Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Vasiliki Lagou; Reedik Mägi; Jouke Jan Hottenga; Harald Grallert; John R. B. Perry; Nabila Bouatia-Naji; Letizia Marullo; Denis Rybin; Rick Jansen; Josine L. Min; Antigone S. Dimas; Anna Ulrich; Liudmila Zudina; Jesper R. Gådin; Longda Jiang; Alessia Faggian; Amélie Bonnefond; Joao Fadista; Maria G. Stathopoulou; Aaron Isaacs; Sara M. Willems; Pau Navarro; Toshiko Tanaka; Anne U. Jackson; May E. Montasser; Jeff R. O’Connell; Lawrence F. Bielak; Rebecca J. Webster; Richa Saxena; Jeanette M. Stafford; Beate St Pourcain; Nicholas J. Timpson; Perttu Salo; So Youn Shin; Najaf Amin; Albert V. Smith; Guo Li; Niek Verweij; Anuj Goel; Ian Ford; Paul C. D. Johnson; Toby Johnson; Karen Kapur; Gudmar Thorleifsson; Alex Doney; Colin N. A. Palmer; George Davey Smith; Nicole Soranzo; Andrew P. Morris; Inga Prokopenko

doi:10.1038/s41467-020-19366-9

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

, Vasiliki Lagou, Reedik Mägi, Jouke Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. StathopoulouAaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Alex Doney, Colin N. A. Palmer, George Davey Smith, Nicole Soranzo, Andrew P. Morris, Inga Prokopenko (Lead / Corresponding author)

Population Health and Genomics

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Abstract

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

Original language	English
Article number	24
Number of pages	18
Journal	Nature Communications
Volume	12
DOIs	https://doi.org/10.1038/s41467-020-19366-9
Publication status	Published - 5 Jan 2021

Keywords

Diagnostic markers
Genome-wide association studies
Pre-diabetes
Quantitative trait
Type 2 diabetes

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-19366-9Licence: CC BY

Final Published VersionFinal published version, 4.66 MBLicence: CC BY

Cite this

, Lagou, V., Mägi, R., Hottenga, J. J., Grallert, H., Perry, J. R. B., Bouatia-Naji, N., Marullo, L., Rybin, D., Jansen, R., Min, J. L., Dimas, A. S., Ulrich, A., Zudina, L., Gådin, J. R., Jiang, L., Faggian, A., Bonnefond, A., Fadista, J., ... Prokopenko, I. (2021). Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability. Nature Communications, 12, Article 24. https://doi.org/10.1038/s41467-020-19366-9

@article{231a07eae3e947db84b3b7ad8295673f,

title = "Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability",

abstract = "Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.",

keywords = "Diagnostic markers, Genome-wide association studies, Pre-diabetes, Quantitative trait, Type 2 diabetes",

author = "Vasiliki Lagou and Reedik M{\"a}gi and Hottenga, {Jouke Jan} and Harald Grallert and Perry, {John R. B.} and Nabila Bouatia-Naji and Letizia Marullo and Denis Rybin and Rick Jansen and Min, {Josine L.} and Dimas, {Antigone S.} and Anna Ulrich and Liudmila Zudina and G{\aa}din, {Jesper R.} and Longda Jiang and Alessia Faggian and Am{\'e}lie Bonnefond and Joao Fadista and Stathopoulou, {Maria G.} and Aaron Isaacs and Willems, {Sara M.} and Pau Navarro and Toshiko Tanaka and Jackson, {Anne U.} and Montasser, {May E.} and O{\textquoteright}Connell, {Jeff R.} and Bielak, {Lawrence F.} and Webster, {Rebecca J.} and Richa Saxena and Stafford, {Jeanette M.} and Pourcain, {Beate St} and Timpson, {Nicholas J.} and Perttu Salo and Shin, {So Youn} and Najaf Amin and Smith, {Albert V.} and Guo Li and Niek Verweij and Anuj Goel and Ian Ford and Johnson, {Paul C. D.} and Toby Johnson and Karen Kapur and Gudmar Thorleifsson and Alex Doney and Palmer, {Colin N. A.} and Smith, {George Davey} and Nicole Soranzo and Morris, {Andrew P.} and Inga Prokopenko",

