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1. Genetic variation at RAB3GAP2 and its role in exercise-related adaptation and recovery

Author

Sebastian Kalamajski, Nicholas L. Smith, Mikko Lehtovirta, Ola Ekström, Tugce Karaderi, Enming Zhang, Abbas Dehghan, Lars Lind, Eri Miyamoto-Mikami, Karl-Fredrik Eriksson, Kerry McGawley, Anna-Maria Dutius Andersson, Łukasz Szczerbiński, Guan Wang, Paul W. Franks, Hans-Christer Holmberg, Motoyuki Iemitsu, Leif Groop, Kristoffer Ström, Maria Sabater-Lleal, Noriyuku Fuku, Kay Pruefer, Andrew D. Morris, Maria F. Gomez, Emma Ahlqvist, Alejandro Santos-Lozano, Adam Kretowski, Anubha Mahajan, Ola Hansson, Steven Reid, Dmytro Kryvokhyzha, Nikolay Oskolkov, Ellen Kakulidis, Kristian Pietras, Alejandro Lucia, Claes Ladenvall, João Fadista, Rashmi B. Prasad, Yannis P. Pitsiladis, and Cecilia M. Lindgren

Subjects
Evolutionary biology, Genetic variation, Biology, Adaptation
Abstract

Skeletal muscle fiber composition and capillary density influence physical performance and whole-body metabolic properties. ~45% of the variance in fiber type is heritable, which motivated us to perform a genome-wide association study of skeletal muscle histology from 656 Swedish men. Four independent variants were associated (p − 8) with proportion of type IIx fibers or capillary-to-fiber ratio (C:F). The strongest signal localized to the rs115660502 variant, where the G-allele corresponded with increased C:F and reduced skeletal muscle expression of the proximal gene, RAB3 GTPase Activating Non-Catalytic Protein Subunit 2 (RAB3GAP2). The G-allele was less frequent in elite short-track sprinters and more frequent in endurance athletes than in matched non-athlete (population) controls; RAB3GAP2 expression was reduced by high-intensity intermittent training. RAB3GAP2 protein was not uniformly expressed in muscle tissue but localized to the endothelium and capillaries. Experimental reduction of RAB3GAP2 in human endothelial cells led to increased tube formation in vitro, to regulation of secreted factors promoting angiogenesis and T-cell activation, to reduced intracellular levels of von Willebrand factor (VWF) and, post-implantation, to increased endothelial cell density in vivo in mice. The amount of RAB3GAP2 in skeletal muscle was positively associated with exercise-induced release of VWF in vivo in humans. By regulating the release of protein factors (VWF, CD70, TNC, TNXB, MCP1, IGFBP3, COL1A1, TFPI2 and tPA), RAB3GAP2 influences fitness adaptation after exercise by improving muscle healing and promotion of capillary formation.

Published
2021
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2. Joint Investigation of 2-Month Post-diagnosis IgG Antibody Levels and Psychological Measures for Assessing Longer Term Multi-Faceted Recovery Among COVID-19 Cases in Northern Cyprus

Author

Burc Barin, Banu Elcin Yoldascan, Fatma Savaskan, Goncagul Ozbalikci, Tugce Karaderi, and Hüseyin Çakal

Subjects
Adult, Male, Adolescent, Stigma (botany), Disease, Antibodies, Viral, Immunoglobulin G, immune response, Serology, COVID-19 Serological Testing, 03 medical and health sciences, recovery, 0302 clinical medicine, antibody, Medicine, Humans, Psychological testing, 030212 general & internal medicine, long COVID, 030304 developmental biology, 0303 health sciences, Psychological Tests, biology, business.industry, SARS-CoV-2, lcsh:Public aspects of medicine, Public Health, Environmental and Occupational Health, Antibody titer, Outbreak, COVID-19, lcsh:RA1-1270, Middle Aged, Brief Research Report, stigma, Cyprus, biology.protein, Harassment, Female, Public Health, psychological impact, business, Biomarkers, Clinical psychology, Follow-Up Studies
Abstract

Following the outbreak of COVID-19, multidisciplinary research focusing on the long-term effects of the COVID-19 infection and the complete recovery is still scarce. With regards to long-term consequences, biomarkers of physiological effects as well as the psychological experiences are of significant importance for comprehensively understanding the complete COVID-19 recovery. The present research surveys the IgG antibody titers and the impact of COVID-19 as a traumatic experience in the aftermath of the active infection period, around 2 months after diagnosis, in a subset of COVID-19 patients from the first wave (March-April 2020) of the outbreak in Northern Cyprus. Associations of antibody titers and psychological survey measures with baseline characteristics and disease severity were explored, and correlations among various measures were evaluated. Of the 47 serology tests conducted for presence of IgG antibodies, 39 (83%) were positive. We identified trends demonstrating individuals experiencing severe or critical COVID-19 disease and/or those with comorbidities are more heavily impacted both physiologically and mentally, with higher IgG titers and negative psychological experience compared to those with milder disease and without comorbidities. We also observed that more than half of the COVID-19 cases had negative psychological experiences, being subjected to discrimination and verbal harassment/insult, by family/friends. In summary, as the first study co-evaluating immune response together with mental status in COVID-19, our findings suggest that further multidisciplinary research in larger sample populations as well as community intervention plans are needed to holistically address the physiological and psychological effects of COVID-19 among the cases.

Published
2021
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3. Host Genetics at the Intersection of Autoimmunity and COVID-19: A Potential Key for Heterogeneous COVID-19 Severity

Author

Tugce Karaderi, Halin Bareke, Imge Kunter, Adil Seytanoglu, Ilgin Cagnan, Deniz Balci, Burc Barin, Mevhibe B. Hocaoglu, Nilufer Rahmioglu, Esra Asilmaz, Bahar Taneri, Institute for Public Health Genomics, and RS: FHML non-thematic output

Subjects
lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Population, LOCI, ACE2, PROTEIN, Susceptibility gene, SUSCEPTIBILITY, IMMUNITY, Biology, medicine.disease_cause, Severity of Illness Index, immune response, Autoimmune Diseases, polymorphism, Autoimmunity, 03 medical and health sciences, 0302 clinical medicine, Immune system, INFLAMMATION, Severity of illness, cytokine, medicine, Genetic predisposition, Humans, Immunology and Allergy, Genetic Predisposition to Disease, education, TMPRSS2, Genetics, education.field_of_study, SARS-CoV-2, autoimmunity, COVID-19, TYROSINE-PHOSPHATASE, PTPN22, 030104 developmental biology, host genetics, 030220 oncology & carcinogenesis, Perspective, lcsh:RC581-607, LYMPHOPENIA
Abstract

COVID-19 presentation is very heterogeneous across cases, and host factors are at the forefront for the variables affecting the disease manifestation. The immune system has emerged as a key determinant in shaping the outcome of SARS-CoV-2 infection. It is mainly the deleterious unconstrained immune response, rather than the virus itself, which leads to severe cases of COVID-19 and the associated mortality. Genetic susceptibility to dysregulated immune response is highly likely to be among the host factors for adverse disease outcome. Given that such genetic susceptibility has also been observed in autoimmune diseases (ADs), a number of critical questions remain unanswered; whether individuals with ADs have a significantly different risk for COVID-19–related complications compared to the general population, and whether studies on the genetics of ADs can shed some light on the host factors in COVID-19. In this perspective, we discuss the host genetic factors, which have been under investigation in association with COVID-19 severity. We touch upon the intricate link between autoimmunity and COVID-19 pathophysiology. We put forth a number of autoimmune susceptibility genes, which have the potential to be additional host genetic factors for modifying the severity of COVID-19 presentation. In summary, host genetics at the intersection of ADs and COVID-19 may serve as a source for understanding the heterogeneity of COVID-19 severity, and hence, potentially holds a key in achieving effective strategies in risk group identification, as well as effective treatments.

