Abstract
Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
| Original language | English |
|---|---|
| Article number | 14977 |
| Pages (from-to) | 14977 |
| Journal | Nature Communications |
| Volume | 8 |
| DOIs | |
| Publication status | Published - 26 Apr 2017 |
Funding
A full list of acknowledgments appears in the Supplementary Note 4. Co-author A.J.M.d.C. recently passed away while this work was in process. This work was performed under the auspices of the Genetic Investigation of ANthropometric Traits (GIANT) consortium. We acknowledge the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium for encouraging CHARGE studies to participate in this effort and for the contributions of CHARGE members to the analyses conducted for this research. Funding for this study was provided by the Aase and Ejner Danielsens Foundation; Academy of Finland (41071, 77299, 102318, 110413, 117787, 121584, 123885, 124243, 124282, 126925, 129378, 134309, 286284); Accare Center for Child and Adolescent Psychiatry; Action on Hearing Loss (G51); Agence Nationale de la 359 Recherche; Agency for Health Care Policy Research (HS06516); ALF/LUA research grant in Gothenburg; ALFEDIAM; ALK-Abelló A/S; Althingi; American Heart Association (13POST16500011); Amgen; Andrea and Charles Bronfman Philanthropies; Ardix Medical; Arthritis Research UK; Association Diabète Risque Vasculaire; Australian National Health and Medical Research Council (241944, 339462, 389875, 389891, 389892, 389927, 389938, 442915, 442981, 496739, 552485, 552498); Avera Institute; Bayer Diagnostics; Becton Dickinson; BHF (RG/14/5/30893); Boston Obesity Nutrition Research Center (DK46200), Bristol-Myers Squibb; British Heart Foundation (RG/10/12/ 28456, RG2008/08, RG2008/014, SP/04/002); Medical Research Council of Canada; Canadian Institutes for Health Research (FRCN-CCT-83028); Cancer Research UK; Cardionics; Cavadis B.V., Center for Medical Systems Biology; Center of Excellence in Genomics; CFI; CIHR; City of Kuopio; CNAMTS; Cohortes Santé TGIR; Contrat de Projets État-Région; Croatian Science Foundation (8875); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research (DFF-1333- 00124, DFF-1331-00730B); County Council of Dalarna; Dalarna University; Danish Council for Strategic Research; Danish Diabetes Academy; Danish Medical Research Council; Department of Health, UK; Development Fund from the University of Tartu (SP1GVARENG); Diabetes Hilfs- und Forschungsfonds Deutschland; Diabetes UK; Diabetes Research and Wellness Foundation Fellowship; Donald W. Reynolds Foundation; Dr Robert Pfleger-Stiftung; Dutch Brain Foundation; Dutch Diabetes Research Foundation; Dutch Inter University Cardiology Institute; Dutch Kidney Foundation (E033); Dutch Ministry of Justice; the DynaHEALTH action No. 633595, Economic Structure Enhancing Fund of the Dutch Government; Else Kröner-Fresenius-Stiftung (2012-A147, P48/08//A11/08); Emil Aaltonen Foundation; Erasmus University Medical Center Rotterdam; Erasmus MC and Erasmus University Rotterdam; the Municipality of Rotterdam; Estonian Government (IUT20-60, IUT24-6); Estonian Research Roadmap through the Estonian Ministry of Education and Research (3.2.0304.11-0312); European Research Council (ERC Starting Grant and 323195:SZ-245 50371-GLUCOSEGENESFP7- IDEAS-ERC); European Regional Development Fund; European Science Foundation (EU/QLRT-2001-01254); European Commission (018947, 018996, 201668, 223004, 230374, 279143, 284167, 305739, BBMRI-LPC-313010, HEALTH-2011.2.4.2-2-EUMASCARA, HEALTH-2011-278913, HEALTH-2011-294713-EPLORE, HEALTH-F2- 2008-201865-GEFOS, HEALTH-F2-2013-601456, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550-HYPERGENES, HEALTH-F7-305507 HOMAGE, IMI/ 115006, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2004-005272, LSHM-CT-2006-037697, LSHM-CT-2007-037273, QLG1-CT-2002-00896, QLG2-CT- 2002-01254); Faculty of Biology and Medicine of Lausanne; Federal Ministry of Education and Research (01ZZ0103, 01ZZ0403, 01ZZ9603, 03IS2061A, 03ZIK012).