note = "Funding Information: The participating studies were supported by the following grants: Academy of Finland (129293, 117844, 40758, 211497, 118590, 102318, 123885, 77299, 124243, 136895, 141005, 129322, 104781, 120315, 129269, 1114194); ADA (7-08-MN-OK); BBSRC (G20234); BHF (PG/07/133/24260); Clinical Translational Science Institute (UL1RR033176); Croatian Ministry of Science (216-1080315-0302); Directorate C - Public Health and Risk Assessment, Health & Consumer Protection (2004310); Dutch Kidney Foundation (E033); Estonian Research Council (IUT20-60, IUT24-6, PUT1660); ERC: (284167, 771057, 230374, GENETARGET-T2D, GA 269045); European Regional Development Fund [2014-2020.4.01.15-0012 GENTRANSMED]; EU grants (HEALTH-F2-2009-223004, HEALTH-F4-2007-201413, HEALTH-F2-2013-601456, HEALTH-F2-2008-201865, 201668, 602768, 201413, 245536, LSHM CT 2006 037697, LSHM-CT-2007-037273, LSHM-CT-2004-503485, LSHM-CT-2004-005272, LSHG-CT-2006-018947, LSHGCT-2004-512066, QLG2-CT-2002-01254, EU/QLRT-2001-01254; QLG1-CT-2000-01643, European Union Horizon 2020 [692145]); Federal Ministry of Education and Research (BMBF), Germany (FKZ: 01EO1501); Finnish Funding Agency for Technology and Innovation (40058/07); German Research Foundation (SFB-1052 “Obesity mechanisms” A01, B03, SPP 1629 TO 718/2-1, B01, C05); Greek General Secretary of Research and Technology (PENED 2003); Icelandic National Bioethics Committee (VSN: 00-063); IFB Adiposity Diseases (AD2-060E, AD2-06E95, AD2-06E99); IngaBritt och Arne Lundberg{\textquoteright}s Research Foundation (359); Italian Ministry of Health (ICS110.1/RF97.71); Knut & Alice Wallenberg foundation (KAW 2009.0243); Kuopio University Hospital from Ministry of Health and Social Affairs (5254); Affy-metrix, Inc for genotyping services (Contract No. N02-HL-6-4278); Lundberg Foundation (359); Medical Research Council, UK (G0500539, G0600705); Mid-Atlantic Nutrition Obesity Research Center (P30 DK072488); Ministry of Education and Culture of Finland (627;2004-2011); MRC-GSK pilot programme (ID 85374); NHLBI (HL054457, HL054464, HL054481, HL119443, HL087660, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL36310, U01 HG004171, N01-HC-25195, HHSN268201500001I, HL080295, HL075366, HL087652, HL105756, 5R01HL087679-02); NIA (NO1-AG-1-2109, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, AG-023629, AG-15928, AG-20098, AG-027058, AG13196, N01-AG-5-0002, 263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111); NIH (N01-AG-1-2100 and HHSN271201200022C, HHSN268200782096C, HHSN268200625226C, AG028555, AG08724, AG04563, AG10175, AG08861, U01 DK062370, R01-HG000376, R01-DK072193, ZIA HG000024, N01-HG-65403, R01 088119, R01 AR046838, U01 HL72515, R01 AG18728, R01HL087641, R01HL59367, R01HL086694, U01HG004402, UL1RR025005, 5R01HL08770003, 5R01HL08821502, 5R01DK07568102, 5R01DK06833603, DK063491, DK U01-066134, LM010098, 1K08AR055688, R01 DK078616, NIDDK K24 DK080140, 1RL1MH083268-01, 5R01MH63706:02, R01 [MP1GV17428], HS06516, M01 RR 16500), R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, R01 DK092127-04, 1RC2 MH089951, 1RC2 MH089995; Nordic Centre of Excellence on Systems biology in controlled dietary interventions and cohort studies, SYSDIET (070014); Novo Nordisk Foundation{\textquoteright}s (NNF15CC0018486); NWO/ZonMW (175.010.2007.006, 916.761.70, 10-000-1002, 2018/EW/00408559, 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 400-07-080, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity program –024.001.003, NWO-Groot 480-15-001/674, NBIC/BioAssist/RK(2008.024), BBMRI –NL, 184.021.007 and 184.033.111); Spinozapremie (NWO-56-464-14192)); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Stockholm County Council (592229, 560283); Swedish Foundation for Strategic Research (ICA08-0047); Swedish Heart-Lung Foundation (201202729); Swedish Research Council (8691, 0593, M-2005-1112, 2009-2298, 521-2010-3490, 521-2010-3490, 521-2010-3490, 521-2007-4037, 521-2008-2974, 349 2006-237P, 12660, 521-2010-2633, 521-2010-3490); Swiss National Science Foundation (3200B0–105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401); TEKES (70103/06, 40058/07); Torsten och Ragnar S{\"o}derbergs Stiftelser (MT33/09); Wellcome Trust (WT098051, 084727/Z/08/Z, 085475/ Z/08/Z, 