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

Lagou, V.; Mägi, R.; Hottenga, J.J.; Grallert, H.; Perry, JRB; 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.; Stathopoulou, M.G.; Isaacs, A.; Willems, S.M.; Navarro, P.; Tanaka, T.; Jackson, A.U.; Montasser, M.E.; O'Connell, J.R.; Bielak, L.F.; Webster, R.J.; Saxena, R.; Stafford, J.M.; Pourcain, B.S.; Timpson, N.J.; Salo, P.; Shin, S.Y.; Amin, N.; Smith, A.V.; Li, G.; Verweij, N.; Goel, A.; Ford, I.; Johnson, PCD; Johnson, T.; Kapur, K.; Thorleifsson, G.; Strawbridge, R.J.; Rasmussen-Torvik, L.J.; Esko, T.; Mihailov, E.; Fall, T.; Fraser, R.M.; Mahajan, A.; Kanoni, S.; Giedraitis, V.; Kleber, M.E.; Silbernagel, G.; Meyer, J.; Müller-Nurasyid, M.; Ganna, A.; Sarin, A.P.; Yengo, L.; Shungin, D.; Luan, J.; Horikoshi, M.; An, P.; Sanna, S.; Boettcher, Y.; Rayner, N.W.; Nolte, I.M.; Zemunik, T.; Iperen, E.V.; Kovacs, P.; Hastie, N.D.; Wild, S.H.; McLachlan, S.; Campbell, S.; Polasek, O.; Carlson, O.; Egan, J.; Kiess, W.; Willemsen, G.; Kuusisto, J.; Laakso, M.; Dimitriou, M.; Hicks, A.A.; Rauramaa, R.; Bandinelli, S.; Thorand, B.; Liu, Y.; Miljkovic, I.; Lind, L.; Doney, A.; Perola, M.; Hingorani, A.; Kivimaki, M.; Kumari, M.; Bennett, A.J.; Groves, C.J.; Herder, C.; Koistinen, H.A.; Kinnunen, L.; Faire, U.; Bakker, SJL; Uusitupa, M.; Palmer, CNA; Jukema, J.W.; Sattar, N.; Pouta, A.; Snieder, H.; Boerwinkle, E.; Pankow, J.S.; Magnusson, P.K.; Krus, U.; Scapoli, C.; de Geus, EJCN; Blüher, M.; Wolffenbuttel, BHR; Province, M.A.; Abecasis, G.R.; Meigs, J.B.; Hovingh, G.K.; Lindström, J.; Wilson, J.F.; Wright, A.F.; Dedoussis, G.V.; Bornstein, S.R.; Schwarz, PEH; Tönjes, A.; Winkelmann, B.R.; Boehm, B.O.; März, W.; Metspalu, A.; Price, J.F.; Deloukas, P.; Körner, A.; Lakka, T.A.; Keinanen-Kiukaanniemi, S.M.; Saaristo, T.E.; Bergman, R.N.; Tuomilehto, J.; Wareham, N.J.; Langenberg, C.; Männistö, S.; Franks, P.W.; Hayward, C.; Vitart, V.; Kaprio, J.; Visvikis-Siest, S.; Balkau, B.; Altshuler, D.; Rudan, I.; Stumvoll, M.; Campbell, H.; van Duijn, C.M.; Gieger, C.; Illig, T.; Ferrucci, L.; Pedersen, N.L.; Pramstaller, P.P.; Boehnke, M.; Frayling, T.M.; Shuldiner, A.R.; Peyser, P.A.; Kardia, SLR; Palmer, L.J.; Penninx, B.W.; Meneton, P.; Harris, T.B.; Navis, G.; Harst, P.V.; Smith, G.D.; Forouhi, N.G.; Loos, RJF; Salomaa, V.; Soranzo, N.; Boomsma, D.I.; Groop, L.; Tuomi, T.; Hofman, A.; Munroe, P.B.; Gudnason, V.; Siscovick, D.S.; Watkins, H.; Lecoeur, C.; Vollenweider, P.; Franco-Cereceda, A.; Eriksson, P.; Jarvelin, M.R.; Stefansson, K.; Hamsten, A.; Nicholson, G.; Karpe, F.; Dermitzakis, E.T.; Lindgren, C.M.; McCarthy, M.I.; Froguel, P.; Kaakinen, M.A.; Lyssenko, V.; Watanabe, R.M.; Ingelsson, E.; Florez, J.C.; Dupuis, J.; Barroso, I.; Morris, A.P.; Prokopenko, I.

doi:10.1038/s41467-020-19366-9

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

Details

Download: Lagous41467-020-19366-9.pdf (4771.38 [Ko])
State: Public
Version: Final published version
License: CC BY 4.0

Serval ID

serval:BIB_165C70D1F41C

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

Nature communications

Author(s)

