore J., Li, Huaixing, Nalls, Mike A., Raitakari, Olli T., Ichihara, Sahoko, Wild, Sarah H., Nelson, Christopher P., Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S., Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J., Kim, Eung Kweon, Adams, Hieab H. H., Ikram, M. Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W., Kraaijeveld, Adriaan O., Beulens, Joline W. J., Shu, Xiao-Ou, Rallidis, Loukianos S., Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W., Kähönen, Mika, Pérusse, Louis, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E., Mori, Trevor A., Lieb, Wolfgang, Franke, Andre, Ohlsson, Claes, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M., Stark, Klaus J., Zimmermann, Martina E., Völzke, Henry, Homuth, Georg, Evans, Michele K., Zonderman, Alan B., Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E., Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J., Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L. R., Peyser, Patricia A., Kato, Norihiro, Schulze, Matthias B., Girotto, Giorgia, Böger, Carsten A., Jung, Bettina, Joshi, Peter K., Bennett, David A., De Jager, Philip L., Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morris, Caulfield, Mark J., Munroe, Patricia B., Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B., Samani, Nilesh J., Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A., Adair, Linda S., Bechayda, Sonny Augustin, de Silva, H. Janaka, Wickremasinghe, Ananda R., Krauss, Ronald M., Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G., Lind, Lars, Heng, Chew-Kiat, Nelson, Amanda E., Golightly, Yvonne M., Wilson, James F., Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J., Rao, D. C., Arnett, Donna K., Hunt, Steven C., Walker, Mark, Koistinen, Heikki A., Chandak, Giriraj R., Mercader, Josep M., Costanzo, Maria C., Jang, Dongkeun, Burtt, Noël P., Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, EShyong, van Dam, Rob M., Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F., McKnight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, McCarthy, Mark I., Palmer, Colin N. A., Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M., Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M.‘t, Elders, Petra J. M., Damrauer, Scott M., Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D., Loos, Ruth J. F., Province, Michael A., Parra, Esteban J., Cruz, Miguel, Psaty, Bruce M., Brandslund, Ivan, Pramstaller, Peter P., Rotimi, Charles N., Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F. A., Kiemeney, Lambertus A. L. M., de Graaf, Jacqueline, Loeffler, Markus, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W., Linneberg, Allan, Jukema, J. Wouter, Khera, Amit V., Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O., van Dijk, Ko Willems, Watkins, Hugh, Strachan, David P., Grarup, Niels, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I., Dantoft, Thomas M., Karpe, Fredrik, Neville, Matt J., Timpson, Nicholas J., Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T., Pedersen, Nancy L., Magnusson, Patrik K. E., Boomsma, Dorret I., Willemsen, Allegonda H. M., Cupples, LAdrienne, van Meurs, Joyce B. J., Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J., Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C., Kooner, Jaspal S., de Vries, Paul S., Morrison, Alanna C., Hazelhurst, Scott, Ramsay, Michèle, North, Kari E., Daviglus, Martha, Kraft, Peter, Martin, Nicholas G., Whitfield, John B., Abbas, Shahid, Saleheen, Danish, Walters, Robin G., Holmes, Michael V., Black, Corri, Smith, Blair H., Baras, Aris, Justice, Anne E., Buring, Julie E., Ridker, Paul M., Chasman, Daniel I., Kooperberg, Charles, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A., Trembath, Richard C., Wei, Wei-Qi, Jarvik, Gail P., Namjou, Bahram, Hayes, M. Geoffrey, Ritchie, Marylyn D., Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, YEugene, Ho, Yuk-Lam, Lynch, Julie A., Rader, Daniel J., Tsao, Philip S., Chang, Kyong-Mi, Cho, Kelly, O’Donnell, Christopher J., Gaziano, John M., Wilson, Peter W. F., Frayling, Timothy M., Hirschhorn, Joel N., Kathiresan, Sekar, Mohlke, Karen L., Sun, Yan V., Morris, Andrew P., Boehnke, Michael, Brown, Christopher D., Natarajan, Pradeep, Deloukas, Panos, Willer, Cristen J., Assimes, Themistocles L., and Peloso, Gina M.
- Published
- 2022
- Full Text
- View/download PDF
17. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- Author
-
Justice, Anne E, Karaderi, Tugce, Highland, Heather M, Young, Kristin L, Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L, Fine, Rebecca S, Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W, Locke, Adam E, Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Dörr, Marcus, Drenos, Fotios, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Fornage, Myriam, Fox, Caroline S, Franks, Paul W, Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, and Hattersley, Andrew T
- Subjects
Clinical Research ,Obesity ,Genetics ,Nutrition ,Prevention ,Biotechnology ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Cardiovascular ,Animals ,Body Fat Distribution ,Body Mass Index ,Case-Control Studies ,Drosophila ,Exome ,Female ,Gene Frequency ,Genetic Predisposition to Disease ,Genetic Variation ,Genome-Wide Association Study ,Homeostasis ,Humans ,Lipids ,Male ,Proteins ,Risk Factors ,Waist-Hip Ratio ,CHD Exome+ Consortium ,Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium ,EPIC-CVD Consortium ,ExomeBP Consortium ,Global Lipids Genetic Consortium ,GoT2D Genes Consortium ,InterAct ,ReproGen Consortium ,T2D-Genes Consortium ,MAGIC Investigators ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF
- Published
- 2019
18. Cornelia de Lange syndrome in diverse populations
- Author
-
Dowsett, Leah, Porras, Antonio R, Kruszka, Paul, Davis, Brandon, Hu, Tommy, Honey, Engela, Badoe, Eben, Thong, Meow‐Keong, Leon, Eyby, Girisha, Katta M, Shukla, Anju, Nayak, Shalini S, Shotelersuk, Vorasuk, Megarbane, Andre, Phadke, Shubha, Sirisena, Nirmala D, Dissanayake, Vajira HW, Ferreira, Carlos R, Kisling, Monisha S, Tanpaiboon, Pranoot, Uwineza, Annette, Mutesa, Leon, Tekendo‐Ngongang, Cedrik, Wonkam, Ambroise, Fieggen, Karen, Batista, Leticia Cassimiro, Moretti‐Ferreira, Danilo, Stevenson, Roger E, Prijoles, Eloise J, Everman, David, Clarkson, Kate, Worthington, Jessica, Kimonis, Virginia, Hisama, Fuki, Crowe, Carol, Wong, Paul, Johnson, Kisha, Clark, Robin D, Bird, Lynne, Masser‐Frye, Diane, McDonald, Marie, Willems, Patrick, Roeder, Elizabeth, Saitta, Sulgana, Anyane‐Yeoba, Kwame, Demmer, Laurie, Hamajima, Naoki, Stark, Zornitza, Gillies, Greta, Hudgins, Louanne, Dave, Usha, Shalev, Stavit, Siu, Victoria, Gupta, Neerja, Kabra, Madhulika, Ades, Ann, Dubbs, Holly, Raible, Sarah, Kaur, Maninder, Salzano, Emanuela, Jackson, Laird, Deardorff, Matthew, Kline, Antonie, Summar, Marshall, Muenke, Maximilian, Linguraru, Marius George, and Krantz, Ian D
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Brain Disorders ,Rare Diseases ,Clinical Research ,Intellectual and Developmental Disabilities (IDD) ,Pediatric ,Neurosciences ,Congenital ,Abnormalities ,Multiple ,Adolescent ,Adult ,Cell Cycle Proteins ,Child ,Child ,Preschool ,Chondroitin Sulfate Proteoglycans ,Chromosomal Proteins ,Non-Histone ,De Lange Syndrome ,Face ,Female ,Humans ,Image Processing ,Computer-Assisted ,Infant ,Infant ,Newborn ,Intellectual Disability ,Male ,Mutation ,Phenotype ,Racial Groups ,Young Adult ,CdLS ,Cornelia de Lange syndrome ,diverse populations ,facial analysis technology ,NIPBL ,underrepresented minorities ,Clinical Sciences ,Clinical sciences - Abstract
Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.