085475/B/08/Z, 090532/Z/09/Z, 203141/Z/16/Z, 201543/B/16/Z, 092447/Z/10/Z, 217065/Z/19/Z, 090532, 098381, 083948, GR069224); Yrj{\"o} Jahnsson Foundation (56358).). Individual acknowledgements A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant number WT098017). A.R.S. is an employee of Regen-eron Pharmaceuticals ALE was supported as a research fellow by the Sarnoff Cardiovascular Research Fellowship. A.S.D. acknowledges support by the Stavros Niarchos Foundation. A.V.S. acknowledges support from the American Diabetes Association (Award No.: 7-08-MN-OK). C. Hayward and V.V. are supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease). C.M.L. is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). D.A. acknowledges support from US National Institutes of Health/National Heart, Lung, and Blood Institute grant (U01 HG004171). D.A. was a Burroughs Wellcome Fund Clinical Scholar in Translational Research and is a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. D.A. acknowledges sponsored research funding from Pfizer, Inc. S.R. is supported by an NIH Career Development Award (1K08AR055688). E.T. D. was funded by the Swiss National Science Foundation, Louis-Jeantet Foundation. H. W. is supported by the British Heart Foundation Centre for Research Excellence. G.D.S.: MC_UU_00011-1. I.B. acknowledges funding from the Wellcome Trust grant 098051, United Kingdom NIHR Cambridge Biomedical Research Centre and the MRC Centre for Obesity and Related Metabolic Diseases. I.P. is funded by the World Cancer Research Fund (WCRF UK) and World Cancer Research Fund International (2017/1641), the Wellcome Trust (WT205915), the European Union{\textquoteright}s Horizon 2020 research and innovation program (DYNAhealth, H2020-PHC-2014-633595, LONGITOOLS, H2020-SC1-2019-874739, the Ministry of Science and Higher Education of Russian Federation (2020-220-08-2197), the ANR, French National Agency for Research (PreciDIAB, reference: ANR-18-IBHU-0001) and the Royal Society (IEC\R2\181075). J. Kaprio acknowledges support by the Academy of Finland (grants 308248, 312073). J.M.: U01 DK078616, K24 DK080140. J.P., A.G. and H.W. acknowledge support from the Wellcome Trust, European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. HEALTH-F2-2013-601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation{\textquoteright}s Grant number NNF15CC0018486. M.A.K. is funded by the LONGITOOLS, H2020-SC1-2019-874739. M.I.M. was a Wellcome Senior Investigator and an NIHR Senior Investigator. Analytical work was supported by the Wellcome Trust (Grants nos. 090532, 106130, 098381, 203141, 212259); Medical Research Council grant no. MR/L020149/1; NIDDK (U01-DK105535, R01-MH101814, R01-MH090941); NIHR (NF-SI-0617-10090). P.B.M. wishes to acknowledge the support of the NIHR Cardiovascular Biomedical Research Unit at Barts and Queen Mary University of London, UK. R.M. was supported by Estonian Research Council grant PUT PRG687 and institutional grant PP1GI19935 from Institute of Genomics, University of Tartu. S.M{\"a}nnist{\"o} was supported by Academy of Finland (# 136895 and 141005). V.L. was supported by a fellowship from the Research Foundation – Flanders (FWO). V.S. has been supported by the Finnish Foundation for Cardiovascular Research. Funding Information: A.R.S. is an employee of Regeneron Pharmaceuticals. As of Januray 2020, A.Mahajan is an employee of Genentech, and a holder of Roche stock. E.I. is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project. Gudmar Thorleifsson and Kari Stefansson are employed by deCODE 4 Genetics/ Amgen inc. I.B. and spouse own stock in GlaxoSmithKline and Incyte. J.C.F. has received consulting honoraria from Pfizer and PanGenX. L.G. has received research funding from Pfizer Inc., Regeneron Pharmaceuticals, Eli Lilly and Astra Zeneca. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.I.M. has served on advisory panels for Pfizer, Novo-Nordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.M is an employee of Genentech, and a holder of Roche stock. V.S. has received honoraria for consultations from Sanofi and Novo Nordisk and travel support from Novo Nordisk. He also has ongoing research collaboration with Bayer Ltd. Other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jan,

