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

Vasiliki Lagou; Reedik Mägi; Jouke- Jan Hottenga; Rick Jansen; Josine L. Min; Gonneke Willemsen; Eco J. C. N. De Geus; Brenda W. Penninx; Dorret I. Boomsma; Inês Barroso; Andrew P. Morris; Inga Prokopenko; MAGIC Collaboration

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, Rick Jansen, Josine L. Min, Gonneke Willemsen, Eco J. C. N. De Geus, Brenda W. Penninx, Dorret I. Boomsma, Inês Barroso, Andrew P. Morris, Inga Prokopenko, MAGIC Collaboration

Research output: Contribution to Journal › Article › Academic › peer-review

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
Pages (from-to)	1-18
Number of pages	18
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19366-9
Publication status	Published - 5 Jan 2021

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Lagou, V., Mägi, R., Hottenga, J. J., Jansen, R., Min, J. L., Willemsen, G., De Geus, E. J. C. N., Penninx, B. W., Boomsma, D. I., Barroso, I., Morris, A. P., Prokopenko, I., & MAGIC Collaboration (2021). Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability. Nature Communications, 12(1), 1-18. [24]. https://doi.org/10.1038/s41467-020-19366-9

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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.",

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

language = "English",

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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 - Strawbridge, Rona J.

AU - Rasmussen-torvik, Laura J.

AU - Esko, Tõnu

AU - Mihailov, Evelin

AU - Fall, Tove

AU - Fraser, Ross M.

AU - Mahajan, Anubha

AU - Kanoni, Stavroula

AU - Giedraitis, Vilmantas

AU - Kleber, Marcus E.

AU - Silbernagel, Günther

AU - Meyer, Julia

AU - Müller-nurasyid, Martina

AU - Ganna, Andrea

AU - Sarin, Antti-pekka

AU - Yengo, Loic

AU - Shungin, Dmitry

AU - Luan, Jian’an

AU - Horikoshi, Momoko

AU - An, Ping

AU - Sanna, Serena

AU - Boettcher, Yvonne

AU - Rayner, N. William

AU - Nolte, Ilja M.

AU - Zemunik, Tatijana

AU - Iperen, Erik Van

AU - Kovacs, Peter

AU - Hastie, Nicholas D.

AU - Wild, Sarah H.

AU - Mclachlan, Stela

AU - Campbell, Susan

AU - Polasek, Ozren

AU - Carlson, Olga

AU - Egan, Josephine

AU - Kiess, Wieland

AU - Willemsen, Gonneke

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Dimitriou, Maria

AU - Hicks, Andrew A.

AU - Rauramaa, Rainer

AU - Bandinelli, Stefania

AU - Thorand, Barbara

AU - Liu, Yongmei

AU - Miljkovic, Iva

AU - Lind, Lars

AU - Doney, Alex

AU - Perola, Markus

AU - Hingorani, Aroon

AU - Kivimaki, Mika

AU - Kumari, Meena

AU - Bennett, Amanda J.

AU - Groves, Christopher J.

AU - Herder, Christian

AU - Koistinen, Heikki A.

AU - Kinnunen, Leena

AU - Faire, Ulf De

AU - Bakker, Stephan J. L.

AU - Uusitupa, Matti

AU - Palmer, Colin N. A.

AU - Jukema, J. Wouter

AU - Sattar, Naveed

AU - Pouta, Anneli

AU - Snieder, Harold

AU - Boerwinkle, Eric

AU - Pankow, James S.

AU - Magnusson, Patrik K.

AU - Krus, Ulrika

AU - Scapoli, Chiara

AU - De Geus, Eco J. C. N.

AU - Blüher, Matthias

AU - Wolffenbuttel, Bruce H. R.

AU - Province, Michael A.

AU - Abecasis, Goncalo R.

AU - Meigs, James B.

AU - Hovingh, G. Kees

AU - Lindström, Jaana

AU - Wilson, James F.

AU - Wright, Alan F.

AU - Dedoussis, George V.

AU - Bornstein, Stefan R.

AU - Schwarz, Peter E. H.

AU - Tönjes, Anke

AU - Winkelmann, Bernhard R.

AU - Boehm, Bernhard O.

AU - März, Winfried

AU - Metspalu, Andres

AU - Price, Jackie F.

AU - Deloukas, Panos

AU - Körner, Antje

AU - Lakka, Timo A.

AU - Keinanen-kiukaanniemi, Sirkka M.

AU - Saaristo, Timo E.

AU - Bergman, Richard N.

AU - Tuomilehto, Jaakko

AU - Wareham, Nicholas J.

AU - Langenberg, Claudia

AU - Männistö, Satu

AU - Franks, Paul W.

AU - Hayward, Caroline

AU - Vitart, Veronique

AU - Kaprio, Jaakko

AU - Visvikis-siest, Sophie

AU - Balkau, Beverley

AU - Altshuler, David

AU - Rudan, Igor

AU - Stumvoll, Michael

AU - Campbell, Harry

AU - Van Duijn, Cornelia M.

AU - Gieger, Christian

AU - Illig, Thomas

AU - Ferrucci, Luigi

AU - Pedersen, Nancy L.

AU - Pramstaller, Peter P.

AU - Boehnke, Michael

AU - Frayling, Timothy M.

AU - Shuldiner, Alan R.

AU - Peyser, Patricia A.

AU - Kardia, Sharon L. R.

AU - Palmer, Lyle J.

AU - Penninx, Brenda W.

AU - Meneton, Pierre

AU - Harris, Tamara B.

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AU - Harst, Pim Van Der

AU - Smith, George Davey

AU - Forouhi, Nita G.

AU - Loos, Ruth J. F.

AU - Salomaa, Veikko

AU - Soranzo, Nicole

AU - Boomsma, Dorret I.

AU - Groop, Leif

AU - Tuomi, Tiinamaija

AU - Hofman, Albert

AU - Munroe, Patricia B.

AU - Gudnason, Vilmundur

AU - Siscovick, David S.

AU - Watkins, Hugh

AU - Lecoeur, Cecile

AU - Vollenweider, Peter

AU - Franco-cereceda, Anders

AU - Eriksson, Per

AU - Jarvelin, Marjo-riitta

AU - Stefansson, Kari

AU - Hamsten, Anders

AU - Nicholson, George

AU - Karpe, Fredrik

AU - Dermitzakis, Emmanouil T.

AU - Lindgren, Cecilia M.

AU - Mccarthy, Mark I.

AU - Froguel, Philippe

AU - Kaakinen, Marika A.

AU - Lyssenko, Valeriya

AU - Watanabe, Richard M.

AU - Ingelsson, Erik

AU - Florez, Jose C.

AU - Dupuis, Josée

AU - Barroso, Inês

AU - Morris, Andrew P.

AU - Prokopenko, Inga

AU - MAGIC Collaboration

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.

U2 - 10.1038/s41467-020-19366-9

DO - 10.1038/s41467-020-19366-9

M3 - Article

SN - 2041-1723

VL - 12

SP - 1

EP - 18

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 24

ER -

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

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