- Published
- 2019
19. An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis
- Author
-
Liu, Jun, Carnero-Montoro, Elena, van Dongen, Jenny, Lent, Samantha, Nedeljkovic, Ivana, Ligthart, Symen, Tsai, Pei-Chien, Martin, Tiphaine C, Mandaviya, Pooja R, Jansen, Rick, Peters, Marjolein J, Duijts, Liesbeth, Jaddoe, Vincent WV, Tiemeier, Henning, Felix, Janine F, Willemsen, Gonneke, de Geus, Eco JC, Chu, Audrey Y, Levy, Daniel, Hwang, Shih-Jen, Bressler, Jan, Gondalia, Rahul, Salfati, Elias L, Herder, Christian, Hidalgo, Bertha A, Tanaka, Toshiko, Moore, Ann Zenobia, Lemaitre, Rozenn N, Jhun, Min A, Smith, Jennifer A, Sotoodehnia, Nona, Bandinelli, Stefania, Ferrucci, Luigi, Arnett, Donna K, Grallert, Harald, Assimes, Themistocles L, Hou, Lifang, Baccarelli, Andrea, Whitsel, Eric A, van Dijk, Ko Willems, Amin, Najaf, Uitterlinden, André G, Sijbrands, Eric JG, Franco, Oscar H, Dehghan, Abbas, Spector, Tim D, Dupuis, Josée, Hivert, Marie-France, Rotter, Jerome I, Meigs, James B, Pankow, James S, van Meurs, Joyce BJ, Isaacs, Aaron, Boomsma, Dorret I, Bell, Jordana T, Demirkan, Ayşe, and van Duijn, Cornelia M
- Subjects
Biological Sciences ,Genetics ,Nutrition ,Diabetes ,Human Genome ,Obesity ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Adult ,Aged ,Aged ,80 and over ,Computer Simulation ,CpG Islands ,DNA Methylation ,Diabetes Mellitus ,Type 2 ,Epigenesis ,Genetic ,Epigenomics ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Genome-Wide Association Study ,Glucose ,Homeostasis ,Humans ,Insulin ,Male ,Metabolic Networks and Pathways ,Middle Aged ,Polymorphism ,Single Nucleotide ,Young Adult - Abstract
Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.
- Published
- 2019
20. Accurate detection of circulating tumor DNA using nanopore consensus sequencing
- Author
-
Alessio Marcozzi, Myrthe Jager, Martin Elferink, Roy Straver, Joost H. van Ginkel, Boris Peltenburg, Li-Ting Chen, Ivo Renkens, Joyce van Kuik, Chris Terhaard, Remco de Bree, Lot A. Devriese, Stefan M. Willems, Wigard P. Kloosterman, and Jeroen de Ridder
- Subjects
Medicine ,Genetics ,QH426-470 - Abstract
Abstract Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant ctDNA molecules based on somatic variants, extremely sensitive sequencing methods are required. Here, we describe a new technique, CyclomicsSeq, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule. Consensus calling of the DNA copies increased the base-calling accuracy ~60×, enabling accurate detection of TP53 mutations at frequencies down to 0.02%. We demonstrate that a TP53-specific CyclomicsSeq assay can be successfully used to monitor tumor burden during treatment for head-and-neck cancer patients. CyclomicsSeq can be applied to any genomic locus and offers an accurate diagnostic liquid biopsy approach that can be implemented in clinical workflows.
- Published
- 2021
- Full Text
- View/download PDF
21. Author Correction: Accurate detection of circulating tumor DNA using nanopore consensus sequencing
- Author
-
Alessio Marcozzi, Myrthe Jager, Martin Elferink, Roy Straver, Joost H. van Ginkel, Boris Peltenburg, Li-Ting Chen, Ivo Renkens, Joyce van Kuik, Chris Terhaard, Remco de Bree, Lot A. Devriese, Stefan M. Willems, Wigard P. Kloosterman, and Jeroen de Ridder
- Subjects
Medicine ,Genetics ,QH426-470 - Published
- 2023
- Full Text
- View/download PDF
22. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- Author
-
Mahajan, Anubha, Wessel, Jennifer, Willems, Sara M, Zhao, Wei, Robertson, Neil R, Chu, Audrey Y, Gan, Wei, Kitajima, Hidetoshi, Taliun, Daniel, Rayner, N William, Guo, Xiuqing, Lu, Yingchang, Li, Man, Jensen, Richard A, Hu, Yao, Huo, Shaofeng, Lohman, Kurt K, Zhang, Weihua, Cook, James P, Prins, Bram Peter, Flannick, Jason, Grarup, Niels, Trubetskoy, Vassily Vladimirovich, Kravic, Jasmina, Kim, Young Jin, Rybin, Denis V, Yaghootkar, Hanieh, Müller-Nurasyid, Martina, Meidtner, Karina, Li-Gao, Ruifang, Varga, Tibor V, Marten, Jonathan, Li, Jin, Smith, Albert Vernon, An, Ping, Ligthart, Symen, Gustafsson, Stefan, Malerba, Giovanni, Demirkan, Ayse, Tajes, Juan Fernandez, Steinthorsdottir, Valgerdur, Wuttke, Matthias, Lecoeur, Cécile, Preuss, Michael, Bielak, Lawrence F, Graff, Marielisa, Highland, Heather M, Justice, Anne E, Liu, Dajiang J, Marouli, Eirini, Peloso, Gina Marie, Warren, Helen R, Afaq, Saima, Afzal, Shoaib, Ahlqvist, Emma, Almgren, Peter, Amin, Najaf, Bang, Lia B, Bertoni, Alain G, Bombieri, Cristina, Bork-Jensen, Jette, Brandslund, Ivan, Brody, Jennifer A, Burtt, Noël P, Canouil, Mickaël, Chen, Yii-Der Ida, Cho, Yoon Shin, Christensen, Cramer, Eastwood, Sophie V, Eckardt, Kai-Uwe, Fischer, Krista, Gambaro, Giovanni, Giedraitis, Vilmantas, Grove, Megan L, de Haan, Hugoline G, Hackinger, Sophie, Hai, Yang, Han, Sohee, Tybjærg-Hansen, Anne, Hivert, Marie-France, Isomaa, Bo, Jäger, Susanne, Jørgensen, Marit E, Jørgensen, Torben, Käräjämäki, Annemari, Kim, Bong-Jo, Kim, Sung Soo, Koistinen, Heikki A, Kovacs, Peter, Kriebel, Jennifer, Kronenberg, Florian, Läll, Kristi, Lange, Leslie A, Lee, Jung-Jin, Lehne, Benjamin, Li, Huaixing, Lin, Keng-Hung, Linneberg, Allan, Liu, Ching-Ti, and Liu, Jun
- Subjects
Diabetes ,Human Genome ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Alleles ,Chromosome Mapping ,Diabetes Mellitus ,Type 2 ,Female ,Genetic Predisposition to Disease ,Genetic Variation ,Genome-Wide Association Study ,Humans ,Male ,White People ,Exome Sequencing ,ExomeBP Consortium ,MAGIC Consortium ,GIANT Consortium ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P
- Published
- 2018
23. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- Author
-
Turcot, Valérie, Lu, Yingchang, Highland, Heather M, Schurmann, Claudia, Justice, Anne E, Fine, Rebecca S, Bradfield, Jonathan P, Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E, Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E, Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L, Alfred, Tamuno, Feitosa, Mary F, Masca, Nicholas GD, Manning, Alisa K, Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie CY, Reiner, Alex P, Vedantam, Sailaja, Willems, Sara M, Winkler, Thomas W, Abecasis, Gonçalo, Aben, Katja K, Alam, Dewan S, Alharthi, Sameer E, Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Bang, Lia E, Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Brumat, Marco, Burt, Amber A, Butterworth, Adam S, Campbell, Peter T, Cappellani, Stefania, Carey, David J, Catamo, Eulalia, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der I, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J, Crosslin, David S, Cuellar-Partida, Gabriel, D’Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul IW, Groot, Mark CH, Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, Heijer, Martin, Hollander, Anneke I, Ruijter, Hester M, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M, and Easton, Douglas F
- Subjects
Genetics ,Biotechnology ,Nutrition ,Obesity ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Cancer ,Stroke ,Metabolic and endocrine ,Cardiovascular ,Oral and gastrointestinal ,Adult ,Animals ,Body Mass Index ,Drosophila ,Energy Intake ,Energy Metabolism ,Female ,Gene Frequency ,Genetic Variation ,Humans ,Male ,Proteins ,Syndrome ,CHD Exome+ Consortium ,EPIC-CVD Consortium ,ExomeBP Consortium ,Global Lipids Genetic Consortium ,GoT2D Genes Consortium ,EPIC InterAct Consortium ,INTERVAL Study ,ReproGen Consortium ,T2D-Genes Consortium ,MAGIC Investigators ,Understanding Society Scientific Group ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
- Published
- 2018
24. A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder
- Author
-
Livia O. Loureiro, Jennifer L. Howe, Miriam S. Reuter, Alana Iaboni, Kristina Calli, Delnaz Roshandel, Iva Pritišanac, Alan Moses, Julie D. Forman-Kay, Brett Trost, Mehdi Zarrei, Olivia Rennie, Lynette Y. S. Lau, Christian R. Marshall, Siddharth Srivastava, Brianna Godlewski, Elizabeth D. Buttermore, Mustafa Sahin, Dean Hartley, Thomas Frazier, Jacob Vorstman, Stelios Georgiades, Suzanne M. E. Lewis, Peter Szatmari, Clarrisa A. (Lisa) Bradley, Anne-Claude Tabet, Marjolaine Willems, Serge Lumbroso, Amélie Piton, James Lespinasse, Richard Delorme, Thomas Bourgeron, Evdokia Anagnostou, and Stephen W. Scherer
- Subjects
Medicine ,Genetics ,QH426-470 - Abstract
Abstract Autism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.