day = "5",

doi = "10.1038/s41467-020-19366-9",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Lagou, V, Mägi, R, Hottenga, JJ, Grallert, H, Perry, JRB, Bouatia-Naji, N, Marullo, L, Rybin, D, Jansen, R, Min, JL, Dimas, AS, Ulrich, A, Zudina, L, Gådin, JR, Jiang, L, Faggian, A, Bonnefond, A, Fadista, J, Stathopoulou, MG, Isaacs, A, Willems, SM, Navarro, P, Tanaka, T, Jackson, AU, Montasser, ME, O’Connell, JR, Bielak, LF, Webster, RJ, Saxena, R, Stafford, JM, Pourcain, BS, Timpson, NJ, Salo, P, Shin, SY, Amin, N, Smith, AV, Li, G, Verweij, N, Goel, A, Ford, I, Johnson, PCD, Johnson, T, Kapur, K, Thorleifsson, G, Doney, A , Palmer, CNA, Smith, GD, Soranzo, N & Morris, AP & Prokopenko, I 2021, 'Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability', Nature Communications, vol. 12, 24. https://doi.org/10.1038/s41467-020-19366-9

TY - JOUR

T1 - Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

AU - Lagou, Vasiliki

AU - Mägi, Reedik

AU - Hottenga, Jouke Jan

AU - Grallert, Harald

AU - Perry, John R. B.

AU - Bouatia-Naji, Nabila

AU - Marullo, Letizia

AU - Rybin, Denis

AU - Jansen, Rick

AU - Min, Josine L.

AU - Dimas, Antigone S.

AU - Ulrich, Anna

AU - Zudina, Liudmila

AU - Gådin, Jesper R.

AU - Jiang, Longda

AU - Faggian, Alessia

AU - Bonnefond, Amélie

AU - Fadista, Joao

AU - Stathopoulou, Maria G.

AU - Isaacs, Aaron

AU - Willems, Sara M.

AU - Navarro, Pau

AU - Tanaka, Toshiko

AU - Jackson, Anne U.

AU - Montasser, May E.

AU - O’Connell, Jeff R.

AU - Bielak, Lawrence F.

AU - Webster, Rebecca J.

AU - Saxena, Richa

AU - Stafford, Jeanette M.

AU - Pourcain, Beate St

AU - Timpson, Nicholas J.

AU - Salo, Perttu

AU - Shin, So Youn

AU - Amin, Najaf

AU - Smith, Albert V.

AU - Li, Guo

AU - Verweij, Niek

AU - Goel, Anuj

AU - Ford, Ian

AU - Johnson, Paul C. D.

AU - Johnson, Toby

AU - Kapur, Karen

AU - Thorleifsson, Gudmar

AU - Doney, Alex

AU - Palmer, Colin N. A.

AU - Smith, George Davey

AU - Soranzo, Nicole

AU - Morris, Andrew P.