Lagou V., Mägi R., Hottenga J.J., Grallert H., Perry JRB, 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., Stathopoulou M.G., Isaacs A., Willems S.M., Navarro P., Tanaka T., Jackson A.U., Montasser M.E., O'Connell J.R., Bielak L.F., Webster R.J., Saxena R., Stafford J.M., Pourcain B.S., Timpson N.J., Salo P., Shin S.Y., Amin N., Smith A.V., Li G., Verweij N., Goel A., Ford I., Johnson PCD, Johnson T., Kapur K., Thorleifsson G., Strawbridge R.J., Rasmussen-Torvik L.J., Esko T., Mihailov E., Fall T., Fraser R.M., Mahajan A., Kanoni S., Giedraitis V., Kleber M.E., Silbernagel G., Meyer J., Müller-Nurasyid M., Ganna A., Sarin A.P., Yengo L., Shungin D., Luan J., Horikoshi M., An P., Sanna S., Boettcher Y., Rayner N.W., Nolte I.M., Zemunik T., Iperen E.V., Kovacs P., Hastie N.D., Wild S.H., McLachlan S., Campbell S., Polasek O., Carlson O., Egan J., Kiess W., Willemsen G., Kuusisto J., Laakso M., Dimitriou M., Hicks A.A., Rauramaa R., Bandinelli S., Thorand B., Liu Y., Miljkovic I., Lind L., Doney A., Perola M., Hingorani A., Kivimaki M., Kumari M., Bennett A.J., Groves C.J., Herder C., Koistinen H.A., Kinnunen L., Faire U., Bakker SJL, Uusitupa M., Palmer CNA, Jukema J.W., Sattar N., Pouta A., Snieder H., Boerwinkle E., Pankow J.S., Magnusson P.K., Krus U., Scapoli C., de Geus EJCN, Blüher M., Wolffenbuttel BHR, Province M.A., Abecasis G.R., Meigs J.B., Hovingh G.K., Lindström J., Wilson J.F., Wright A.F., Dedoussis G.V., Bornstein S.R., Schwarz PEH, Tönjes A., Winkelmann B.R., Boehm B.O., März W., Metspalu A., Price J.F., Deloukas P., Körner A., Lakka T.A., Keinanen-Kiukaanniemi S.M., Saaristo T.E., Bergman R.N., Tuomilehto J., Wareham N.J., Langenberg C., Männistö S., Franks P.W., Hayward C., Vitart V., Kaprio J., Visvikis-Siest S., Balkau B., Altshuler D., Rudan I., Stumvoll M., Campbell H., van Duijn C.M., Gieger C., Illig T., Ferrucci L., Pedersen N.L., Pramstaller P.P., Boehnke M., Frayling T.M., Shuldiner A.R., Peyser P.A., Kardia SLR, Palmer L.J., Penninx B.W., Meneton P., Harris T.B., Navis G., Harst P.V., Smith G.D., Forouhi N.G., Loos RJF, Salomaa V., Soranzo N., Boomsma D.I., Groop L., Tuomi T., Hofman A., Munroe P.B., Gudnason V., Siscovick D.S., Watkins H., Lecoeur C., Vollenweider P., Franco-Cereceda A., Eriksson P., Jarvelin M.R., Stefansson K., Hamsten A., Nicholson G., Karpe F., Dermitzakis E.T., Lindgren C.M., McCarthy M.I., Froguel P., Kaakinen M.A., Lyssenko V., Watanabe R.M., Ingelsson E., Florez J.C., Dupuis J., Barroso I., Morris A.P., Prokopenko I.

Working group(s)

Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

ISSN

2041-1723 (Electronic)

ISSN-L

2041-1723

Publication state

Published

Issued date

05/01/2021

Peer-reviewed

Oui

Volume

Number

Pages

Language

english

Notes

Publication types: Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish

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

Adult, Anorexia Nervosa/blood, Anorexia Nervosa/ethnology, Anorexia Nervosa/genetics, Anorexia Nervosa/physiopathology, Blood Glucose/metabolism, European Continental Ancestry Group, Fasting/blood, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance/blood, Glucose Intolerance/ethnology, Glucose Intolerance/genetics, Glucose Intolerance/physiopathology, Humans, Insulin/blood, Insulin Receptor Substrate Proteins/blood, Insulin Receptor Substrate Proteins/genetics, Insulin Resistance/genetics, Kruppel-Like Transcription Factors/blood, Kruppel-Like Transcription Factors/genetics, Male, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio

URN

urn:nbn:ch:serval-BIB_165C70D1F41C0

OAI-PMH

oai:serval.unil.ch:BIB_165C70D1F41C

DOI

10.1038/s41467-020-19366-9

Pubmed

33402679

Web of science

000610431700001

Open Access

Yes