- Published
- 2021
- Full Text
- View/download PDF
25. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- Author
-
Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, William N, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, Kong, Augustine, Sigurðsson, Gunnar, Kerrison, Nicola D, Luan, Jian'an, Liang, Liming, Meitinger, Thomas, Roden, Michael, Thorand, Barbara, Esko, Tõnu, Mihailov, Evelin, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Isomaa, Bo, Lyssenko, Valeriya, Tuomi, Tiinamaija, Couper, David J, Pankow, James S, Grarup, Niels, Have, Christian T, Jørgensen, Marit E, Jørgensen, Torben, Linneberg, Allan, Cornelis, Marilyn C, van Dam, Rob M, Hunter, David J, Kraft, Peter, Sun, Qi, Edkins, Sarah, Owen, Katharine R, Perry, John RB, Wood, Andrew R, Zeggini, Eleftheria, Tajes-Fernandes, Juan, Abecasis, Goncalo R, Bonnycastle, Lori L, Chines, Peter S, Stringham, Heather M, Koistinen, Heikki A, Kinnunen, Leena, Sennblad, Bengt, Mühleisen, Thomas W, Nöthen, Markus M, Pechlivanis, Sonali, Baldassarre, Damiano, Gertow, Karl, Humphries, Steve E, Tremoli, Elena, Klopp, Norman, Meyer, Julia, and Steinbach, Gerald
- Subjects
Human Genome ,Diabetes ,Obesity ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Diabetes Mellitus ,Type 2 ,Gene Expression Regulation ,Genetic Variation ,Genome-Wide Association Study ,Humans ,White People ,DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium ,Medical and Health Sciences ,Endocrinology & Metabolism - Abstract
To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
- Published
- 2017
26. Interpreting short tandem repeat variations in humans using mutational constraint
- Author
-
Gymrek, Melissa, Willems, Thomas, Reich, David, and Erlich, Yaniv
- Subjects
Biological Sciences ,Genetics ,Human Genome ,Computational Biology ,Diploidy ,Evolution ,Molecular ,Genetic Diseases ,Inborn ,Genetic Fitness ,Genetics ,Medical ,Genotype ,Heterozygote ,Humans ,Microsatellite Instability ,Microsatellite Repeats ,Models ,Genetic ,Molecular Sequence Annotation ,Mutation Rate ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Identifying regions of the genome that are depleted of mutations can distinguish potentially deleterious variants. Short tandem repeats (STRs), also known as microsatellites, are among the largest contributors of de novo mutations in humans. However, per-locus studies of STR mutations have been limited to highly ascertained panels of several dozen loci. Here we harnessed bioinformatics tools and a novel analytical framework to estimate mutation parameters for each STR in the human genome by correlating STR genotypes with local sequence heterozygosity. We applied our method to obtain robust estimates of the impact of local sequence features on mutation parameters and used these estimates to create a framework for measuring constraint at STRs by comparing observed versus expected mutation rates. Constraint scores identified known pathogenic variants with early-onset effects. Our metric will provide a valuable tool for prioritizing pathogenic STRs in medical genetics studies.
- Published
- 2017
27. Contextual Exceptionalism After Death: An Information Ethics Approach to Post-Mortem Privacy in Health Data Research
- Author
-
Bak, Marieke A. R. and Willems, Dick L.
- Published
- 2022
- Full Text
- View/download PDF
28. Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism
- Author
-
Evin M. Padhi, Tristan J. Hayeck, Zhang Cheng, Sumantra Chatterjee, Brandon J. Mannion, Marta Byrska-Bishop, Marjolaine Willems, Lucile Pinson, Sylvia Redon, Caroline Benech, Kevin Uguen, Séverine Audebert-Bellanger, Cédric Le Marechal, Claude Férec, Stephanie Efthymiou, Fatima Rahman, Shazia Maqbool, Reza Maroofian, Henry Houlden, Rajeeva Musunuri, Giuseppe Narzisi, Avinash Abhyankar, Riana D. Hunter, Jennifer Akiyama, Lauren E. Fries, Jeffrey K. Ng, Elvisa Mehinovic, Nick Stong, Andrew S. Allen, Diane E. Dickel, Raphael A. Bernier, David U. Gorkin, Len A. Pennacchio, Michael C. Zody, and Tychele N. Turner
- Subjects
Autism ,Neurodevelopmental disorder ,Enhancer ,Gene regulatory network ,EBF3 ,hs737 ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. Results We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10−3), and combined dataset (p = 1.1 × 10−4). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10−35, loss-of-function p = 2.26 × 10−13) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10−6, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia. Conclusions In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.
- Published
- 2021
- Full Text
- View/download PDF
29. The global dissemination of hospital clones of Enterococcus faecium
- Author
-
Sebastiaan J. van Hal, Rob J. L. Willems, Theodore Gouliouris, Susan A. Ballard, Teresa M. Coque, Anette M. Hammerum, Kristin Hegstad, Hendrik T. Westh, Benjamin P. Howden, Surbhi Malhotra-Kumar, Guido Werner, Katsunori Yanagihara, Ashlee M. Earl, Katherine E. Raven, Jukka Corander, Rory Bowden, and Enterococcal Group
- Subjects
Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background The hospital-adapted A1 group of Enterococcus faecium remains an organism of significant concern in the context of drug-resistant hospital-associated infections. How this pathogen evolves and disseminates remains poorly understood. Methods A large, globally representative collection of short-read genomic data from the hospital-associated A1 group of Enterococcus faecium was assembled (n = 973). We analysed, using a novel analysis approach, global diversity in terms of both the dynamics of the accessory genome and homologous recombination among conserved genes. Results Two main modes of genomic evolution continue to shape E. faecium: the acquisition and loss of genes, including antimicrobial resistance genes, through mobile genetic elements including plasmids, and homologous recombination of the core genome. These events lead to new clones emerging at the local level, followed by the erosion of signals of clonality through recombination, and in some identifiable cases producing new clonal clusters. These patterns lead to new, emerging lineages which are able to spread globally over relatively short timeframes. Conclusions The ability of A1 E. faecium to continually present new combinations of genes for potential selection suggests that controlling this pathogen will remain challenging but establishing a framework for understanding genomic evolution is likely to aid in tracking the threats posed by newly emerging lineages.
- Published
- 2021
- Full Text
- View/download PDF
30. Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.
- Author
-
Willems, Sara M, Wright, Daniel J, Day, Felix R, Trajanoska, Katerina, Joshi, Peter K, Morris, John A, Matteini, Amy M, Garton, Fleur C, Grarup, Niels, Oskolkov, Nikolay, Thalamuthu, Anbupalam, Mangino, Massimo, Liu, Jun, Demirkan, Ayse, Lek, Monkol, Xu, Liwen, Wang, Guan, Oldmeadow, Christopher, Gaulton, Kyle J, Lotta, Luca A, Miyamoto-Mikami, Eri, Rivas, Manuel A, White, Tom, Loh, Po-Ru, Aadahl, Mette, Amin, Najaf, Attia, John R, Austin, Krista, Benyamin, Beben, Brage, Søren, Cheng, Yu-Ching, Cięszczyk, Paweł, Derave, Wim, Eriksson, Karl-Fredrik, Eynon, Nir, Linneberg, Allan, Lucia, Alejandro, Massidda, Myosotis, Mitchell, Braxton D, Miyachi, Motohiko, Murakami, Haruka, Padmanabhan, Sandosh, Pandey, Ashutosh, Papadimitriou, Ioannis, Rajpal, Deepak K, Sale, Craig, Schnurr, Theresia M, Sessa, Francesco, Shrine, Nick, Tobin, Martin D, Varley, Ian, Wain, Louise V, Wray, Naomi R, Lindgren, Cecilia M, MacArthur, Daniel G, Waterworth, Dawn M, McCarthy, Mark I, Pedersen, Oluf, Khaw, Kay-Tee, Kiel, Douglas P, GEFOS Any-Type of Fracture Consortium, Pitsiladis, Yannis, Fuku, Noriyuki, Franks, Paul W, North, Kathryn N, van Duijn, Cornelia M, Mather, Karen A, Hansen, Torben, Hansson, Ola, Spector, Tim, Murabito, Joanne M, Richards, J Brent, Rivadeneira, Fernando, Langenberg, Claudia, Perry, John RB, Wareham, Nick J, and Scott, Robert A
- Subjects
GEFOS Any-Type of Fracture Consortium ,Hand ,Humans ,Actins ,Transforming Growth Factor alpha ,Membrane Proteins ,Neoplasm Proteins ,Nuclear Proteins ,Repressor Proteins ,Hand Strength ,Cohort Studies ,Genetics ,Population ,Polymorphism ,Single Nucleotide ,Adult ,Aged ,Middle Aged ,European Continental Ancestry Group ,Female ,Male ,Genome-Wide Association Study ,Genetic Loci ,United Kingdom ,Prevention ,Genetics ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Musculoskeletal - Abstract
Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P
- Published
- 2017
31. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance
- Author
-
Lotta, Luca A, Gulati, Pawan, Day, Felix R, Payne, Felicity, Ongen, Halit, van de Bunt, Martijn, Gaulton, Kyle J, Eicher, John D, Sharp, Stephen J, Luan, Jian'an, De Lucia Rolfe, Emanuella, Stewart, Isobel D, Wheeler, Eleanor, Willems, Sara M, Adams, Claire, Yaghootkar, Hanieh, Forouhi, Nita G, Khaw, Kay-Tee, Johnson, Andrew D, Semple, Robert K, Frayling, Timothy, Perry, John RB, Dermitzakis, Emmanouil, McCarthy, Mark I, Barroso, Inês, Wareham, Nicholas J, Savage, David B, Langenberg, Claudia, O'Rahilly, Stephen, and Scott, Robert A
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Clinical Research ,Human Genome ,Genetics ,Diabetes ,Aetiology ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Adipose Tissue ,Animals ,Blood Glucose ,Body Mass Index ,Cardiovascular Diseases ,Case-Control Studies ,Disease Models ,Animal ,Female ,Genome-Wide Association Study ,Genomics ,Humans ,Insulin Resistance ,Male ,Metabolic Diseases ,Mice ,Obesity ,Phenotype ,EPIC-InterAct Consortium ,Cambridge FPLD1 Consortium ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
- Published
- 2017
32. Genomewide meta‐analysis identifies loci associated with IGF‐I and IGFBP‐3 levels with impact on age‐related traits
- Author
-
Teumer, Alexander, Qi, Qibin, Nethander, Maria, Aschard, Hugues, Bandinelli, Stefania, Beekman, Marian, Berndt, Sonja I, Bidlingmaier, Martin, Broer, Linda, Group, CHARGE Longevity Working, Cappola, Anne, Ceda, Gian Paolo, Chanock, Stephen, Chen, Ming‐Huei, Chen, Tai C, Chen, Yii‐Der Ida, Chung, Jonathan, Del Greco Miglianico, Fabiola, Eriksson, Joel, Ferrucci, Luigi, Friedrich, Nele, Gnewuch, Carsten, Goodarzi, Mark O, Grarup, Niels, Guo, Tingwei, Hammer, Elke, Hayes, Richard B, Hicks, Andrew A, Hofman, Albert, Houwing‐Duistermaat, Jeanine J, Hu, Frank, Hunter, David J, Husemoen, Lise L, Isaacs, Aaron, Jacobs, Kevin B, Janssen, Joop AMJL, Jansson, John‐Olov, Jehmlich, Nico, Johnson, Simon, Juul, Anders, Karlsson, Magnus, Kilpelainen, Tuomas O, Kovacs, Peter, Kraft, Peter, Li, Chao, Linneberg, Allan, Liu, Yongmei, Loos, Ruth JF, Consortium, Body Composition Genetics, Lorentzon, Mattias, Lu, Yingchang, Maggio, Marcello, Magi, Reedik, Meigs, James, Mellström, Dan, Nauck, Matthias, Newman, Anne B, Pollak, Michael N, Pramstaller, Peter P, Prokopenko, Inga, Psaty, Bruce M, Reincke, Martin, Rimm, Eric B, Rotter, Jerome I, Pierre, Aude Saint, Schurmann, Claudia, Seshadri, Sudha, Sjögren, Klara, Slagboom, P Eline, Strickler, Howard D, Stumvoll, Michael, Suh, Yousin, Sun, Qi, Zhang, Cuilin, Svensson, Johan, Tanaka, Toshiko, Tare, Archana, Tönjes, Anke, Uh, Hae‐Won, van Duijn, Cornelia M, van Heemst, Diana, Vandenput, Liesbeth, Vasan, Ramachandran S, Völker, Uwe, Willems, Sara M, Ohlsson, Claes, Wallaschofski, Henri, and Kaplan, Robert C
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Clinical Research ,Aging ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Cardiovascular ,Adult ,Female ,Gene Expression Regulation ,Genome-Wide Association Study ,Humans ,Insulin-Like Growth Factor Binding Protein 3 ,Insulin-Like Growth Factor I ,Male ,Metabolome ,Quantitative Trait Loci ,Quantitative Trait ,Heritable ,Regulatory Sequences ,Nucleic Acid ,aging ,genomewide association study ,growth hormone axis ,IGF-I ,IGFBP-3 ,longevity ,CHARGE Longevity Working Group ,Body Composition Genetics Consortium ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.