AU - Prokopenko, Inga

N1 - Funding Information: The participating studies were supported by the following grants: Academy of Finland (129293, 117844, 40758, 211497, 118590, 102318, 123885, 77299, 124243, 136895, 141005, 129322, 104781, 120315, 129269, 1114194); ADA (7-08-MN-OK); BBSRC (G20234); BHF (PG/07/133/24260); Clinical Translational Science Institute (UL1RR033176); Croatian Ministry of Science (216-1080315-0302); Directorate C - Public Health and Risk Assessment, Health & Consumer Protection (2004310); Dutch Kidney Foundation (E033); Estonian Research Council (IUT20-60, IUT24-6, PUT1660); ERC: (284167, 771057, 230374, GENETARGET-T2D, GA 269045); European Regional Development Fund [2014-2020.4.01.15-0012 GENTRANSMED]; EU grants (HEALTH-F2-2009-223004, HEALTH-F4-2007-201413, HEALTH-F2-2013-601456, HEALTH-F2-2008-201865, 201668, 602768, 201413, 245536, LSHM CT 2006 037697, LSHM-CT-2007-037273, LSHM-CT-2004-503485, LSHM-CT-2004-005272, LSHG-CT-2006-018947, LSHGCT-2004-512066, QLG2-CT-2002-01254, EU/QLRT-2001-01254; QLG1-CT-2000-01643, European Union Horizon 2020 [692145]); Federal Ministry of Education and Research (BMBF), Germany (FKZ: 01EO1501); Finnish Funding Agency for Technology and Innovation (40058/07); German Research Foundation (SFB-1052 “Obesity mechanisms” A01, B03, SPP 1629 TO 718/2-1, B01, C05); Greek General Secretary of Research and Technology (PENED 2003); Icelandic National Bioethics Committee (VSN: 00-063); IFB Adiposity Diseases (AD2-060E, AD2-06E95, AD2-06E99); IngaBritt och Arne Lundberg’s Research Foundation (359); Italian Ministry of Health (ICS110.1/RF97.71); Knut & Alice Wallenberg foundation (KAW 2009.0243); Kuopio University Hospital from Ministry of Health and Social Affairs (5254); Affy-metrix, Inc for genotyping services (Contract No. N02-HL-6-4278); Lundberg Foundation (359); Medical Research Council, UK (G0500539, G0600705); Mid-Atlantic Nutrition Obesity Research Center (P30 DK072488); Ministry of Education and Culture of Finland (627;2004-2011); MRC-GSK pilot programme (ID 85374); NHLBI (HL054457, HL054464, HL054481, HL119443, HL087660, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL36310, U01 HG004171, N01-HC-25195, HHSN268201500001I, HL080295, HL075366, HL087652, HL105756, 5R01HL087679-02); NIA (NO1-AG-1-2109, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, AG-023629, AG-15928, AG-20098, AG-027058, AG13196, N01-AG-5-0002, 263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111); NIH (N01-AG-1-2100 and HHSN271201200022C, HHSN268200782096C, HHSN268200625226C, AG028555, AG08724, AG04563, AG10175, AG08861, U01 DK062370, R01-HG000376, R01-DK072193, ZIA HG000024, N01-HG-65403, R01 088119, R01 AR046838, U01 HL72515, R01 AG18728, R01HL087641, R01HL59367, R01HL086694, U01HG004402, UL1RR025005, 5R01HL08770003, 5R01HL08821502, 5R01DK07568102, 5R01DK06833603, DK063491, DK U01-066134, LM010098, 1K08AR055688, R01 DK078616, NIDDK K24 DK080140, 1RL1MH083268-01, 5R01MH63706:02, R01 [MP1GV17428], HS06516, M01 RR 16500), R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, R01 DK092127-04, 1RC2 MH089951, 1RC2 MH089995; Nordic Centre of Excellence on Systems biology in controlled dietary interventions and cohort studies, SYSDIET (070014); Novo Nordisk Foundation’s (NNF15CC0018486); NWO/ZonMW (175.010.2007.006, 916.761.70, 10-000-1002, 2018/EW/00408559, 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 400-07-080, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity program –024.001.003, NWO-Groot 480-15-001/674, NBIC/BioAssist/RK(2008.024), BBMRI –NL, 184.021.007 and 184.033.111); Spinozapremie (NWO-56-464-14192)); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Stockholm County Council (592229, 560283); Swedish Foundation for Strategic Research (ICA08-0047); Swedish Heart-Lung Foundation (201202729); Swedish Research Council (8691, 0593, M-2005-1112, 2009-2298, 521-2010-3490, 521-2010-3490, 521-2010-3490, 521-2007-4037, 521-2008-2974, 349 2006-237P, 12660, 521-2010-2633, 521-2010-3490); Swiss National Science Foundation (3200B0–105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401); TEKES (70103/06, 40058/07); Torsten och Ragnar Söderbergs Stiftelser (MT33/09); Wellcome Trust (WT098051, 084727/Z/08/Z, 085475/ Z/08/Z, 085475/B/08/Z, 090532/Z/09/Z, 203141/Z/16/Z, 201543/B/16/Z, 092447/Z/10/Z, 217065/Z/19/Z, 090532, 098381, 083948, GR069224); Yrjö Jahnsson Foundation (56358).). Individual acknowledgements A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant number WT098017). A.R.S. is an employee of Regen-eron Pharmaceuticals ALE was supported as a research fellow by the Sarnoff Cardiovascular Research Fellowship. A.S.D. acknowledges support by the Stavros Niarchos Foundation. A.V.S. acknowledges support from the American Diabetes Association (Award No.: 7-08-MN-OK). C. Hayward and V.V. are supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease). C.M.L. is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). D.A. acknowledges support from US National Institutes of Health/National Heart, Lung, and Blood Institute grant (U01 HG004171). D.A. was a Burroughs Wellcome Fund Clinical Scholar in Translational Research and is a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. D.A. acknowledges sponsored research funding from Pfizer, Inc. S.R. is supported by an NIH Career Development Award (1K08AR055688). E.T. D. was funded by the Swiss National Science Foundation, Louis-Jeantet Foundation. H. W. is supported by the British Heart Foundation Centre for Research Excellence. G.D.S.: MC_UU_00011-1. I.B. acknowledges funding from the Wellcome Trust grant 098051, United Kingdom NIHR Cambridge Biomedical Research Centre and the MRC Centre for Obesity and Related Metabolic Diseases. I.P. is funded by the World Cancer Research Fund (WCRF UK) and World Cancer Research Fund International (2017/1641), the Wellcome Trust (WT205915), the European Union’s Horizon 2020 research and innovation program (DYNAhealth, H2020-PHC-2014-633595, LONGITOOLS, H2020-SC1-2019-874739, the Ministry of Science and Higher Education of Russian Federation (2020-220-08-2197), the ANR, French National Agency for Research (PreciDIAB, reference: ANR-18-IBHU-0001) and the Royal Society (IEC\R2\181075). J. Kaprio acknowledges support by the Academy of Finland (grants 308248, 312073). J.M.: U01 DK078616, K24 DK080140. J.P., A.G. and H.W. acknowledge support from the Wellcome Trust, European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. HEALTH-F2-2013-601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. M.A.K. is funded by the LONGITOOLS, H2020-SC1-2019-874739. M.I.M. was a Wellcome Senior Investigator and an NIHR Senior Investigator. Analytical work was supported by the Wellcome Trust (Grants nos. 090532, 106130, 098381, 203141, 212259); Medical Research Council grant no. MR/L020149/1; NIDDK (U01-DK105535, R01-MH101814, R01-MH090941); NIHR (NF-SI-0617-10090). P.B.M. wishes to acknowledge the support of the NIHR Cardiovascular Biomedical Research Unit at Barts and Queen Mary University of London, UK. R.M. was supported by Estonian Research Council grant PUT PRG687 and institutional grant PP1GI19935 from Institute of Genomics, University of Tartu. S.Männistö was supported by Academy of Finland (# 136895 and 141005). V.L. was supported by a fellowship from the Research Foundation – Flanders (FWO). V.S. has been supported by the Finnish Foundation for Cardiovascular Research. Funding Information: A.R.S. is an employee of Regeneron Pharmaceuticals. As of Januray 2020, A.Mahajan is an employee of Genentech, and a holder of Roche stock. E.I. is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project. Gudmar Thorleifsson and Kari Stefansson are employed by deCODE 4 Genetics/ Amgen inc. I.B. and spouse own stock in GlaxoSmithKline and Incyte. J.C.F. has received consulting honoraria from Pfizer and PanGenX. L.G. has received research funding from Pfizer Inc., Regeneron Pharmaceuticals, Eli Lilly and Astra Zeneca. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.I.M. has served on advisory panels for Pfizer, Novo-Nordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.M is an employee of Genentech, and a holder of Roche stock. V.S. has received honoraria for consultations from Sanofi and Novo Nordisk and travel support from Novo Nordisk. He also has ongoing research collaboration with Bayer Ltd. Other authors declare no competing interests. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/1/5

Y1 - 2021/1/5

N2 - Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

AB - Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

KW - Diagnostic markers

KW - Genome-wide association studies

KW - Pre-diabetes

KW - Quantitative trait

KW - Type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85099096262&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-19366-9

DO - 10.1038/s41467-020-19366-9

M3 - Article

C2 - 33402679

AN - SCOPUS:85099096262

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

M1 - 24

ER -

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

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