Published
2020
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4. Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Author

Daniel I. Chasman, Torben Hansen, Rebecca S. Fine, Kari E. North, Harald Grallert, Jeffrey Haesser, Jie Yao, Arund D. Pradhan, Peter Kovacs, Mariaelisa Graff, Rebecca D. Jackson, Zoltán Kutalik, James G. Wilson, Neil Robertson, Mika Kähönen, Linda S. Adair, Jennifer Kriebel, Ruth J. F. Loos, Massimo Mangino, Jayne F. Martin Carli, Yiying Zhang, M. Arfan Ikram, Paraskevi Christofidou, Linda Broer, Paul M. Ridker, Barbara McKnight, Satu Männistö, Sophia Metz, Tea Skaaby, Jette Bork-Jensen, Craig E. Pennell, Sophie Molnos, Michael A. Province, Xiuqing Guo, Laura B. L. Wittemans, Stephen J. Lye, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Tim Kacprowski, America A. Sandoval-Zárate, Hermina Jakupović, Tuomas O. Kilpeläinen, Michael Preuss, Jaeyoung Hong, Cristina Venturini, Ying Wu, Germán D. Carrasquilla, Ivana Prokic, Mary F. Feitosa, Melissa E. Garcia, Paul L. Auer, Leslie A. Lange, Leo-Pekka Lyytikäinen, Kristin L. Young, Tugce Karaderi, Alexander P. Reiner, Tim D. Spector, Anubha Mahajan, Claudia Schurmann, Jerome I. Rotter, Rudolph L. Leibel, Georg Homuth, Claudia A. Doege, Hakon Hakonarson, Nicholas J. Wareham, Najaf Amin, Shuai Wang, Matthias Blüher, Ayse Demirkan, Andrew P. Morris, Charles A. LeDuc, Claudia Langenberg, Hanieh Yaghootkar, Mike A. Nalls, Erik Ingelsson, Dennis O. Mook-Kanamori, Jorge R. Kizer, Carolina Medina-Gomez, Timothy M. Frayling, Colleen M. Sitlani, David A. Mackey, Bruce M. Psaty, Matthias Nauck, Struan F.A. Grant, Konstantin Strauch, Olli T. Raitakari, Alexander Teumer, Mark Walker, Jonathan P. Bradfield, Judith B. Borja, Karen L. Mohlke, Lars Lind, André G. Uitterlinden, Renée de Mutsert, Ruifang Li-Gao, Cassandra N. Spracklen, Jin Li, Anne E. Justice, Cecilia M. Lindgren, Kaiying Guo, Terho Lehtimäki, Pekka Jousilahti, Yingchang Lu, Yii-Der Ida Chen, Sara M. Willems, Tamara B. Harris, Matthew A. Allison, Carol A. Wang, Niels Grarup, Lam Opal Huang, Veikko Salomaa, Jian'an Luan, Robert A. Scott, Kent D. Taylor, James B. Meigs, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, Department of Organisation and Personnel Management, Health Services Management & Organisation (HSMO), Yaghootkar, Hanieh [0000-0001-9672-9477], Kilpeläinen, Tuomas O [0000-0002-8349-3028], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Leptin, Models, Molecular, medicine.medical_specialty, Genotype, Protein Conformation, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, KLF14, Biology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Missense mutation, Humans, Allele, Exome, Adiposity, 2. Zero hunger, Racial Groups, digestive, oral, and skin physiology, Gene Expression Regulation, Developmental, Genetic Variation, Genetics/Genomes/Proteomics/Metabolomics, medicine.disease, Obesity, 030104 developmental biology, Endocrinology, hormones, hormone substitutes, and hormone antagonists
Abstract

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10-16, n=3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

Published
2020

5. Publisher Correction: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations

Author

Ryan Sisk, Margrit Urbanek, Roland James, M G Hayes, Corrine K. Welt, Richard S. Legro, Thomas M. Barber, Cecilia M. Lindgren, Mark O. Goodarzi, Yi Zhang, Elisabet Stener-Victorin, Joongoo Lee, David A. Ehrmann, Andrea Dunaif, Michael Olivier, Ahmed H. Kissebah, Mark I. McCarthy, Evanthia Diamanti-Kandarakis, Ricardo Azziz, Tugce Karaderi, Loren L. Armstrong, Dimitrios Panidis, Stephen Franks, and MRC

Subjects
Adult, medicine.medical_specialty, Adolescent, Science, Quantitative Trait Loci, General Physics and Astronomy, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, White People, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, Internal medicine, medicine, Humans, lcsh:Science, Reproductive Medicine Network, Multidisciplinary, General Chemistry, Middle Aged, Publisher Correction, Polycystic ovary, Gonadotropin secretion, Endocrinology, Gene Expression Regulation, Case-Control Studies, lcsh:Q, Female, Genome-Wide Association Study, Polycystic Ovary Syndrome
Abstract

Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case–control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis., Polycystic Ovary Sydrome is a highly heritable, complex reproductive disorder with unknown underlying genetic factors. Here Hayes and Urbanek et al. identify three loci in European women strongly associated with neuroendocrine changes and disease susceptibility.

Published
2020
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6. Correction: Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria

Author

Benjamin M. Neale, Benjamin H. Mullin, Barbara Obermayer-Pietsch, Richard S. Legro, Joop S.E. Laven, Richa Saxena, Ken K. Ong, Scott Wilson, Jenny A. Visser, Alexander W. Drong, Tim D. Spector, Triin Laisk, Margrit Urbanek, Unnur Styrkarsdottir, Felix R. Day, John R. B. Perry, Juan Fernández-Tajes, Andres Salumets, Bronwyn G. A. Stuckey, Anubha Mahajan, Andrea Dunaif, Linda Broer, Marianne Andersen, Mark O. Goodarzi, Matthew Jones, Mark I. McCarthy, Steve Franks, Elisabet Stener-Victorin, Kari Stefansson, Lea K. Davis, Marjo-Riitta Järvelin, Verneri Anttila, Irina Kowalska, Laure Morin-Papunen, Bart C.J.M. Fauser, Reedik Mägi, Tugce Karaderi, Nan Lin, Geoffrey Hayes, Unnur Thorsteinsdottir, Gudmar Thorleifsson, Cindy Meun, Peter Kraft, Hongyan Huang, André G. Uitterlinden, Cecilia M. Lindgren, Corrine K. Welt, David A. Ehrmann, Chunyan He, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Day, Felix [0000-0003-3789-7651], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Medical Research Council (MRC), Genesis Research Trust, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Obstetrics & Gynecology, Internal Medicine, and 'European Union (EU)' and 'Horizon 2020'