- Published
- 2016
33. Genome-wide associations for birth weight and correlations with adult disease
- Author
-
Horikoshi, Momoko, Beaumont, Robin N, Day, Felix R, Warrington, Nicole M, Kooijman, Marjolein N, Fernandez-Tajes, Juan, Feenstra, Bjarke, van Zuydam, Natalie R, Gaulton, Kyle J, Grarup, Niels, Bradfield, Jonathan P, Strachan, David P, Li-Gao, Ruifang, Ahluwalia, Tarunveer S, Kreiner, Eskil, Rueedi, Rico, Lyytikäinen, Leo-Pekka, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Hottenga, Jouke-Jan, Vilor-Tejedor, Natalia, Joshi, Peter K, Boh, Eileen Tai Hui, Ntalla, Ioanna, Pitkänen, Niina, Mahajan, Anubha, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Nodzenski, Michael, Diver, Louise A, Zondervan, Krina T, Bustamante, Mariona, Marques-Vidal, Pedro, Mercader, Josep M, Bennett, Amanda J, Rahmioglu, Nilufer, Nyholt, Dale R, Ma, Ronald CW, Tam, Claudia HT, Tam, Wing Hung, Ganesh, Santhi K, van Rooij, Frank JA, Jones, Samuel E, Loh, Po-Ru, Ruth, Katherine S, Tuke, Marcus A, Tyrrell, Jessica, Wood, Andrew R, Yaghootkar, Hanieh, Scholtens, Denise M, Paternoster, Lavinia, Prokopenko, Inga, Kovacs, Peter, Atalay, Mustafa, Willems, Sara M, Panoutsopoulou, Kalliope, Wang, Xu, Carstensen, Lisbeth, Geller, Frank, Schraut, Katharina E, Murcia, Mario, van Beijsterveldt, Catharina EM, Willemsen, Gonneke, Appel, Emil VR, Fonvig, Cilius E, Trier, Caecilie, Tiesler, Carla MT, Standl, Marie, Kutalik, Zoltán, Bonàs-Guarch, Sílvia, Hougaard, David M, Sánchez, Friman, Torrents, David, Waage, Johannes, Hollegaard, Mads V, de Haan, Hugoline G, Rosendaal, Frits R, Medina-Gomez, Carolina, Ring, Susan M, Hemani, Gibran, McMahon, George, Robertson, Neil R, Groves, Christopher J, Langenberg, Claudia, Luan, Jian’an, Scott, Robert A, Zhao, Jing Hua, Mentch, Frank D, MacKenzie, Scott M, Reynolds, Rebecca M, Lowe, William L, Tönjes, Anke, Stumvoll, Michael, Lindi, Virpi, Lakka, Timo A, and van Duijn, Cornelia M
- Subjects
Nutrition ,Perinatal Period - Conditions Originating in Perinatal Period ,Human Genome ,Genetics ,Clinical Research ,Preterm ,Low Birth Weight and Health of the Newborn ,Obesity ,Prevention ,Pediatric ,Infant Mortality ,2.1 Biological and endogenous factors ,Aetiology ,Adult ,Aging ,Anthropometry ,Birth Weight ,Blood Pressure ,Chromatin Assembly and Disassembly ,Cohort Studies ,Coronary Artery Disease ,Datasets as Topic ,Diabetes Mellitus ,Type 2 ,Female ,Fetus ,Genetic Loci ,Genetic Predisposition to Disease ,Genetic Variation ,Genome-Wide Association Study ,Genomic Imprinting ,Genotype ,Glucose ,Glycogen ,Humans ,Insulin ,Male ,Phenotype ,Signal Transduction ,CHARGE Consortium Hematology Working Group ,Early Growth Genetics (EGG) Consortium ,General Science & Technology - Abstract
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P
- Published
- 2016
34. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations
- Author
-
Mallick, Swapan, Li, Heng, Lipson, Mark, Mathieson, Iain, Gymrek, Melissa, Racimo, Fernando, Zhao, Mengyao, Chennagiri, Niru, Nordenfelt, Susanne, Tandon, Arti, Skoglund, Pontus, Lazaridis, Iosif, Sankararaman, Sriram, Fu, Qiaomei, Rohland, Nadin, Renaud, Gabriel, Erlich, Yaniv, Willems, Thomas, Gallo, Carla, Spence, Jeffrey P, Song, Yun S, Poletti, Giovanni, Balloux, Francois, van Driem, George, de Knijff, Peter, Romero, Irene Gallego, Jha, Aashish R, Behar, Doron M, Bravi, Claudio M, Capelli, Cristian, Hervig, Tor, Moreno-Estrada, Andres, Posukh, Olga L, Balanovska, Elena, Balanovsky, Oleg, Karachanak-Yankova, Sena, Sahakyan, Hovhannes, Toncheva, Draga, Yepiskoposyan, Levon, Tyler-Smith, Chris, Xue, Yali, Abdullah, M Syafiq, Ruiz-Linares, Andres, Beall, Cynthia M, Di Rienzo, Anna, Jeong, Choongwon, Starikovskaya, Elena B, Metspalu, Ene, Parik, Jüri, Villems, Richard, Henn, Brenna M, Hodoglugil, Ugur, Mahley, Robert, Sajantila, Antti, Stamatoyannopoulos, George, Wee, Joseph TS, Khusainova, Rita, Khusnutdinova, Elza, Litvinov, Sergey, Ayodo, George, Comas, David, Hammer, Michael F, Kivisild, Toomas, Klitz, William, Winkler, Cheryl A, Labuda, Damian, Bamshad, Michael, Jorde, Lynn B, Tishkoff, Sarah A, Watkins, W Scott, Metspalu, Mait, Dryomov, Stanislav, Sukernik, Rem, Singh, Lalji, Thangaraj, Kumarasamy, Pääbo, Svante, Kelso, Janet, Patterson, Nick, and Reich, David
- Subjects
Human Genome ,Genetics ,Animals ,Australia ,Black People ,Datasets as Topic ,Genetic Variation ,Genetics ,Population ,Genome ,Human ,Genomics ,History ,Ancient ,Human Migration ,Humans ,Mutation Rate ,Native Hawaiian or Other Pacific Islander ,Neanderthals ,New Guinea ,Phylogeny ,Racial Groups ,Sequence Analysis ,DNA ,Species Specificity ,Time Factors ,General Science & Technology - Abstract
Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.
- Published
- 2016
35. Association of the IGF1 gene with fasting insulin levels
- Author
-
Willems, Sara M, Cornes, Belinda K, Brody, Jennifer A, Morrison, Alanna C, Lipovich, Leonard, Dauriz, Marco, Chen, Yuning, Liu, Ching-Ti, Rybin, Denis V, Gibbs, Richard A, Muzny, Donna, Pankow, James S, Psaty, Bruce M, Boerwinkle, Eric, Rotter, Jerome I, Siscovick, David S, Vasan, Ramachandran S, Kaplan, Robert C, Isaacs, Aaron, Dupuis, Josée, van Duijn, Cornelia M, and Meigs, James B
- Subjects
Biological Sciences ,Genetics ,Human Genome ,Diabetes ,Aetiology ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Adult ,Aged ,Fasting ,Female ,Humans ,Insulin ,Insulin-Like Growth Factor I ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,Clinical Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (PSKAT=5.7 × 10(-4)). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (Pconditional=0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology.
- Published
- 2016
36. Mode and dynamics of vanA-type vancomycin resistance dissemination in Dutch hospitals
- Author
-
Sergio Arredondo-Alonso, Janetta Top, Jukka Corander, Rob J. L. Willems, and Anita C. Schürch
- Subjects
Enterococcus faecium ,Genome sequencing ,Vancomycin resistance ,Network ,Clonal dissemination ,Horizontal dissemination ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Enterococcus faecium is a commensal of the gastrointestinal tract of animals and humans but also a causative agent of hospital-acquired infections. Resistance against glycopeptides and to vancomycin has motivated the inclusion of E. faecium in the WHO global priority list. Vancomycin resistance can be conferred by the vanA gene cluster on the transposon Tn1546, which is frequently present in plasmids. The vanA gene cluster can be disseminated clonally but also horizontally either by plasmid dissemination or by Tn1546 transposition between different genomic locations. Methods We performed a retrospective study of the genomic epidemiology of 309 vancomycin-resistant E. faecium (VRE) isolates across 32 Dutch hospitals (2012–2015). Genomic information regarding clonality and Tn1546 characterization was extracted using hierBAPS sequence clusters (SC) and TETyper, respectively. Plasmids were predicted using gplas in combination with a network approach based on shared k-mer content. Next, we conducted a pairwise comparison between isolates sharing a potential epidemiological link to elucidate whether clonal, plasmid, or Tn1546 spread accounted for vanA-type resistance dissemination. Results On average, we estimated that 59% of VRE cases with a potential epidemiological link were unrelated which was defined as VRE pairs with a distinct Tn1546 variant. Clonal dissemination accounted for 32% cases in which the same SC and Tn1546 variants were identified. Horizontal plasmid dissemination accounted for 7% of VRE cases, in which we observed VRE pairs belonging to a distinct SC but carrying an identical plasmid and Tn1546 variant. In 2% of cases, we observed the same Tn1546 variant in distinct SC and plasmid types which could be explained by mixed and consecutive events of clonal and plasmid dissemination. Conclusions In related VRE cases, the dissemination of the vanA gene cluster in Dutch hospitals between 2012 and 2015 was dominated by clonal spread. However, we also identified outbreak settings with high frequencies of plasmid dissemination in which the spread of resistance was mainly driven by horizontal gene transfer (HGT). This study demonstrates the feasibility of distinguishing between modes of dissemination with short-read data and provides a novel assessment to estimate the relative contribution of nested genomic elements in the dissemination of vanA-type resistance.
- Published
- 2021
- Full Text
- View/download PDF
37. Proceedings of the EuBIC-MS 2020 Developers’ Meeting
- Author
-
Christopher Ashwood, Wout Bittremieux, Eric W. Deutsch, Nadezhda T. Doncheva, Viktoria Dorfer, Ralf Gabriels, Vladimir Gorshkov, Surya Gupta, Andrew R. Jones, Lukas Käll, Dominik Kopczynski, Lydie Lane, Ludwig Lautenbacher, Marc Legeay, Marie Locard-Paulet, Bart Mesuere, Yasset Perez-Riverol, Eugen Netz, Julianus Pfeuffer, Timo Sachsenberg, Renee Salz, Patroklos Samaras, Henning Schiebenhoefer, Tobias Schmidt, Veit Schwämmle, Alessio Soggiu, Julian Uszkoreit, Tim Van Den Bossche, Bart Van Puyvelde, Joeri Van Strien, Pieter Verschaffelt, Henry Webel, and Sander Willems
- Subjects
Computational mass spectrometry ,Mass spectrometry ,Proteomics ,Bioinformatics ,Spectrum clustering ,Phosphoproteomics ,Genetics ,QH426-470 - Abstract
The 2020 European Bioinformatics Community for Mass Spectrometry (EuBIC-MS) Developers’ meeting was held from January 13th to January 17th 2020 in Nyborg, Denmark. Among the participants were scientists as well as developers working in the field of computational mass spectrometry (MS) and proteomics. The 4-day program was split between introductory keynote lectures and parallel hackathon sessions. During the latter, the participants developed bioinformatics tools and resources addressing outstanding needs in the community. The hackathons allowed less experienced participants to learn from more advanced computational MS experts, and to actively contribute to highly relevant research projects. We successfully produced several new tools that will be useful to the proteomics community by improving data analysis as well as facilitating future research. All keynote recordings are available on https://doi.org/10.5281/zenodo.3890181.
- Published
- 2020
- Full Text
- View/download PDF
38. No gene by stressful life events interaction on individual differences in adults' self-control.
- Author
-
Willems, Yayouk Eva, Raffington, Laurel, Ligthart, Lannie, Pool, Rene, Hottenga, Jouke Jan, Finkenauer, Catrin, and Bartels, Meike
- Subjects
LIFE change events ,INDIVIDUAL differences ,SELF-control ,TRAFFIC accidents ,INTERPERSONAL conflict ,HEALTH behavior ,ADULTS - Abstract
Background: Difficulty with self-control, or the ability to alter impulses and behavior in a goal-directed way, predicts interpersonal conflict, lower socioeconomic attainments, and more adverse health outcomes. Etiological understanding, and intervention for low self-control is, therefore, a public health goal. A prominent developmental theory proposes that individuals with high genetic propensity for low self-control that are also exposed to stressful environments may be most at-risk of low levels of self-control. Here we examine if polygenic measures associated with behaviors marked by low self-control interact with stressful life events in predicting self-control. Methods: Leveraging molecular data from a large population-based Dutch sample (N = 7,090, Mage = 41.2) to test for effects of genetics (i.e., polygenic scores for ADHD and aggression), stressful life events (e.g., traffic accident, violent assault, financial problems), and a gene-by-stress interaction on selfcontrol (measured with the ASEBA Self-Control Scale). Results: Both genetics (b =.03 -.04, p <.001) and stressful life events (b = .11 -.14, p <.001) were associated with individual differences in self-control. We find no evidence of a gene-by-stressful life events interaction on individual differences in adults' self-control. Conclusion: Our findings are consistent with the notion that genetic influences and stressful life events exert largely independent effects on adult self-control. However, the small effect sizes of polygenic scores increases the likelihood of null results. Genetically-informed longitudinal research in large samples can further inform the etiology of individual differences in self-control from early childhood into later adulthood and its downstream implications for public health. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
39. Investigating the association between family connectedness and self-control in adolescence in a genetically sensitive design
- Author
-
Willems, Yayouk E., Laceulle, Odilia M., Bartels, Meike, and Finkenauer, Catrin
- Published
- 2020
- Full Text
- View/download PDF
40. Direct and indirect costs and cost-driving factors in adults with tuberous sclerosis complex: a multicenter cohort study and a review of the literature
- Author
-
Zöllner, Johann Philipp, Grau, Janina, Rosenow, Felix, Sauter, Matthias, Knuf, Markus, Kurlemann, Gerhard, Mayer, Thomas, Hertzberg, Christoph, Bertsche, Astrid, Immisch, Ilka, Klein, Karl Martin, Knake, Susanne, Marquard, Klaus, Meyer, Sascha, Noda, Anna H., von Podewils, Felix, Schäfer, Hannah, Thiels, Charlotte, Willems, Laurent M., Zukunft, Bianca, Schubert-Bast, Susanne, and Strzelczyk, Adam
- Published
- 2021
- Full Text
- View/download PDF
41. Network Analysis Prioritizes DEWAX and ICE1 as the Candidate Genes for Major eQTL Hotspots in Seed Germination of Arabidopsis thaliana
- Author
-
Margi Hartanto, Ronny V. L. Joosen, Basten L. Snoek, Leo A. J. Willems, Mark G. Sterken, Dick de Ridder, Henk W. M. Hilhorst, Wilco Ligterink, and Harm Nijveen
- Subjects
arabidopsis ,eqtl ,network analysis ,seed germination ,Genetics ,QH426-470 - Abstract
Seed germination is characterized by a constant change of gene expression across different time points. These changes are related to specific processes, which eventually determine the onset of seed germination. To get a better understanding on the regulation of gene expression during seed germination, we performed a quantitative trait locus mapping of gene expression (eQTL) at four important seed germination stages (primary dormant, after-ripened, six-hour after imbibition, and radicle protrusion stage) using Arabidopsis thaliana Bay x Sha recombinant inbred lines (RILs). The mapping displayed the distinctness of the eQTL landscape for each stage. We found several eQTL hotspots across stages associated with the regulation of expression of a large number of genes. Interestingly, an eQTL hotspot on chromosome five collocates with hotspots for phenotypic and metabolic QTL in the same population. Finally, we constructed a gene co-expression network to prioritize the regulatory genes for two major eQTL hotspots. The network analysis prioritizes transcription factors DEWAX and ICE1 as the most likely regulatory genes for the hotspot. Together, we have revealed that the genetic regulation of gene expression is dynamic along the course of seed germination.
- Published
- 2020
- Full Text
- View/download PDF
42. A genome-wide scan study identifies a single nucleotide substitution in MC1R gene associated with white coat colour in fallow deer (Dama dama)
- Author
-
Gerald Reiner, Tim Weber, Florian Nietfeld, Dominik Fischer, Christine Wurmser, Ruedi Fries, and Hermann Willems
- Subjects
Fallow deer ,White coat colour ,MC1R ,Next generation sequencing ,Genetics ,QH426-470 - Abstract
Abstract Background The coat colour of fallow deer is highly variable and even white animals can regularly be observed in game farming and in the wild. Affected animals do not show complete albinism but rather some residual pigmentation resembling a very pale beige dilution of coat colour. The eyes and claws of the animals are pigmented. To facilitate the conservation and management of such animals, it would be helpful to know the responsible gene and causative variant. We collected 102 samples from 22 white animals and from 80 animals with wildtype coat colour. The samples came from 12 different wild flocks or game conservations located in different regions of Germany, at the border to Luxembourg and in Poland. The genomes of one white hind and her brown calf were sequenced. Results Based on a list of colour genes of the International Federation of Pigment Cell Societies ( http://www.ifpcs.org/albinism/ ), a variant in the MC1R gene (NM_174108.2:c.143 T > C) resulting in an amino acid exchange from leucine to proline at position 48 of the MC1R receptor protein (NP_776533.1:p.L48P) was identified as a likely cause of coat colour dilution. A gene test revealed that all animals of the white phenotype were of genotype CC whereas all pigmented animals were of genotype TT or TC. The study showed that 14% of the pigmented (brown or dark pigmented) animals carried the white allele. Conclusions A genome-wide scan study led to a molecular test to determine the coat colour of fallow deer. Identification of the MC1R gene provides a deeper insight into the mechanism of dilution. The gene marker is now available for the conservation of white fallow deer in wild and farmed animals.
- Published
- 2020
- Full Text
- View/download PDF
43. Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels
- Author
-
van Leeuwen, Elisabeth M, Sabo, Aniko, Bis, Joshua C, Huffman, Jennifer E, Manichaikul, Ani, Smith, Albert V, Feitosa, Mary F, Demissie, Serkalem, Joshi, Peter K, Duan, Qing, Marten, Jonathan, van Klinken, Jan B, Surakka, Ida, Nolte, Ilja M, Zhang, Weihua, Mbarek, Hamdi, Li-Gao, Ruifang, Trompet, Stella, Verweij, Niek, Evangelou, Evangelos, Lyytikäinen, Leo-Pekka, Tayo, Bamidele O, Deelen, Joris, van der Most, Peter J, van der Laan, Sander W, Arking, Dan E, Morrison, Alanna, Dehghan, Abbas, Franco, Oscar H, Hofman, Albert, Rivadeneira, Fernando, Sijbrands, Eric J, Uitterlinden, Andre G, Mychaleckyj, Josyf C, Campbell, Archie, Hocking, Lynne J, Padmanabhan, Sandosh, Brody, Jennifer A, Rice, Kenneth M, White, Charles C, Harris, Tamara, Isaacs, Aaron, Campbell, Harry, Lange, Leslie A, Rudan, Igor, Kolcic, Ivana, Navarro, Pau, Zemunik, Tatijana, Salomaa, Veikko, Study, The LifeLines Cohort, Kooner, Angad S, Kooner, Jaspal S, Lehne, Benjamin, Scott, William R, Tan, Sian-Tsung, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda WJH, Willemsen, Gonneke, de Mutsert, Renée, Ford, Ian, Gansevoort, Ron T, Segura-Lepe, Marcelo P, Raitakari, Olli T, Viikari, Jorma S, Nikus, Kjell, Forrester, Terrence, McKenzie, Colin A, de Craen, Anton JM, de Ruijter, Hester M, Group, CHARGE Lipids Working, Pasterkamp, Gerard, Snieder, Harold, Oldehinkel, Albertine J, Slagboom, P Eline, Cooper, Richard S, Kähönen, Mika, Lehtimäki, Terho, Elliott, Paul, van der Harst, Pim, Jukema, J Wouter, Mook-Kanamori, Dennis O, Boomsma, Dorret I, Chambers, John C, Swertz, Morris, Ripatti, Samuli, van Dijk, Ko Willems, Vitart, Veronique, Polasek, Ozren, Hayward, Caroline, Wilson, James G, Wilson, James F, Gudnason, Vilmundur, Rich, Stephen S, Psaty, Bruce M, Borecki, Ingrid B, Boerwinkle, Eric, Rotter, Jerome I, Cupples, L Adrienne, and van Duijn, Cornelia M
- Subjects
Biological Sciences ,Genetics ,Biotechnology ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Angiopoietin-Like Protein 4 ,Angiopoietins ,Exons ,Fasting ,Female ,Genome ,Human ,Genome-Wide Association Study ,Genotype ,Humans ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,LifeLines Cohort Study ,CHARGE Lipids Working Group ,Complex traits ,Epidemiology ,Genome-wide ,circulating lipid levels ,Medical and Health Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
BackgroundSo far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.MethodsWe used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.ResultsOur study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.ConclusionsThis study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
- Published
- 2016
44. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- Author
-
Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian’an, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, consortium, The CVD50, Cupples, L Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, Hoed, Marcel den, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jørgensen, Marit E, Jukema, J Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller-Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Markus, Peters, Annette, Poole, Christopher J, Quirós, J Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María-José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, and Trompet, Stella
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Clinical Research ,Diabetes ,Human Genome ,Cardiovascular ,Prevention ,Obesity ,Genetics ,Heart Disease ,Heart Disease - Coronary Heart Disease ,Clinical Trials and Supportive Activities ,Aetiology ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Good Health and Well Being ,Alleles ,Coronary Disease ,Diabetes Mellitus ,Type 2 ,Dipeptidyl Peptidase 4 ,Genotype ,Glucagon-Like Peptide-1 Receptor ,Humans ,Receptor ,Cannabinoid ,CB2 ,Receptor ,Serotonin ,5-HT2C ,Receptors ,Somatostatin ,Sodium-Glucose Transporter 1 ,CVD50 consortium ,GERAD_EC Consortium ,Neurology Working Group of the Cohorts for Heart ,Aging Research in Genomic Epidemiology ,Alzheimer’s Disease Genetics Consortium ,Pancreatic Cancer Cohort Consortium ,European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease ,EPIC-InterAct ,CHARGE consortium ,CHD Exome+ Consortium ,CARDIOGRAM Exome Consortium ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - Abstract
Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
- Published
- 2016
45. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- Author
-
Okbay, Aysu, Baselmans, Bart ML, De Neve, Jan-Emmanuel, Turley, Patrick, Nivard, Michel G, Fontana, Mark Alan, Meddens, S Fleur W, Linnér, Richard Karlsson, Rietveld, Cornelius A, Derringer, Jaime, Gratten, Jacob, Lee, James J, Liu, Jimmy Z, de Vlaming, Ronald, Ahluwalia, Tarunveer S, Buchwald, Jadwiga, Cavadino, Alana, Frazier-Wood, Alexis C, Furlotte, Nicholas A, Garfield, Victoria, Geisel, Marie Henrike, Gonzalez, Juan R, Haitjema, Saskia, Karlsson, Robert, van der Laan, Sander W, Ladwig, Karl-Heinz, Lahti, Jari, van der Lee, Sven J, Lind, Penelope A, Liu, Tian, Matteson, Lindsay, Mihailov, Evelin, Miller, Michael B, Minica, Camelia C, Nolte, Ilja M, Mook-Kanamori, Dennis, van der Most, Peter J, Oldmeadow, Christopher, Qian, Yong, Raitakari, Olli, Rawal, Rajesh, Realo, Anu, Rueedi, Rico, Schmidt, Börge, Smith, Albert V, Stergiakouli, Evie, Tanaka, Toshiko, Taylor, Kent, Thorleifsson, Gudmar, Wedenoja, Juho, Wellmann, Juergen, Westra, Harm-Jan, Willems, Sara M, Zhao, Wei, Amin, Najaf, Bakshi, Andrew, Bergmann, Sven, Bjornsdottir, Gyda, Boyle, Patricia A, Cherney, Samantha, Cox, Simon R, Davies, Gail, Davis, Oliver SP, Ding, Jun, Direk, Nese, Eibich, Peter, Emeny, Rebecca T, Fatemifar, Ghazaleh, Faul, Jessica D, Ferrucci, Luigi, Forstner, Andreas J, Gieger, Christian, Gupta, Richa, Harris, Tamara B, Harris, Juliette M, Holliday, Elizabeth G, Hottenga, Jouke-Jan, De Jager, Philip L, Kaakinen, Marika A, Kajantie, Eero, Karhunen, Ville, Kolcic, Ivana, Kumari, Meena, Launer, Lenore J, Franke, Lude, Li-Gao, Ruifang, Liewald, David C, Koini, Marisa, Loukola, Anu, Marques-Vidal, Pedro, Montgomery, Grant W, Mosing, Miriam A, Paternoster, Lavinia, Pattie, Alison, Petrovic, Katja E, Pulkki-Råback, Laura, Quaye, Lydia, Räikkönen, Katri, Rudan, Igor, and Scott, Rodney J
- Subjects
Biological Sciences ,Genetics ,Mental Health ,Human Genome ,Depression ,Anxiety Disorders ,Bayes Theorem ,Genome-Wide Association Study ,Humans ,Neuroticism ,Phenotype ,Polymorphism ,Single Nucleotide ,LifeLines Cohort Study ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
- Published
- 2016
46. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- Author
-
Kilpeläinen, Tuomas O, Carli, Jayne F Martin, Skowronski, Alicja A, Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F, Hedman, Åsa K, Drong, Alexander W, Hayes, James E, Zhao, Jinghua, Pers, Tune H, Schick, Ursula, Grarup, Niels, Kutalik, Zoltán, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikäinen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian’an, Greco M, Fabiola Del, Pasko, Dorota, Renström, Frida, Willems, Sara M, Mahajan, Anubha, Rose, Lynda M, Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E, Pérusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S, Ju Sung, Yun, Ramos, Yolande F, Amin, Najaf, Amuzu, Antoinette, Barroso, Inês, Bellis, Claire, Blangero, John, Buckley, Brendan M, Böhringer, Stefan, I Chen, Yii-Der, de Craen, Anton JN, Crosslin, David R, Dale, Caroline E, Dastani, Zari, Day, Felix R, Deelen, Joris, Delgado, Graciela E, Demirkan, Ayse, Finucane, Francis M, Ford, Ian, Garcia, Melissa E, Gieger, Christian, Gustafsson, Stefan, Hallmans, Göran, Hankinson, Susan E, Havulinna, Aki S, Herder, Christian, Hernandez, Dena, Hicks, Andrew A, Hunter, David J, Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S, Jørgensen, Marit E, Jørgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A, Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P, Myers, Richard H, Männistö, Satu, Nalls, Mike A, Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D, Rankinen, Tuomo, Rasmussen-Torvik, Laura J, Rathmann, Wolfgang, Rice, Treva K, Brent Richards, J, Ridker, Paul M, Sattar, Naveed, and Savage, David B
- Subjects
Obesity ,Human Genome ,Nutrition ,Clinical Research ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Cancer ,Stroke ,Cardiovascular ,Oral and gastrointestinal ,Metabolic and endocrine ,Adipose Tissue ,Animals ,Gene Expression Regulation ,Gene Knockdown Techniques ,Genome-Wide Association Study ,Leptin ,Male ,Mice ,RNA ,Messenger ,Tissue Culture Techniques - Abstract
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P
- Published
- 2016
47. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
- Author
-
Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blüher, Matthias, Boeing, Heiner, Bonnycastle, Lori L, Bottinger, Erwin P, Burtt, Noël P, Carey, Jason, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Doney, Alex SF, Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G, Esko, Tonu, Eury, Elodie, Fadista, João, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B, Grarup, Niels, Groves, Christopher J, Hassinen, Maija, Have, Christian T, Herder, Christian, Holmen, Oddgeir L, Hreidarsson, Astradur B, Humphries, Steve E, Hunter, David J, Jackson, Anne U, Jonsson, Anna, Jørgensen, Marit E, Jørgensen, Torben, Kao, Wen-Hong L, Kerrison, Nicola D, Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, and Langford, Cordelia
- Subjects
Biological Sciences ,Genetics ,Liver Disease ,Diabetes ,Human Genome ,Digestive Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Binding Sites ,Case-Control Studies ,Chromatin Immunoprecipitation ,Chromosome Mapping ,Diabetes Mellitus ,Type 2 ,Gene Expression Regulation ,Genetic Loci ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genomics ,Hepatocyte Nuclear Factor 3-beta ,Humans ,Islets of Langerhans ,Liver ,Molecular Sequence Annotation ,Polymorphism ,Single Nucleotide ,Receptor ,Melatonin ,MT2 ,DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
- Published
- 2015
48. Conditionally essential genes for survival during starvation in Enterococcus faecium E745
- Author
-
Vincent de Maat, Sergio Arredondo-Alonso, Rob J. L. Willems, and Willem van Schaik
- Subjects
Enterococcus faecium ,Starvation ,Stress response ,Functional genomics ,Tn-seq ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background The nosocomial pathogen Enterococcus faecium can survive for prolonged periods of time on surfaces in the absence of nutrients. This trait is thought to contribute to the ability of E. faecium to spread among patients in hospitals. There is currently a lack of data on the mechanisms that are responsible for the ability of E. faecium to survive in the absence of nutrients. Results We performed a high-throughput transposon mutant library screening (Tn-seq) to identify genes that have a role in long-term survival during incubation in phosphate-buffered saline (PBS) at 20 °C. A total of 24 genes were identified by Tn-seq to contribute to survival in PBS, with functions associated with the general stress response, DNA repair, metabolism, and membrane homeostasis. The gene which was quantitatively most important for survival in PBS was usp (locus tag: EfmE745_02439), which is predicted to encode a 17.4 kDa universal stress protein. After generating a targeted deletion mutant in usp, we were able to confirm that usp significantly contributes to survival in PBS and this defect was restored by in trans complementation. The usp gene is present in 99% of a set of 1644 E. faecium genomes that collectively span the diversity of the species. Conclusions We postulate that usp is a key determinant for the remarkable environmental robustness of E. faecium. Further mechanistic studies into usp and other genes identified in this study may shed further light on the mechanisms by which E. faecium can survive in the absence of nutrients for prolonged periods of time.
- Published
- 2020
- Full Text
- View/download PDF
49. A genome-wide scan study identifies a single nucleotide substitution in the tyrosinase gene associated with white coat colour in a red deer (Cervus elaphus) population
- Author
-
Gerald Reiner, Kirsten Tramberend, Florian Nietfeld, Klaus Volmer, Christine Wurmser, Ruedi Fries, and Hermann Willems
- Subjects
Red deer ,White coat colour ,Next generation sequencing ,Genetics ,QH426-470 - Abstract
Abstract Background Red deer with very pale coat colour are observed sporadically. In the red deer (Cervus elaphus) population of Reinhardswald in Germany, about 5% of animals have a white coat colour that is not associated with albinism. In order to facilitate the conservation of the animals, it should be determined whether and to what extent brown animals carry the white gene. For this purpose, samples of one white hind and her brown calf were available for whole genome sequencing to identify the single nucleotide polymorphism(s) responsible for the white phenotype. Subsequently, samples from 194 brown and 11 white animals were genotyped. Results Based on a list of colour genes of the International Federation of Pigment Cell Societies, a non-synonymous mutation with exchange of a glycine residue at position 291 of the tyrosinase protein by arginine was identified as the cause of dilution of the coat colour. A gene test led to exactly matching genotypes in all examined animals. The study showed that 14% of the brown animals carry the white gene. This provides a simple and reliable way of conservation for the white animals. However, results could not be transferred to another, unrelated red deer population with white animals. Although no brown animals with a white tyrosinase genotype were detected, the cause for the white colouring in this population was different. Conclusions A gene test for the conservation of white red deer is available for the population of the Reinhardswald. While mutations in the tyrosinase are commonly associated with oculocutaneous albinism type 1, the amino acid exchange at position 291 was found to be associated with coat colour dilution in Cervus elaphus.
- Published
- 2020
- Full Text
- View/download PDF
50. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity
- Author
-
Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar
- Subjects
Advanced and Specialized Nursing ,Incidence ,risk assessment ,Smoking/epidemiology ,intracranial aneurysm ,genetic heterogeneity ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Risk Factors ,Intracranial Aneurysm/epidemiology ,Humans ,Subarachnoid Hemorrhage/epidemiology ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,genetics ,Neurology (clinical) ,aneurysmal subarachnoid hemorrhage ,genetic ,Cardiology and Cardiovascular Medicine - Abstract
Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
- Published
- 2023
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.