Abstract
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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Acknowledgements
A full list of acknowledgments appears in the Supplementary Note. Funding was provided by the Aarno Koskelo Foundation; the Academy of Finland; the Agency for Science, Technology and Research of Singapore; the Australian National Health and Medical Research Council; the Australian Research Council; BDA Research; the BioSHaRE Consortium; the British Heart Foundation; the Cedars-Sinai Board of Governors' Chair in Medical Genetics; the Centre for Clinical Research at the University of Leipzig; the Centre of Excellence in Genomics and the University of Tartu; the Chief Scientist Office of the Scottish government; the City of Kuopio and the Social Insurance Institution of Finland; the Department of Educational Assistance, the University and Research of the Autonomous Province of Bolzano; the Donald W. Reynolds Foundation; the Dutch Ministry for Health, Welfare and Sports; the Dutch Ministry of Education, Culture and Science; Dutch BBRMI-NL; the Dutch Brain Foundation; the Dutch Centre for Medical Systems Biology; the Dutch Diabetes Research Foundation; the Dutch Government Economic Structure–Enhancing Fund; the Dutch Inter-University Cardiology Institute; the Dutch Kidney Foundation; the Dutch Ministry of Economic Affairs; the Dutch Ministry of Justice; the Dutch Research Institute for Diseases in the Elderly; Eleanor Nichols endowments; the Emil Aaltonen Foundation; Erasmus Medical Center and Erasmus University; the Estonian government; the European Commission; the European Regional Development Fund; the European Research Council; the European Science Foundation; the Faculty of Biology and Medicine of Lausanne; Finland's Slot Machine Association; the Finnish Cultural Foundation; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Funding Agency for Technology and Innovation; the Finnish Heart Association; the Finnish Medical Society; the Finnish Ministry of Education and Culture; the Finnish Ministry of Health and Social Affairs; the Finnish National Institute for Health and Welfare; the Finnish Social Insurance Institution; Finska Läkaresällskapet; the Folkhälsan Research Foundation; the Foundation for Life and Health in Finland; the French Ministry of Research; the French National Research Agency; the Genetic Association Information Network; the German Diabetes Association; the German Federal Ministry of Education and Research; the German Ministry of Cultural Affairs; the German National Genome Research Network; the German Research Foundation; GlaxoSmithKline; the Göteborg Medical Society; the Greek General Secretary of Research and Technology; the Gyllenberg Foundation; Health Care Centers in Vasa, Närpes and Korsholm; the Heinz Nixdorf Foundation; Helmholtz Zentrum München–German Research Center for Environmental Health; the Icelandic Heart Association; the Icelandic Parliament; the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, the National Cancer Institute, NIH; Italian Ministry of Education, Universities and Research; Italian Ministry of Health; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International; the Knut and Alice Wallenberg Foundation; Kuopio, Tampere and Turku University Hospital Medical Funds; the Leducq Foundation; the Lundberg Foundation; the March of Dimes; the Munich Center of Health Sciences as part of LMUinnovativ; the Municipal Health Care Center and Hospital in Jakobstad; the Municipality of Rotterdam; the Närpes Health Care Foundation; National Alliance for Research on Schizophrenia and Depression Young Investigator Awards; the Netherlands Genomics Initiative; the Netherlands Organization for Health Research and Development; UK NHSBT; US National Institutes of Health; the Nordic Center of Cardiovascular Research; the Nordic Center of Excellence in Disease Genetics; the Nordic Centre of Excellence on Systems Biology in Controlled Dietary Interventions and Cohort Studies; the Northern Netherlands Collaboration of Provinces; the Novo Nordisk Foundation; the Ollqvist Foundation; the Orion-Farmos Research Foundation; the Paavo Nurmi Foundation; the Päivikki and Sakari Sohlberg Foundation; the Perklen Foundation; the Petrus and Augusta Hedlunds Foundation; the Province of Groningen; the Republic of Croatia Ministry of Science, Education and Sport; the Reynold's Foundation; the Royal Society; Samfundet Folkhälsan; the Signe and Ane Gyllenberg Foundation; the Sigrid Juselius Foundation; the Social Ministry of the Federal State of Mecklenburg–West Pomerania; the Sophia Foundation for Medical Research; the South Tyrolean Sparkasse Foundation; the Southern California Diabetes Endocrinology Research Center; the Stockholm County Council; the Strategic Cardiovascular Program of Karolinska Institutet; Strategic Support for Epidemiological Research at Karolinska Institutet; the Susan G. Komen Breast Cancer Foundation; the Swedish Ministry for Higher Education; the Swedish Cancer Society; the Swedish Cultural Foundation in Finland; the Swedish Diabetes Association; the Swedish Foundation for Strategic Research; the Swedish Heart-Lung Foundation; the Swedish Medical Research Council; the Swedish Ministry of Education; the Swedish Research Council; the Swedish Royal Academy of Science; the Swedish Society for Medical Research; the Swedish Society of Medicine; the Swiss National Science Foundation; the Tampere Tuberculosis Foundation; The Great Wine Estates of the Margaret River Region of Western Australia; The Paul Michael Donovan Charitable Foundation; the Torsten and Ragnar Söderberg Foundation; Cancer Research UK; the UK Diabetes Association; the UK Heart Foundation; the UK MRC; the UK NIHR, Biomedical Research Centre; UK West Anglia Primary and Community Care; the University Medical Center Groningen and the University of Groningen; the Västra Götaland Foundation; VU University: the Institute for Health and Care Research and the Neuroscience Campus Amsterdam; the Wellcome Trust; and the Yrjö Jahnsson Foundation.