Subjects
endocrine system diseases, Genome-wide association study, Body Mass Index, 0302 clinical medicine, Human genetics, Glucose homeostasis, Polycystic ovary syndrome, Body mass index, Genetics & Heredity, 0303 health sciences, 030219 obstetrics & reproductive medicine, Statistics, 1184 Genetics, developmental biology, physiology, WOMEN, Genomics, ASSOCIATION, female genital diseases and pregnancy complications, 3. Good health, Phenotypes, Oncology, Physical Sciences, Medical genetics, Polycystic Ovary Syndrome, medicine.medical_specialty, Genetic loci, SYNDROME PCOS, White People, 03 medical and health sciences, Asian People, Genome-Wide Association Studies, Genetics, Humans, Statistical Methods, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, Science & Technology, IDENTIFICATION, Hyperandrogenism, Correction, Biology and Life Sciences, Computational Biology, medicine.disease, 030104 developmental biology, Genetic Loci, Eggjastokkar, Case-Control Studies, Mathematics, Developmental Biology, 0301 basic medicine, Líkamsþyngdarstuðull, Linkage disequilibrium, Cancer Research, Physiology, Type 2 diabetes, QH426-470, Bioinformatics, Genome-wide association studies, Cohort Studies, Mathematical and Statistical Techniques, 3123 Gynaecology and paediatrics, Medicine and Health Sciences, Genetics of disease, Genetics (clinical), 2. Zero hunger, RISK, HYPERANDROGENEMIA, Metaanalysis, Polycystic ovary, Kvensjúkdómar, PREVALENCE, Phenotype, Physiological Parameters, Female, Life Sciences & Biomedicine, Research Article, SUSCEPTIBILITY LOCI, TWIN, Biology, Research and Analysis Methods, 23andMe Research Team, Insulin resistance, Mendelian randomization, medicine, Erfðafræði, Genetic Predisposition to Disease, 030304 developmental biology, business.industry, Body Weight, Cancers and Neoplasms, Human Genetics, Rannsóknir, Genome Analysis, Genetic architecture, Genetics of Disease, business, Gynecological Tumors, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health., This work has been supported by MRC grant MC_U106179472 (FD, KO, JRBP), Samuel Oschin Comprehensive Cancer Institute Developmental Funds, Center for Bioinformatics and Functional Genomics and Department of Biomedical Sciences Developmental Funds (MRJ), NCI P30CA177558 (CH), NCI UM1CA186107 (PK), European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) and the European Union’s Horizon 2020 research and innovation program under grant agreements No 692065 (TL, RM, AS) and 692145 (RM), NICHD R01HD065029 (RS), Estonian Ministry of Education and Research (grant IUT34-16 to TL), NICHD R01HD057450 (MU), NICHD P50HD044405 (AD), NICHD R01HD057223 (AD), R01HD085227 (MGH, AD), deCode Genetics (GT, UT, KS, US), Raine Medical Research Foundation Priming Grant (BHM), SCGOPHCG RAC 2015-16/034 (SGW, BGAS), 2016-17/018 (BGAS), NIHR BRC, Wellcome Trust, MRC (TDS), Eris M. Field Chair in Diabetes Research (MOG), NIDDK P30 DK063491 (MOG), NIDDK U01DK094431, U01DK048381 (DE), NICHD U10HD38992 (RL), Estonian Ministry of Education and Research (grant IUT34-16), Enterprise Estonia (grant EU48695); the EU-FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, grant SARM, EU324509 to AS), Wellcome (090532, 098381, 203141); European Commission (ENGAGE: HEALTH-F4-2007-201413 to MIM), MRC G0802782, MR/M012638/1 (SF), Li Ka Shing Foundation, WT-SSI/John Fell Funds, NIHR Biomedical Research Centre, Oxford, Widenlife and NICHD 5P50HD028138-27 (CML), NICHD R01HD065029, ADA 1-10-CT-57, Harvard Clinical and Translational Science Center, from the National Center for Research Resources 1UL1 RR025758 (CKW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Published
2019
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7. Exome-derived adiponectin-associated variants implicate obesity and lipid biology

Author

Peter Kovacs, Judith B. Borja, Karen L. Mohlke, Jennifer Kriebel, Kent D. Taylor, Stuart MacGregor, Ruth J. F. Loos, Carol A. Wang, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Jaeyoung Hong, Yingchang Lu, Leslie A. Lange, Terho Lehtimäki, Matthias Blüher, Cassandra N. Spracklen, Michael A. Province, Craig E. Pennell, Laura B. L. Wittemans, Yii-Der Ida Chen, Alex P. Reiner, Nicholas J. Wareham, Massimo Mangino, Kristin L. Young, Tuomas O. Kilpeläinen, David A. Mackey, Michael Preuss, Mika Kähönen, Sara M. Willems, Paraskevi Chirstofidou, Tamara B. Harris, Matthew A. Allison, Michael Boehnke, Jian'an Luan, Cristina Venturini, Kari E. North, Chelsea K. Raulerson, Linda Broer, Paul M. Ridker, Colleen M. Sitlani, Xiuqing Guo, Leo-Pekka Lyytikäinen, Neil Roberston, Pekka Jousilahti, Barbara McKnight, M. Arfan Ikram, Heather M. Highland, Torben Hansen, Niels Grarup, Satu Männistö, James G. Wilson, Konstantin Strauch, Mariaelisa Graff, Ayse Demirkan, Rebecca S. Fine, Tugce Karaderi, Linda S. Adair, Jie Yao, Olli T. Raitakari, Zoltán Kutalik, Jeffrey Haesser, Veikko Salomaa, Sophie Molnos, Rebecca D. Jackson, Renée de Mutsert, Markku Laakso, Mark I. McCarthy, Carolina Medina-Gomez, America A. Sandoval-Zárate, Anke Tönjes, Daniel I. Chasman, Shuai Wang, Michael Stumvoll, Jette Bork-Jensen, Claudia Langenberg, Paul L. Auer, Anubha Mahajan, Claudia Schurmann, Mary F. Feitosa, Melissa E. Garcia, Tim D. Spector, Aruna D. Pradhan, Jorge R. Kizer, Timothy M. Frayling, Ying Wu, James B. Meigs, Andrew P. Morris, Harald Grallert, André G. Uitterlinden, Cecilia M. Lindgren, Traci M. Bartz, Mike A. Nalls, Erik Ingelsson, Jerome I. Rotter, Mark Walker, Ruifang Li-Gao, Ivana Nedeljkovic, Najaf Amin, Hanieh Yaghootkar, Dennis O. Mook-Kanamori, Betina H. Thuesen, Lars Lind, Jin Li, Epidemiology, Internal Medicine, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, University Management, Biostatistics Helsinki, University of Helsinki, Institute for Molecular Medicine Finland, Complex Disease Genetics, and Medical and Clinical Psychology

Subjects
Male, 0301 basic medicine, Candidate gene, Adipose tissue, Genome-wide association study, DISEASE, CANDIDATE GENES, 0302 clinical medicine, Cqardio metabolic traits, RARE, Exome, Genetics (clinical), Aged, 80 and over, Genetics, 0303 health sciences, 1184 Genetics, developmental biology, physiology, Hispanic or Latino, Middle Aged, Lipids, Phenotype, ADIPOSE-TISSUE, Adipose Tissue, 030220 oncology & carcinogenesis, Medical genetics, Female, CIRCULATING ADIPONECTIN, Adiponectin, Adult, EXPRESSION, medicine.medical_specialty, Adolescent, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, Polymorphism, Single Nucleotide, Article, White People, Young Adult, 03 medical and health sciences, Cardio Metabolic Traits, Genome-wide Association Study, Obesity, SDG 3 - Good Health and Well-being, medicine, GLYCEMIC TRAITS, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Gene, METAANALYSIS, 030304 developmental biology, Aged, PLASMA ADIPONECTIN, Correction, medicine.disease, Human genetics, Black or African American, 030104 developmental biology, Expression quantitative trait loci, 3111 Biomedicine
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 -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 -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
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8. Coding Variant In  LEP Associated with Lower Leptin Concentrations Implicates Leptin in the Regulation of Early Adiposity

Author

Rebecca D. Jackson, Jeffrey Haesser, Lars Lind, Germán D. Carrasquilla, Michael A. Province, Paraskevi Christofidou, Charles A. LeDuc, Neil R. Robertson, Tim Kacprowski, Michael Preuss, James G. Wilson, Paul L. Auer, Barbara McKnight, Tuomas O. Kilpeläinen, Satu Männistö, André G. Uitterlinden, Kent D. Taylor, Konstantin Strauch, Cristina Venturini, Mike A. Nalls, Erik Ingelsson, Daniel I. Chasman, Anubha Mahajan, Claudia Schurmann, Mary F. Feitosa, Melissa E. Garcia, Jin Li, Sophia Metz, Torben Hansen, Linda S. Adair, Alexander P. Reiner, Leo-Pekka Lyytikäinen, Cassandra N. Spracklen, Rebecca S. Fine, Tim D. Spector, Leslie A. Lange, Cecilia M. Lindgren, Timothy M. Frayling, Jaeyoung Hong, M. Arfan Ikram, Yingchang Lu, Jette Bork-Jensen, Mark Walker, Mariaelisa Graff, Craig E. Pennell, Paul M. Ridker, Kristin L. Young, Stephen J. Lye, Zoltán Kutalik, Yii-Der Ida Chen, Carolina Medina-Gomez, Ruifang Li-Gao, Cornelia M. van Duijn, Samuli Ripatti, Xiuqing Guo, Laura B. L. Wittemans, Nicholas J. Wareham, Sophie Molnos, Anne E. Justice, Ko Willems van Dijk, Sara M. Willems, Tugce Karaderi, Ivana Nedeljkovic, Massimo Mangino, Ying Wu, James B. Meigs, Matthias Blüher, Matthew A. Allison, Kari E. North, Peter Kovacs, Najaf Amin, Tamara Harris, Judith B. Borja, Karen L. Mohlke, Mika Kähönen, Colleen M. Sitlani, Jorge R. Kizer, David A. Mackey, Hanieh Yaghootkar, Niels Grarup, Dennis O. Mook-Kanamori, Matthias Nauck, Struan F.A. Grant, Lam Opal Huang, Jayne F. Martin Carli, Yiying Zhang, Kaiying Guo, Georg Homuth, Claudia A. Doege, Linda Broer, Ayse Demirkan, Veikko Salomaa, Harald Grallert, Tea Skaaby, Andrew P. Morris, Alexander Teumer, Olli T. Raitakari, Jerome I. Rotter, Jonathan P. Bradfield, Jennifer Kriebel, Rudolph L. Leibel, Hakon Hakonarson, Jian'an Luan, Robert A. Scott, Renée de Mutsert, America A. Sandoval-Zárate, Hermina Jakupović, Shuai Wang, Claudia Langenberg, Pekka Jousilahti, Arund D. Pradhan, Jie Yao, Terho Lehtimäki, Carol A. Wang, Bruce M. Psaty, and Ruth J. F. Loos

Subjects
2. Zero hunger, medicine.medical_specialty, Food intake, Leptin, digestive, oral, and skin physiology, Genome-wide association study, Biology, medicine.disease, Obesity, Minor allele frequency, Endocrinology, Internal medicine, medicine, Missense mutation, Allele, Exome, hormones, hormone substitutes, and hormone antagonists
Abstract

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin concentrations 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 confirmed five previously established and identified five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The novel missense Val94Met (rs17151919) variant in LEP was common in individuals with African ancestry ( minor allele frequency ( MAF) AFR=8%; MAFEUR=0.02%) and was associated with 0.34 standard deviations lower leptin concentrations per Met94 allele in adults (P=2x10-16, n=3,901). Using in vitro analyses, we showed that the Met94 allele decreases leptin secretion (P=0.025). The Met94 allele was associated with higher BMI in young African-ancestry children (P=0.002, n=2,030) but not in adults, suggesting leptin regulates early adiposity.

Published
2019
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9. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, 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 Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, 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 G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., 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, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, 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 I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center

Subjects
0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, 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
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10. Sexual dimorphisms in genetic loci linked to body fat distribution

Author

Tugce Karaderi, Sara L. Pulit, and Cecilia M. Lindgren

Subjects
Male, 0301 basic medicine, obesity, medicine.medical_specialty, Waist, Biophysics, Adipose tissue, Review Article, Type 2 diabetes, Biology, Biochemistry, Body Mass Index, 03 medical and health sciences, Classification of obesity, Internal medicine, medicine, Animals, Body Fat Distribution, Humans, sex, genetics, Review Articles, Molecular Biology, 2. Zero hunger, Sex Characteristics, Cell Biology, medicine.disease, Obesity, 3. Good health, Sexual dimorphism, 030104 developmental biology, Endocrinology, Genetic Loci, Female, Body mass index, Genome-Wide Association Study, Sex characteristics
Abstract

Obesity is a chronic condition associated with increased morbidity and mortality and is a risk factor for a number of other diseases including type 2 diabetes and cardiovascular disease. Obesity confers an enormous, costly burden on both individuals and public health more broadly. Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes. Body fat distribution is distinct from overall obesity in measurement, but studies of body fat distribution can yield insights into the risk factors for and causes of overall obesity. Sexual dimorphism in body fat distribution is present throughout life. Though sexual dimorphism is subtle in early stages of life, it is attenuated in puberty and during menopause. This phenomenon could be, at least in part, due to the influence of sex hormones on the trait. Findings from recent large genome-wide association studies (GWAS) for various measures of body fat distribution (including waist-to-hip ratio, hip or waist circumference, trunk fat percentage and the ratio of android and gynoid fat percentage) emphasize the strong sexual dimorphism in the genetic regulation of fat distribution traits. Importantly, sexual dimorphism is not observed for overall obesity (as assessed by body mass index or total fat percentage). Notably, the genetic loci associated with body fat distribution, which show sexual dimorphism, are located near genes that are expressed in adipose tissues and/or adipose cells. Considering the epidemiological and genetic evidence, sexual dimorphism is a prominent feature of body fat distribution. Research that specifically focuses on sexual dimorphism in fat distribution can provide novel insights into human physiology and into the development of obesity and its comorbidities, as well as yield biological clues that will aid in the improvement of disease prevention and treatment.

Published
2017
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11. A common functional variant of endoplasmic reticulum aminopeptidase 2 (ERAP2) that reduces major histocompatibility complex class I expression is not associated with ankylosing spondylitis

Author

D Harvey, L H Appleton, C. Farrar, J J Pointon, B P Wordsworth, and Tugce Karaderi

Subjects
Genetics, Linkage disequilibrium, Single-nucleotide polymorphism, Biology, Endoplasmic reticulum aminopeptidase 2, Aminopeptidases, Polymorphism, Single Nucleotide, Genotype frequency, Major Histocompatibility Complex, Minor allele frequency, Rheumatology, Case-Control Studies, Genotype, Humans, Spondylitis, Ankylosing, Pharmacology (medical), RNA, Messenger, Allele, Letters to the Editor, Allele frequency
Abstract

Sir, The strong genetic association between AS and HLA-B27 has defied explanation for nearly 40 years. However, the additional discovery of a strong association between AS and ERAP1 (endoplasmic reticulum aminopeptidase 1), a gene that almost certainly operates in the trimming of peptides for optimal binding to MHC class I molecules, has rekindled hopes of rapid advances in this field [1]. It has been suggested that another aminopeptidase, endoplasmic reticulum aminopeptidase 2 (ERAP2), may act in concert with ERAP1, trimming residues inefficiently removed by ERAP1 [2]. The association described recently between ERAP2 and Crohn’s disease, which shares many clinical and genetic overlaps with AS [3], suggests that ERAP2 is worthy of further study in AS. An experiment of nature allows us to do this relatively simply. ERAP2 has evolved under balancing selection, similar to the MHC, and includes a high-frequency variant (∼50%) that influences antigen presentation [4]. A single nucleotide polymorphism (SNP), rs2248374 (A to G), located within the 5′ canonical splice site of exon 10, results in an alternatively spliced ERAP2 mRNA that is degraded by nonsense-mediated decay (NMD). Homozygosity for the minor G allele (carried by ∼25% of the population) results in failure to express ERAP2 protein; in turn this genotype is also associated with reduced surface MHC Class I expression on human B cells [4]. Such a dramatic phenotypic effect provides a great opportunity for studying the potential role of ERAP2 in AS, analogous to using a knockout model. We therefore specifically tested for differences in frequency of rs2248374 in 470 sporadic AS cases and 420 healthy, ethnically matched blood donors to determine whether this functionally important variant is implicated in AS. All patients were Caucasians, of UK origin and fulfilled the modified New York criteria for AS. Eighty-four per cent of the AS patients were HLA-B27 positive. All patients gave informed consent and ethical approval was obtained (Multicentre Research Ethics Committee 98/5/23). Genotyping involved restriction fragment length polymorphism (RFLP) analysis of PCR products performed under standard conditions. Primers (forward 5′-GCATCCATGGCTAATGTGCR and reverse 5′-GTTGTGGGAAAGCCGAACTA) amplified a 370-bp product that, in the presence of the G allele, was digested to 214 and 156 bp products by HphI. Genotype and allele frequencies in AS cases and controls were compared using the Cochrane–Armitage test of trend and the chi-squared test, respectively. This study had 80% power under a log-additive model to detect an odds ratio (OR) of 1.3 with a population risk of AS of 0.04% and a risk allele frequency of 46% (frequency in our controls) at a significance level of 0.05. There were no significant differences between allele or genotype frequencies in AS cases and controls at rs2248374 (Table 1). Additionally, due to the potential functional significance of homozygosity at the minor G allele (i.e. no functional ERAP2 protein), we also compared the frequency of GG homozygotes in AS cases and controls, but these proved almost identical again (Table 1). Table 1 Genotypes, minor allele frequency (MAF), OR, 95% CI and P-value for the ERAP2 SNP rs2248374 The association between ERAP1 and AS is the second only to HLA-B27, but formal testing for additional association with the neighbouring gene, ERAP2, had not been previously undertaken. A study of familial AS that typed one marker within ERAP2 reported that an ERAP1/ERAP2 haplotype was over-represented in affected family members [5]. However, such studies are frequently confounded by linkage disequilibrium effects. If genetic variation at ERAP2 were to play a role in susceptibility to AS, then a dramatic loss-of-function variant, such as rs2248374, would appear to be a prime candidate for the ‘causal variant’ at this locus. However, we have now excluded any significant effect arising from this important functional ERAP2 variant. Nonetheless, the possibility of other associations between ERAP2 and AS has not been excluded by this study. This could be done only by systematic mapping of the gene with tagging SNPs in a very large sample after controlling for the significant linkage disequilibrium between ERAP1 and ERAP2 would this be achievable. Our study was insufficiently powered to do this.

Published
2016
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12. Investigating the genetic association between ERAP1 and ankylosing spondylitis

Author

David Harvey, B P Wordsworth, J J Pointon, Millicent A. Stone, David M. Evans, Roger D. Sturrock, Tugce Karaderi, Louise Appleton, Udo Oppermann, C. Farrar, and Matthew A. Brown

Subjects
Models, Molecular, Linkage disequilibrium, Genotype, Protein Conformation, Single-nucleotide polymorphism, Biology, Aminopeptidases, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Cohort Studies, Minor Histocompatibility Antigens, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Genetics, Humans, Genetic Predisposition to Disease, Spondylitis, Ankylosing, Genetic variability, International HapMap Project, Allele, Molecular Biology, Allele frequency, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Association Studies Articles, General Medicine, Sequence Analysis, DNA, 3. Good health, Protein Structure, Tertiary, Logistic Models, Case-Control Studies, Imputation (genetics), 030215 immunology
Abstract

A strong association between ERAP1 and ankylosing spondylitis (AS) was recently identified by the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium (WTCCC-TASC) study. ERAP1 is highly polymorphic with strong linkage disequilibrium evident across the gene. We therefore conducted a series of experiments to try to identify the primary genetic association(s) with ERAP1. We replicated the original associations in an independent set of 730 patients and 1021 controls, resequenced ERAP1 to define the full extent of coding polymorphisms and tested all variants in additional association studies. The genetic association with ERAP1 was independently confirmed; the strongest association was with rs30187 in the replication set (P = 3.4 x 10(-3)). When the data were combined with the original WTCCC-TASC study the strongest association was with rs27044 (P = 1.1 x 10(-9)). We identified 33 sequence polymorphisms in ERAP1, including three novel and eight known non-synonymous polymorphisms. We report several new associations between AS and polymorphisms distributed across ERAP1 from the extended case-control study, the most significant of which was with rs27434 (P = 4.7 x 10(-7)). Regression analysis failed to identify a primary association clearly; we therefore used data from HapMap to impute genotypes for an additional 205 non-coding SNPs located within and adjacent to ERAP1. A number of highly significant associations (P < 5 x 10(-9)) were identified in regulatory sequences which are good candidates for causing susceptibility to AS, possibly by regulating ERAP1 expression.

Published
2016
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13. The histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis

Author

C. Farrar, L H Appleton, D Harvey, Tugce Karaderi, B P Wordsworth, and J J Pointon

Subjects
Genetics, Histone Demethylases, Linkage disequilibrium, Ankylosing spondylitis, Immunology, Haplotype, Single-nucleotide polymorphism, Genome-wide association study, Odds ratio, Biology, medicine.disease, Polymorphism, Single Nucleotide, Gene Expression Regulation, Case-Control Studies, medicine, Humans, Genetic Predisposition to Disease, Spondylitis, Ankylosing, RNA, Messenger, Retinoblastoma-Binding Protein 2, Allele frequency, Genetics (clinical), Genetic association, Genome-Wide Association Study
Abstract

Associations with disease identified by genome-wide association studies (GWAS) must be replicated and refined to validate causative variants. In the Wellcome Trust Case Control Consortium (WTCCC) GWAS using 14 500 non-synonymous single nucleotide polymorphisms (nsSNP), rs11062385 (a nsSNP in JARID1A) showed nominal association with ankylosing spondylitis (AS) (P=0.0006, odds ratio (OR)=1.26, 95% confidence interval (95% CI)=1.1-1.4). To replicate and refine the association of JARID1A, rs11062385 was genotyped in 730 further cases and compared with allele frequencies in non-AS disease cohorts typed by WTCCC. We replicated the initial association (P=0.04, OR=1.16, 95% CI=1.01-1.34) and identified a strengthened association with AS in a meta-analysis of this new study combined with the original WTCCC study (P=0.0001, OR=1.21, 95% CI=1.10-1.33). We also genotyped nine further intronic tagging SNPs in JARID1A in 1604 AS cases and 1020 new control samples, but none was associated with AS. JARID1A or a locus in strong linkage disequilibrium with it is a positional candidate for susceptibility to AS.

Published
2016
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14. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

Author

Peter Donnelly, Tugce Karaderi, Dafna D. Gladman, Shim S-C., Karl Gafney, Crusius Jba., J Mulero, Karena Pryce, Proton Rahman, Louise Appleton, Matthew A. Brown, Johanna Hadler, Vibeke Videm, R. Valle-Oñate, Jian Yang, Consuelo Romero-Sánchez, José Luis Fernández-Sueiro, Tony J. Kenna, Øystein Førre, Inger Myrnes Hansen, Hill Gaston, Lei Jiang, David M. Evans, Huji Xu, B P Wordsworth, Jessica Harris, Kim T-H., Panagiotis Deloukas, Gilles Chiocchia, Simon Stebbings, Benedicte A. Lie, Minghong Ward, Adrian Cortes, Javier Martín, J. D. Reveille, Philip Robinson, Maxime Breban, Michael H. Weisman, Dirk Elewaut, Walter P. Maksymowych, Xiaodong Zhou, Garchon H-J., Johannes C. Nossent, Yu Liu, Xin Wu, Nigil Haroon, J. Tuomilehto, Claire Farrah, Fernando Pimentel-Santos, Paul Leo, Miguel A. Gonzalez-Gay, J.P. Pointon, Paul Bowness, Carlos López-Larrea, Kyung Bin Joo, Ruben Burgos-Vargas, I E van der Horst-Bruinsma, Manuel A. R. Ferreira, K. Laiho, Sang-Gug Lee, Robert D. Inman, Katie Cremin, Chou C-T., J. Lau, Linda A. Bradbury, Rheumatology, CCA - Disease profiling, and Medical Microbiology and Infection Prevention

Subjects
HLA CLASS-I, GENETIC SUSCEPTIBILITY, Genotype, Genotyping Techniques, DISEASE SUSCEPTIBILITY LOCI, DNA Mutational Analysis, ENDOPLASMIC-RETICULUM, Genome-wide association study, medicine.disease_cause, Major histocompatibility complex, T-CELL, ERAP1, Polymorphism, Single Nucleotide, Article, Autoimmunity, ACTIVATION, Immune System Phenomena, Risk Factors, Genetics, medicine, Medicine and Health Sciences, Humans, Genetic Predisposition to Disease, Spondylitis, Ankylosing, GENOME-WIDE ASSOCIATION, Spondylitis, Genotyping, COMMON, Alleles, HLA-B27 Antigen, Ankylosing spondylitis, BEHCETS-DISEASE, biology, Haplotype, High-Throughput Nucleotide Sequencing, medicine.disease, Endoplasmic reticulum aminopeptidase 2, Genetic Loci, Case-Control Studies, Immunology, biology.protein, Genome-Wide Association Study
Abstract

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

Published
2012
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15. Genetics of ankylosing spondylitis

Author

Tugce Karaderi, B. Paul Wordsworth, Jennifer J. Pointon, and David M. Evans

Subjects
Medical Sciences, Multiple Sclerosis, Epidemiology, Genetics (medical sciences), Immunology, Computationally-intensive statistics, Orthopaedics, Biology and other natural sciences (mathematics), Rheumotology, Biology (medical sciences), Clinical genetics, Molecular genetics, Genetics (life sciences), Mathematical genetics and bioinformatics (statistics), Bioinformatics (life sciences), Biology
Abstract

Ankylosing spondylitis (AS) is a common inflammatory arthritis of the spine and other affected joints, which is highly heritable, being strongly influenced by the HLA-B27 status, as well as hundreds of mostly unknown genetic variants of smaller effect. The aim of my research was to confirm some of the previously observed genetic associations and to identify new associations, many of which are in biological pathways relevant to AS pathogenesis, most notably the IL-23/TH17 axis (IL23R) and antigen presentation (ERAP1 and ERAP2). Studies presented in this thesis include replication and refinement of several potential associations initially identified by earlier GWAS (WTCCC-TASC, 2007 and TASC, 2010). I conducted an extended study of IL23R association with AS and undertook a meta-analysis, confirming the association between AS and IL23R (non-synonymous SNP rs11209026, p=1.5 x 10-9, OR=0.61). An extensive re-sequencing and fine mapping project, including a meta-analysis, to replicate and refine the association of TNFRSF1A with AS was also undertaken; a novel variant in intron 6 was identified and a weak association with a low frequency variant, rs4149584 (p=0.01, OR=1.58), was detected. Somewhat stronger associations were seen with rs4149577 (p=0.002, OR=0.91) and rs4149578 (p=0.015, OR=1.14) in the meta-analysis. Associations at several additional loci had been identified by a more recent GWAS (WTCCC2-TASC, 2011). I used in silico techniques, including imputation using a denser panel of variants from the 1000 Genomes Project, conditional analysis and rare/low frequency variant analysis, to refine these associations. Imputation analysis (1782 cases/5167 controls) revealed novel associations with ERAP2 (rs4869313, p=7.3 x 10-8, OR=0.79) and several additional candidate loci including IL6R, UBE2L3 and 2p16.3. Ten SNPs were then directly typed in an independent sample (1804 cases/1848 controls) to replicate selected associations and to determine the imputation accuracy. I established that imputation using the 1000 Genomes Project pilot data was largely reliable, specifically for common variants (genotype concordence~97%). However, more accurate imputation of low frequency variants may require larger reference populations, like the most recent 1000 Genomes reference panels. The results of my research provide a better understanding of the complex genetics of AS, and help identify future targets for genetic and functional studies.

Published
2012

16. Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene

Author

B P Wordsworth, Roger D. Sturrock, J J Pointon, Matthew A. Brown, C Farrar, Millicent A. Stone, David Harvey, Tugce Karaderi, and L H Appleton

Subjects
Male, Linkage disequilibrium, Candidate gene, genetic association, Association (object-oriented programming), Immunology, Chromosome 9, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Genetics, Humans, Spondylitis, Ankylosing, spondyloarthropathy, Allele frequency, innate immunity, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, Genetic association, 030203 arthritis & rheumatology, 0303 health sciences, Odds ratio, 3. Good health, CARD Signaling Adaptor Proteins, DNA-Binding Proteins, Case-Control Studies, 030221 ophthalmology & optometry, Female, Chromosomes, Human, Pair 9, Transcription Factors
Abstract

Ankylosing spondylitis (AS) is polygenic with contributions from the immunologically relevant genes HLA-B*27, ERAP1 and IL23R. A recent genome-wide association screen (GWAS) identified associations (P approximately 0.005) with the non-synonymous single-nucleotide polymorphisms (nsSNPs), rs4077515 and rs3812571, in caspase recruitment domain-containing protein 9 (CARD9) and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) on chromosome 9q that had previously been linked to AS. We replicated these associations in a study of 730 AS patients compared with 2879 historic disease controls (rs4077515 P=0.0004, odds ratio (OR)=1.2, 95% confidence interval (CI)=1.1-1.4; rs3812571 P=0.0003, OR=1.2, 95% CI=1.1-1.4). Meta-analysis revealed strong associations of both SNPs with AS, rs4077515 P=0.000005, OR=1.2, 95% CI=1.1-1.3 and rs3812571 P=0.000006, OR=1.2, 95% CI=1.1-1.3. We then typed 1604 AS cases and 1020 controls for 13 tagging SNPs; 6 showed at least nominal association, 5 of which were in CARD9. We imputed genotypes for 13 additional SNPs but none was more strongly associated with AS than the tagging SNPs. Finally, interrogation of an mRNA expression database revealed that the SNPs most strongly associated with AS (or in strong linkage disequilibrium) were those most associated with CARD9 expression. CARD9 is a plausible candidate for AS given its central role in the innate immune response.

Published
2011

17. The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (TRADD)

Author

Roger D. Sturrock, L H Appleton, Tugce Karaderi, Matthew A. Brown, David Harvey, John D. Reveille, Michael H. Weisman, Millicent A. Stone, C Farrar, Michael M. Ward, J J Pointon, and B. Paul Wordsworth

Subjects
Oncology, medicine.medical_specialty, Candidate gene, Immunology, Single-nucleotide polymorphism, Biology, Medical sciences, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Chromosome 16, Gene Frequency, Rheumatology, Internal medicine, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Spondylitis, Ankylosing, Allele, Allele frequency, 030304 developmental biology, Genetic association, 030203 arthritis & rheumatology, Genetics, 0303 health sciences, Haplotype, TRADD, TNF Receptor-Associated Death Domain Protein, Case-Control Studies, Chromosomes, Human, Pair 16
Abstract

ObjectiveTo replicate and refine the reported association of ankylosing spondylitis (AS) with two non-synonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1.MethodsFirstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls.ResultsThe association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified.ConclusionsThe region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain (TRADD), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.

Published
2010

18. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

Author

Panos Deloukas, Michael M. Ward, Linda A. Bradbury, Johanna Hadler, Jacqueline Taylor, Walter P. Maksymowych, L H Appleton, Xiaodong Zhou, R Mogg, Vasudev Kumanduri, Emma Pomeroy, Patrick Danoy, Tugce Karaderi, Karena Pryce, J J Pointon, John D. Reveille, Matthew A. Brown, Gethin P. Thomas, Evgeny A. Glazov, Susan M. Ring, Tracey Doan, John C. Davis, B. Paul Wordsworth, Pamela Whittaker, Ran Duan, David M. Evans, Robert D. Inman, Millicent A. Stone, Alison Dowling, C Farrar, David Harvey, Anne Marie Sims, Laura Diekman, Rui Jin, L. Savage, Leena Peltonen, Michael H. Weisman, Emma L. Duncan, and Paul Leo

Subjects
Interleukin-23 receptor, Genetics, Ankylosing spondylitis, Reproducibility of Results, Genome-wide association study, Single-nucleotide polymorphism, Biology, medicine.disease, Polymorphism, Single Nucleotide, Article, Cohort Studies, Major Histocompatibility Complex, Genetic Loci, Immunology, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Spondylitis, Ankylosing, Spondylitis, Genetic association, Histocompatibility gene, Genome-Wide Association Study
Abstract

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

Published
2010

19. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Dragana Vuckovic, Mariaelisa Graff, M. Arfan Ikram, Marit E. Jørgensen, Lia E. Bang, Gerome Breen, Torben Jørgensen, Matthias Blüher, Ivan Brandslund, Hester M. den Ruijter, Ian Ford, Timo A. Lakka, Jennifer Wessel, J. Wouter Jukema, Adam S. Butterworth, Iris M. Heid, Xiuqing Guo, Shuai Wang, Paul L. Auer, Tamuno Alfred, Katja K.H. Aben, Inês Barroso, Gail Davies, Helen Griffiths, Heather M. Highland, Myriam Fornage, Claudia Langenberg, Daniel R. Witte, Ilaria Gandin, Kent D. Taylor, Patrick T. Ellinor, Matti Uusitupa, Laura M. Yerges-Armstrong, Fotios Drenos, Lars Wallentin, Joanna M. M. Howson, Jaakko Tuomilehto, Andrew D. Morris, Lawrence F. Bielak, Mengmeng Du, Andrew J. Lotery, Ailith Pirie, Francis S. Collins, Eva Rabing Brix Petersen, Carolina Medina-Gomez, Manuel A. Rivas, Maria Karaleftheri, Jan-Håkan Jansson, Peter Kovacs, Jaspal S. Kooner, Markku Laakso, Fredrik Karpe, Markus Perola, Anubha Mahajan, Heather M. Stringham, Rohit Varma, Alex W. Hewitt, Chris J. Packard, Andrew C. Heath, Claudia Schurmann, Nele Friedrich, David Lamparter, Vanisha Mistry, Renée de Mutsert, Unnur Thorsteinsdottir, Naveed Sattar, Jennifer E. Huffman, Dale R. Nyholt, Johanna Kuusisto, Angela L. Mazul, Hanieh Yaghootkar, George Dedoussis, Yadav Sapkota, Elizabeth K. Speliotes, Amanda J. Cox, Jane Gibson, Christian Theil Have, Penny Gordon-Larsen, Alisa K. Manning, Jaakko Kaprio, Sita H. Vermeulen, Stella Trompet, Yucheng Jia, Dennis O. Mook-Kanamori, Torben Hansen, Kathleen Stirrups, Jean Ferrières, Douglas F. Easton, Ruth J. F. Loos, Gerard Pasterkamp, John M. Starr, Tellervo Korhonen, Betina H. Thuesen, Olov Rolandsson, Veikko Salomaa, Eric B. Larson, Thomas F. Vogt, John Danesh, Honghuang Lin, Gaëlle Marenne, Timothy M. Frayling, Anette Varbo, Daniel I. Chasman, Aliki-Eleni Farmaki, Lorraine Southam, Martina Müller-Nurasyid, Katharine R. Owen, Paul Mitchell, Ching-Ti Liu, Massimiliano Cocca, Anette P. Gjesing, Charles Kooperberg, Rebecca S. Fine, Wei Gan, Amy J. Swift, Gerard Tromp, Krina T. Zondervan, Henrik Vestergaard, Katherine S. Ruth, Angela D'Eustacchio, Uwe Völker, Beverley Balkau, Hayato Tada, Ingrid B. Borecki, Xueling Sim, Gudmar Thorleifsson, Wei Zhou, Yiqin Wang, Eleftheria Zeggini, Cora E. Lewis, Michael Boehnke, Evangelos Evangelou, Gabriel Cuellar-Partida, Sven Bergmann, Tinca J. C. Polderman, Philippe Amouyel, Roberta McKean-Cowdin, Ellen W. Demerath, Marco Brumat, Kjell Nikus, Anneke I den Hollander, Stefan Gustafsson, Allan Linneberg, Peter T. Campbell, Weihua Zhang, Leslie A. Lange, Gina M. Peloso, Jonathan P. Bradfield, Cornelia M. van Duijn, Xiaowei Zhan, Marie-Pierre Dubé, Liang He, André G. Uitterlinden, Anne Tybjærg-Hansen, Yingchang Lu, Wei Zhao, Liang Sun, Yii-Der Ida Chen, Paul I. W. de Bakker, Børge G. Nordestgaard, Karina Meidtner, Carsten A. Böger, Lynne E. Wagenknecht, Eric Kim, Pang Yao, Olli T. Raitakari, Nanette R. Lee, René S. Kahn, Lili Milani, Tessel E. Galesloot, Jussi Hernesniemi, Valgerdur Steinthorsdottir, Jie Yao, Eulalia Catamo, Kerrin S. Small, Sara M. Willems, Marcelo P. Segura-Lepe, Cecilia M. Lindgren, Asif Rasheed, Gonçalo R. Abecasis, Adam E. Locke, Konstantin Strauch, Albert V. Smith, Anke R. Hammerschlag, Frida Renström, Zoltán Kutalik, Giovanni Veronesi, Paul M. Ridker, David J. Carey, Yao Hu, Jaana Lindström, John Andrew Pospisilik, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Mary F. Feitosa, John R. B. Perry, Anne E. Justice, Ele Ferrannini, Shuang Feng, Helen R. Warren, David J. Roberts, Igor Rudan, Jeffrey R. O'Connel, Alison Pattie, Christopher P. Nelson, Lars Lind, Feijie Wang, Tamara B. Harris, Keng-Hung Lin, Jerome I. Rotter, Matthew A. Allison, Robin Young, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Stefan Johansson, Alexander P. Reiner, Jing Hua Zhao, Poorva Mudgal, Tim D. Spector, Paul W. Franks, Loes M. Olde Loohuis, Harvey D. White, Pirjo Komulainen, Michelle L. O'Donoghue, Todd L. Edwards, Ozren Polasek, Andrew R. Wood, Dermot F. Reilly, Myriam Rheinberger, Cramer Christensen, G. Kees Hovingh, Hidetoshi Kitajima, Kristin L. Young, Audrey Y. Chu, Megan L. Grove, Suthesh Sivapalaratnam, Lisa Bastarache, Martin den Heijer, Oddgeir L. Holmen, Vilmundur Gudnason, Sameer E. Al-Harthi, Dewan S. Alam, Robert E. Schoen, Jin Li, Sascha Fauser, Janie Corley, Paolo Gasparini, Niels Grarup, Guillaume Lettre, Thomas N. Person, Mark I. McCarthy, Joel N. Hirschhorn, Ying Wu, Pia R. Kamstrup, Nilesh J. Samani, Panos Deloukas, Ethan M. Lange, Helena Kuivaniemi, Mika Kähönen, Michiel L. Bots, Annette Peters, Peggy L. Peissig, Wayne Huey-Herng Sheu, Steven A. Lubitz, Stefania Cappellani, Mauno Vanhala, Andrew P. Morris, Struan F.A. Grant, Mark Walker, Trevor A. Mori, Jian'an Luan, Matthias B. Schulze, Josh C. Denny, Sarah E. Medland, Sander W. van der Laan, Maggie C.Y. Ng, Eric Boerwinkle, Tibor V. Varga, Øyvind Helgeland, Anke Tönjes, Jessica van Setten, James P. Cook, Patricia B. Munroe, Heiner Boeing, Robert A. Scott, Karen L. Mohlke, Leena Moilanen, Ayush Giri, Andrew J. Slater, Andrew T. Hattersley, Mark J. Caulfield, Tõnu Esko, Mark C. H. Groot, Nancy L. Heard-Costa, Narisu Narisu, Danish Saleheen, Valérie Turcot, Lambertus A. Kiemeney, Nicholas G. D. Masca, Ruifang Li-Gao, Jean-Claude Tardif, Xu Lin, Kathleen Mullan Harris, Antonietta Robino, Alison M. Dunning, Jonathan Tyrer, Audrey E. Hendricks, Linda Broer, Patricia A. Peyser, Jessica D. Faul, Jose C. Florez, Anne U. Jackson, Eirini Marouli, Jette Bork-Jensen, John C. Chambers, Jordi Corominas Galbany, Ruth Frikke-Schmidt, David S. Crosslin, Bratati Kahali, Stavroula Kanoni, Gorm B. Jensen, Nicholas J. Wareham, Paul Elliott, Tune H. Pers, James A. Perry, Tugce Karaderi, Matt J. Neville, Marianne Benn, Svati H. Shah, Mathias Gorski, Michael Stumvoll, David Ellinghaus, Amber A. Burt, Kari E. North, Jeffrey Haessler, Rajiv Chowdhury, Folkert W. Asselbergs, Marie Moitry, Aniruddh P. 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Subjects
0301 basic medicine, 2. Zero hunger, 0303 health sciences, ComputerSystemsOrganization_COMPUTERSYSTEMIMPLEMENTATION, Published Erratum, Computational biology, Biology, medicine.disease, Obesity, Genealogy, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, ddc:570, Genetics, medicine, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Biological sciences, Body mass index, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

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