| Funders | Funder number |
|---|---|
| Ardix Medical | |
| Avera Institute | |
| Bayer Diagnostics | |
| Becton Dickinson | |
| Cohorts for Heart and Aging Research in Genomic | |
| Diabetes Hilfs- und Forschungsfonds Deutschland | |
| Dutch Brain Foundation | |
| Dutch Inter University Cardiology Institute | |
| Dutch Ministry of Justice | 633595 |
| EUMASCARA | HEALTH-2011-278913, LSHG-CT-2006-01947, LSHM-CT-2006-037697, HEALTH-F4-2007-201550-HYPERGENES, LSHM-CT-2007-037273, QLG1-CT-2002-00896, IMI/ 115006, QLG2-CT- 2002-01254, HEALTH-2011-294713-EPLORE, HEALTH-F4-2007-201413, LSHM-CT-2004-005272, HEALTH-F7-305507 HOMAGE, HEALTH-F2- 2008-201865-GEFOS, HEALTH-F2-2013-601456, LSHG-CT-2006-018947 |
| Erasmus University Medical Center Rotterdam | |
| Estonian Government | IUT20-60, IUT24-6 |
| Faculty of Biology and Medicine of Lausanne | |
| Municipality of Rotterdam | |
| National Heart, Lung, and Blood Institute | R01HL085144 |
| American Heart Association | 13POST16500011 |
| Amgen | |
| Bristol-Myers Squibb | |
| Minnesota Department of Health | |
| Strategiske Forskningsråd | |
| Cummings Foundation | |
| Sundhed og Sygdom, Det Frie Forskningsråd | |
| Agency for Health Care Policy and Research | HS06516 |
| FP7 Ideas: European Research Council | |
| Danish Diabetes Academy | |
| Engineering Research Centers | SZ-245 50371-GLUCOSEGENESFP7, 323195 |
| Boston Nutrition Obesity Research Center, Boston University | DK46200 |
| Canadian Institutes of Health Research | FRCN-CCT-83028 |
| Diabetes Research and Wellness Foundation | |
| British Heart Foundation | RG/14/5/30893, RG2008/08, RG/10/12/ 28456, RG2008/014, SP/04/002 |
| Cancer Research UK | |
| Arthritis Research UK | |
| Diabetes UK | |
| European Commission | 018947, 305739, 230374, 201668, 279143, 018996, 223004, 284167, HEALTH-2011.2.4.2-2, BBMRI-LPC-313010 |
| European Research Council | |
| European Science Foundation | EU/QLRT-2001-01254 |
| National Health and Medical Research Council | 442981, 552498, 496739, 389875, 339462, 389892, 389891, 442915, 241944, 552485, 389927, 389938 |
| Agence Nationale de la Recherche | |
| Danish Agency for Science and Higher Education | |
| Erasmus Universiteit Rotterdam | |
| Academy of Finland | 110413, 129378, 124243, 134309, 124282, 126925, 77299, 121584, 123885, 117787, 102318, 286284, 41071 |
| Bundesministerium für Bildung und Forschung | 01ZZ0403, 03ZIK012, 03IS2061A, 01ZZ0103, 01ZZ9603 |
| Nierstichting | E033 |
| Aase og Ejnar Danielsens Fond | |
| Else Kröner-Fresenius-Stiftung | 2012-A147, P48/08//A11/08 |
| Erasmus Medisch Centrum | |
| Diabetes Fonds | |
| Haridus- ja Teadusministeerium | 3.2.0304.11-0312 |
| Hrvatska Zaklada za Znanost | 8875 |
| Emil Aaltosen Säätiö | |
| Danmarks Frie Forskningsfond | DFF-1333- 00124, DFF-1331-00730B |
| Högskolan Dalarna | |
| Landstinget Dalarnas | |
| Medical Research Council Canada | |
| Tartu Ülikool | SP1GVARENG |
| European Regional Development Fund | |
| Association Diabète Risque Vasculaire |
Keywords
- Journal Article
Cohort Studies
- Netherlands Twin Register (NTR)
