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

V Lagou; R Mägi; JJ Hottenga; H Grallert; JRB Perry; N Bouatia-Naji; L Marullo; D Rybin; R Jansen; JL Min; AS Dimas; A Ulrich; L Zudina; JR Gådin; L Jiang; A Faggian; A Bonnefond; J Fadista; MG Stathopoulou; A Isaacs; SM Willems; P Navarro; T Tanaka; AU Jackson; ME Montasser; JR O'Connell; LF Bielak; RJ Webster; R Saxena; JM Stafford; BS Pourcain; NJ Timpson; P Salo; SY Shin; N Amin; AV Smith; G Li; N Verweij; A Goel; I Ford; PCD Johnson; T Johnson; K Kapur; G Thorleifsson; RJ Strawbridge; LJ Rasmussen-Torvik; T Esko; E Mihailov; T Fall; RM Fraser; A Mahajan; S Kanoni; V Giedraitis; ME Kleber; G Silbernagel; J Meyer; M Müller-Nurasyid; A Ganna; AP Sarin; L Yengo; D Shungin; J Luan; M Horikoshi; P An; S Sanna; Y Boettcher; NW Rayner; IM Nolte; T Zemunik; EV Iperen; P Kovacs; ND Hastie; SH Wild; S McLachlan; S Campbell; O Polasek; O Carlson; J Egan; W Kiess; G Willemsen; J Kuusisto; M Laakso; M Dimitriou; Andrew A. Hicks; R Rauramaa; S Bandinelli; B Thorand; Y Liu; I Miljkovic; L Lind; A Doney; M Perola; A Hingorani; M Kivimaki; M Kumari; AJ Bennett; CJ Groves; C Herder; HA Koistinen; L Kinnunen; U Faire; SJL Bakker; M Uusitupa; CNA Palmer; JW Jukema; N Sattar; A Pouta; H Snieder; E Boerwinkle; JS Pankow; PK Magnusson; U Krus; C Scapoli; EJCN de Geus; M Blüher; BHR Wolffenbuttel; MA Province; GR Abecasis; JB Meigs; GK Hovingh; J Lindström; JF Wilson; AF Wright; GV Dedoussis; SR Bornstein; PEH Schwarz; A Tönjes; BR Winkelmann; BO Boehm; W März; A Metspalu; JF Price; P Deloukas; A Körner; TA Lakka; SM Keinanen-Kiukaanniemi; TE Saaristo; RN Bergman; J Tuomilehto; NJ Wareham; C Langenberg; S Männistö; PW Franks; C Hayward; V Vitart; J Kaprio; S Visvikis-Siest; B Balkau; D Altshuler; I Rudan; M Stumvoll; H Campbell; CM van Duijn; C Gieger; T Illig; L Ferrucci; NL Pedersen; Peter P. Pramstaller; M Boehnke; TM Frayling; AR Shuldiner; PA Peyser; SLR Kardia; LJ Palmer; BW Penninx; P Meneton; TB Harris; G Navis; PV Harst; GD Smith; NG Forouhi; RJF Loos; V Salomaa; N Soranzo; DI Boomsma; L Groop; T Tuomi; A Hofman; PB Munroe; V Gudnason; DS Siscovick; H Watkins; C Lecoeur; P Vollenweider; A Franco-Cereceda; P Eriksson; MR Jarvelin; K Stefansson; A Hamsten; G Nicholson; F Karpe; ET Dermitzakis; CM Lindgren; MI McCarthy; P Froguel; MA Kaakinen; V Lyssenko; RM Watanabe; E Ingelsson; JC Florez; J Dupuis; I Barroso; AP Morris; I Prokopenko

doi:10.1038/s41467-020-19366-9

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

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

V Lagou, R Mägi, JJ Hottenga, H Grallert, JRB Perry, N Bouatia-Naji, L Marullo, D Rybin, R Jansen, JL Min, …

Nature Communications, Vol.12(1)

05/01/2021

DOI: https://doi.org/10.1038/s41467-020-19366-9

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https://hdl.handle.net/10863/19906

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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Title: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
Creators: V Lagou - University of Oxford
R Mägi - University of Tartu
JJ Hottenga
H Grallert
JRB Perry
N Bouatia-Naji
L Marullo - University of Ferrara
D Rybin - Boston University
R Jansen - Amsterdam UMC Location VUmc
JL Min - University of Bristol
AS Dimas
A Ulrich - Imperial College London
L Zudina - Imperial College London
JR Gådin - Karolinska University Hospital
L Jiang - Imperial College London
A Faggian - Imperial College London
A Bonnefond - Imperial College London
J Fadista - Statens Serum Institut
MG Stathopoulou - Université de Lorraine
A Isaacs - Maastricht University
SM Willems - Erasmus University Rotterdam
P Navarro - Western General Hospital
T Tanaka - National Institutes of Health
AU Jackson - University of Michigan
ME Montasser - University of Maryland, