University of Oulu

Lagou, V., Mägi, R., Hottenga, J.J. et al. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability. Nat Commun 12, 24 (2021). https://doi.org/10.1038/s41467-020-19366-9

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

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Author: Lagou, Vasiliki1,2,3; Maegi, Reedik4; Hottenga, Jouke- Jan5,6;
Grallert, Harald7,8; Perry, John R. B.9; Bouatia-Naji, Nabila10,11,12; Marullo, Letizia13; Rybin, Denis14; Jansen, Rick15; Min, Josine L.16,17; Dimas, Antigone S.18; Ulrich, Anna19; Zudina, Liudmila19; Gadin, Jesper R.20; Jiang, Longda19,21; Faggian, Alessia19; Bonnefond, Amelie10,11,19; Fadista, Joao22; Stathopoulou, Maria G.23; Isaacs, Aaron24,25,26,27; Willems, Sara M.24; Navarro, Pau28; Tanaka, Toshiko29; Jackson, Anne U.30,31; Montasser, May E.32; O'Connell, Jeff R.32; Bielak, Lawrence F.33; Webster, Rebecca J.34; Saxena, Richa35,36,37,38; Stafford, Jeanette M.39; Pourcain, Beate St16,17; Timpson, Nicholas J.16,17; Salo, Perttu40; Shin, So-Youn41; Amin, Najaf42; Smith, Albert V.30,31,43,44; Li, Guo45,46; Verweij, Niek47; Goel, Anuj1,48; Ford, Ian49; Johnson, Paul C. D.49,50; Johnson, Toby51,52; Kapur, Karen53; Thorleifsson, Gudmar54; Strawbridge, Rona J.55,56,57,58; Rasmussen-Torvik, Laura J.59; Esko, Tonu4; Mihailov, Evelin4; Fall, Tove60; Fraser, Ross M.61,62; Mahajan, Anubha1,63; Kanoni, Stavroula51,64; Giedraitis, Vilmantas65; Kleber, Marcus E.66; Silbernagel, Guenther67; Meyer, Julia68; Mueller-Nurasyid, Martina68,69,70,71; Ganna, Andrea72,73,74; Sarin, Antti-Pekka75,76; Yengo, Loic10,11,21; Shungin, Dmitry77,78,79; Luan, Jian'an9; Horikoshi, Momoko1,80,81; An, Ping82; Sanna, Serena83,84; Boettcher, Yvonne85,86; Rayner, N. William1,64,80; Nolte, Ilja M.87; Zemunik, Tatijana88; Iperen, Erik van89; Kovacs, Peter86; Hastie, Nicholas D.28; Wild, Sarah H.61; McLachlan, Stela61; Campbell, Susan28; Polasek, Ozren88; Carlson, Olga90; Egan, Josephine90; Kiess, Wieland86,91; Willemsen, Gonneke5; Kuusisto, Johanna92,92,93; Laakso, Markku92,92,93; Dimitriou, Maria94; Hicks, Andrew A.95; Rauramaa, Rainer96,97; Bandinelli, Stefania98; Thorand, Barbara8,99; Liu, Yongmei100; Miljkovic, Iva101; Lind, Lars102; Doney, Alex103,104; Perola, Markus40,75,105; Hingorani, Aroon106; Kivimaki, Mika106; Kumari, Meena106,107; Bennett, Amanda J.80; Groves, Christopher J.80; Herder, Christian8,108,109; Koistinen, Heikki A.110,111,112,113; Kinnunen, Leena110; Faire, Ulf de114; Bakker, Stephan J. L.115; Uusitupa, Matti116; Palmer, Colin N. A.103,104; Jukema, J. Wouter117,118; Sattar, Naveed119; Pouta, Anneli120,121,122; Snieder, Harold87; Boerwinkle, Eric123,124; Pankow, James S.125; Magnusson, Patrik K.126; Krus, Ulrika127; Scapoli, Chiara13; de Geus, Eco J. C. N.5,6; Blueher, Matthias85,128; Wolffenbuttel, Bruce H. R.129; Province, Michael A.82; Abecasis, Goncalo R.30,31; Meigs, James B.73,130,131; Hovingh, G. Kees132,133; Lindstroem, Jaana134; Wilson, James F.28,61; Wright, Alan F.28; Dedoussis, George V.94; Bornstein, Stefan R.135; Schwarz, Peter E. H.136,137,138,139; Toenjes, Anke85,86; Winkelmann, Bernhard R.140; Boehm, Bernhard O.141; Maerz, Winfried66,142; Metspalu, Andres4; Price, Jackie F.61; Deloukas, Panos51,64,143; Koerner, Antje86,144; Lakka, Timo A.96,145; Keinanen-Kiukaanniemi, Sirkka M.146,147; Saaristo, Timo E.148,149; Bergman, Richard N.150; Tuomilehto, Jaakko151,152,153,154; Wareham, Nicholas J.9; Langenberg, Claudia9; Maennistoe, Satu110; Franks, Paul W.78,155,156; Hayward, Caroline28; Vitart, Veronique28; Kaprio, Jaakko75,152; Visvikis-Siest, Sophie23; Balkau, Beverley157,158; Altshuler, David35,36,131; Rudan, Igor61; Stumvoll, Michael85,86; Campbell, Harry61; van Duijn, Cornelia M.24,159; Gieger, Christian7,8,99; Illig, Thomas7,160,161; Ferrucci, Luigi162; Pedersen, Nancy L.126; Pramstaller, Peter P.95,163,164; Boehnke, Michael30,31; Frayling, Timothy M.165; Shuldiner, Alan R.32,166; Peyser, Patricia A.33; Kardia, Sharon L. R.33; Palmer, Lyle J.167; Penninx, Brenda W.15; Meneton, Pierre168; Harris, Tamara B.169; Navis, Gerjan115; Harst, Pim van der47,170; Smith, George Davey171; Forouhi, Nita G.9; Loos, Ruth J. F.9,172; Salomaa, Veikko173; Soranzo, Nicole41; Boomsma, Dorret I.5; Groop, Leif75,127; Tuomi, Tiinamaija75,127,174,175,176,177; Hofman, Albert42,178,179; Munroe, Patricia B.51,52; Gudnason, Vilmundur43,44; Siscovick, David S.45,46,180; Watkins, Hugh1,48; Lecoeur, Cecile10,11; Vollenweider, Peter181; Franco-Cereceda, Anders182; Eriksson, Per20; Jarvelin, Marjo-Riitta183,184,185; Stefansson, Kari54,44; Hamsten, Anders55,56,57,186; Nicholson, George187; Karpe, Fredrik80,188; Dermitzakis, Emmanouil T.189; Lindgren, Cecilia M.1,35,80,190; McCarthy, Mark I.1,80,188,63; Froguel, Philippe10,11,19; Kaakinen, Marika A.19,191; Lyssenko, Valeriya127,192; Watanabe, Richard M.128,193,194; Ingelsson, Erik60,195,196; Florez, Jose C.36,144; Dupuis, Josee197; Barroso, Ines41,198,199,200; Morris, Andrew P.1,105,201,202; Prokopenko, Inga1,19,80,191,203,200
Organizations: 1Univ Oxford, Wellcome Ctr Human Genet, Oxford, England.
2Katholieke Univ Leuven, Lab Adapt Immun, Dept Microbiol & Immunol, Leuven, Belgium.
3VIB KU Leuven Ctr Brain & Dis Res, Leuven, Belgium.
4Univ Tartu, Inst Genom, Estonian Genome Ctr, Tartu, Estonia.
5Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands.
6Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Med Ctr, Amsterdam, Netherlands.
7Helmholtz Zentrum Munchen, Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Inst Epidemiol, Neuherberg, Germany.
8German Ctr Diabet Res DZD, Munich, Germany.
9Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge, England.
10Univ Lille Nord France, Lille, France.
11Inst Pasteur, CNRS UMR8199, Lille, France.
12Paris Cardiovasc Res Ctr PARCC, INSERM U970, F-75006 Paris, France.
13Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy.
14Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA.
15Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands.
16Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
17Univ Bristol, Bristol Med Sch, Bristol, Avon, England.
18Biomed Sci Res Ctr Al, Inst Bioinnovat, Vari, Greece.
19Imperial Coll, Dept Med, London, England.
20Karolinska Univ Hosp, Karolinska Inst, Dept Med, Cardiovasc Med Unit,Ctr Mol Med, Solna, Sweden.
21Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia.
22Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark.
23Univ Lorraine, IGE PCV, F-54000 Nancy, France.
24Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands.
25Maastricht Univ, CARIM Sch Cardiovasc Dis, Maastricht, Netherlands.
26Maastricht Univ, Maastricht Ctr Syst Biol MaCSBio, Maastricht, Netherlands.
27Maastricht Univ, Dept Physiol, Maastricht, Netherlands.
28Univ Edinburgh, MRC Human Genet Unit, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.
29NIA, Translat Gerontol Branch, Longitudinal Study Sect, Baltimore, MD 21224 USA.
30Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.
31Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
32Univ Maryland, Div Endocrinol Diabet & Nutr, Dept Med, Sch Med, Baltimore, MD 21201 USA.
33Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
34Univ Western Australia, Med Res Ctr, Harry Perkins Inst Med Res, Lab Canc Med, Nedlands, WA, Australia.
35Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA.
36Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.
37Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
38MGH, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA.
39Wake Forest Univ, Div Publ Hlth Sci, Dept Biostat & Data Sci, Winston Salem, NC 27101 USA.
40Finnish Inst Hlth & Welf, Dept Chron Dis Prevent, Publ Hlth Genom Unit, Helsinki, Finland.
41Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England.
42Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
43Iceland Heart Assoc, Kopavogur, Iceland.
44Univ Iceland, Fac Med, Reykjavik, Iceland.
45Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA USA.
46Univ Washington, Dept Med, Seattle, WA USA.
47Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
48Univ Oxford, Radcliffe Dept Med, Cardiovasc Med, Oxford, England.
49Univ Glasgow, Inst Biodivers Anim Hlth & Comparat Med, Glasgow, Lanark, Scotland.
50Queen Mary Univ London, Barts & London Sch Med & Dent, Glasgow, Lanark, Scotland.
51Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.
52Queen Mary Univ London, Barts & London Sch Med & Dent, NIHR Barts Cardiovasc Biomed Res Unit, London, England.
53Univ Lausanne, Dept Med Genet, Lausanne, Switzerland.
54deCODE Genet, Reykjavik, Iceland.
55Dept Med, Cardiovasc Med Unit, Solna, Sweden.
56Karolinska Inst, Stockholm, Sweden.
57Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden.
58Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland.
59Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA.
60Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden.
61Univ Edinburgh, Usher Inst, Edinburgh, Midlothian, Scotland.
62Synpr Ltd, Roslin Innovat Ctr, Easter Bush Campus, Edinburgh EH25 9RG, Midlothian, Scotland.
63Genentech Inc, 340 Point San Bruno Blvd, San Francisco, CA 94080 USA.
64Wellcome Trust Sanger Inst, Hinxton, England.
65Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden.
66Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany.
67Med Univ Graz, Dept Internal Med, Div Angiol, Graz, Austria.
68Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany.
69Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol & Chair Genet Epidemiol, Munich, Germany.
70Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany.
71Johannes Gutenberg Univ Mainz, Univ Med Ctr, IMBEI, D-55101 Mainz, Germany.
72Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA.
73Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
74Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA.
75Univ Helsinki, FIMM, Inst Mol Med Finland, Helsinki, Finland.
76Finnish Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland.
77Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
78Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.
79Umea Univ, Dept Odontol, Umea, Sweden.
80Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
81RIKEN, Ctr Integrat Med Sci, Lab Endocrinol Metab & Kidney Dis, Yokohama, Kanagawa, Japan.
82Washington Univ, Div Stat Genom, Sch Med, Washington, DC USA.
83CNR, Ist Ric Genet & Biomed, Monserrato, Italy.
84Univ Groningen, Univ Med Ctr, Dept Genet, Groningen, Netherlands.
85Univ Leipzig, Dept Med, Leipzig, Germany.
86Univ Leipzig, IFB Adiposity Dis, Leipzig, Germany.
87Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.
88Univ Split, Fac Med, Split, Croatia.
89Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol & Biostat, Amsterdam, Netherlands.
90NIA, Lab Clin Invest, Baltimore, MD 21224 USA.
91Univ Leipzig, Dept Womens & Child Hlth, Pediat Res Ctr, Leipzig, Germany.
92Univ Eastern Finland, Dept Med, Kuopio, Finland.
93Kuopio Univ Hosp, Kuopio, Finland.
94Harokopio Univ, Dept Dietet Nutr, Athens, Greece.
95Univ Lubeck Lubeck Germany, Ctr Biomed, European Acad Bozen Bolzano EURAC, Affiliated Inst, Bolzano, Italy.
96Kuopio Res Inst Exercise Med, Kuopio, Finland.
97Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland.
98Azienda Sanitaria Firenze ASF, Geriatr Unit, Florence, Italy.
99German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.
100Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27101 USA.
101Univ Pittsburgh, Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA USA.
102Uppsala Univ, Dept Med Sci, Akad Sjukhuset, Uppsala, Sweden.
103Univ Dundee, Pat McPherson Ctr Pharmacogenet & Pharmacogenom, Div Mol & Clin Med, Ninewells Hosp, Dundee, Scotland.
104Univ Dundee, Sch Med, Dundee, Scotland.
105Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
106UCL, Dept Epidemiol & Publ Hlth, London, England.
107Univ Essex, Wivenhoe Pk, Colchester, Essex, England.
108Heinrich Heine Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.
109Heinrich Heine Univ Dusseldorf, Fac Med, Div Endocrinol & Diabetol, Dusseldorf, Germany.
110Finnish Inst Hlth & Welf, Dept Publ Hlth Solut, POB 30, FI-00271 Helsinki, Finland.
111Univ Helsinki, Dept Med, POB 340Haartmaninkatu 4, FI-00029 Helsinki, Finland.
112Univ Helsinki, Cent Hosp, POB 340Haartmaninkatu 4, FI-00029 Helsinki, Finland.
113Biomedicum 2U, Minerva Fdn Inst Med Res, Tukholmankatu 8, FI-00290 Helsinki, Finland.
114Karolinska Inst, Div Cardiovasc Epidemiol, Inst Environm Med, Stockholm, Sweden.
115Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands.
116Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland.
117Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.
118Netherlands Heart Inst, Utrecht, Netherlands.
119Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
120Finnish Inst Hlth & Welf, Dept Govt Serv, Helsinki, Finland.
121Oulu Univ Hosp, PEDEGO Res Unit, Med Res Ctr Oulu, Oulu, Finland.
122Univ Oulu, Oulu, Finland.
123Univ Texas Hlth Sci Ctr Houston, IMM Ctr Human Genet, Houston, TX 77030 USA.
124Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol, Houston, TX 77030 USA.
125Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA.
126Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
127Lund Univ, Dept Clin Sci, Diabet & Endocrinol Res Unit, Malmo Univ Hosp, Lund, Sweden.
128USC, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.
129Univ Groningen, Dept Endocrinol, Univ Med Ctr Groningen, Groningen, Netherlands.
130Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA.
131Harvard Med Sch, Dept Med, Boston, MA 02115 USA.
132Amsterdam UMC, Dept Vasc Med, Amsterdam, Netherlands.
133Novo Nordisk AS, Copenhagen, Denmark.
134Finnish Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland.
135Tech Univ Dresden, Dept Med, Div Prevent & Care Diabet, Fac Med Carl Gustav Carus, Dresden, Germany.
136Tech Univ Dresden, Dept Prevent & Care Diabet, Fac Med Carl Gustav Carus, Dresden, Germany.
137Tech Univ Dresden, Paul Langerhans Inst Dresden, Helmholtz Ctr Munich, Univ Hosp, Dresden, Germany.
138Tech Univ Dresden, Fac Med, Dresden, Germany.
139German Ctr Diabet Res DZD eV, Neuherberg, Germany.
140Cardiol Grp, Frankfurt, Germany.
141Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore.
142Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany.
143King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia.
144Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA.
145Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland.
146Univ Oulu, Ctr Life Course Hlth Res, Fac Med, Oulu, Finland.
147Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland.
148Finnish Diabet Assoc, Tampere, Finland.
149Pirkanmaa Hosp Dist, Tampere, Finland.
150Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA USA.
151Finnish Diabet Assoc, Helsinki, Finland.
152Inst Biomed Physiol, Helsinki, Finland.
153Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.
154King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.
155Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.
156Umea Univ, Units Med & Nutr Res, Dept Publ Hlth & Clin Med, Umea, Sweden.
157CESP Ctr Res Epidemiol & Publ Hlth, Inserm, U1018, Villejuif, France.
158Univ Paris Sud, Univ Paris Saclay, UVSQ, UMRS 1018,UMRS 1018, Villejuif, France.
159Ctr Med Syst Biol, Leiden, Netherlands.
160Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany.
161Hannover Med Sch, Inst Human Genet, Hannover, Germany.
162Natl Inst Aging, Clin Res Branch, Baltimore, MD USA.
163Gen Cent Hosp, Dept Neurol, Bolzano, Italy.
164Univ Lubeck, Dept Neurol, Lubeck, Germany.
165Univ Exeter, Genet Complex Traits, Peninsula Med Sch, Exeter, Devon, England.
166Regeneron Pharmaceut, Regeneron Genet Ctr, Tarrytown, NY USA.
167Univ Adelaide, Sch Publ Hlth, Adelaide, SA, Australia.
168Ctr Rech Cordeliers, INSERM, U872, F-75006 Paris, France.
169NIA, Geriatr Epidemiol Sect, Lab Epidemiol, Bethesda, MD USA.
170Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
171Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England.
172Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.
173Finnish Inst Hlth & Welf, Helsinki, Finland.
174Univ Helsinki, Abdominal Ctr, Endocrinol, Helsinki, Finland.
175Helsinki Univ Hosp, Helsinki, Finland.
176Univ Helsinki, Res Program Clin & Mol Metab, Helsinki, Finland.
177Folkhalsan Res Ctr, Helsinki, Finland.
178Netherlands Consortium Hlth Ageing, The Hague, Netherlands.
179Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
180Univ Washington, Dept Epidemiol, Seattle, WA USA.
181Univ Lausanne Hosp, Dept Med, Lausanne, Switzerland.
182Karolinska Inst, Dept Mol Med & Surg, Cardiothorac Surg Unit, Stockholm, Sweden.
183Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England.
184Imperial Coll London, HPA MRC Ctr, Sch Publ Hlth, London, England.
185Univ Oulu, Inst Hlth Sci, Oulu, Finland.
186Karolinska Univ Hosp Solna, Dept Cardiol, Stockholm, Sweden.
187Univ Oxford, Dept Stat, Oxford, England.
188Churchill Hosp, Oxford Natl Inst Hlth, Res Biomed Res Ctr, Oxford, England.
189Univ Geneva, Med Sch, Dept Genet Med & Dev, Geneva, Switzerland.
190Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England.
191Univ Surrey, Dept Clin & Expt Med, Sch Biosci & Med, Guildford, Surrey, England.
192Univ Bergen, Dept Clin Sci, Bergen, Norway.
193USC, Keck Sch Med, Dept Physiol & Neurosci, Los Angeles, CA USA.
194USC Diabet & Obes Res Inst, Los Angeles, CA USA.
195Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
196Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
197Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA.
198Univ Cambridge, Metab Res Labs, Cambridge, England.
199Univ Cambridge, NIHR Cambridge Biomed Res Ctr, Cambridge, England.
200Univ Exeter, Exeter Ctr ExcEllence Diabet ExCEED, Sch Med, Exeter, Devon, England.
201Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.
202Univ Manchester, Ctr Genet & Genom Versus Arthrit, Ctr Musculoskeletal Res, Manchester, Lancs, England.
203Russian Acad Sci, Ufa Fed Res Ctr, Inst Biochem & Genet, Ufa, Russia.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.7 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021051930608
Language: English
Published: Springer Nature, 2021
Publish Date: 2021-05-19
Description:

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.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 12
Issue: 1
Article number: 24
DOI: 10.1038/s41467-020-19366-9
OADOI: https://oadoi.org/10.1038/s41467-020-19366-9
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: 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); Affymetrix, 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 Regeneron 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.
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(874739) LONGITOOLS - Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases
Academy of Finland Grant Number: 129269
Detailed Information: 129269 (Academy of Finland Funding decision)
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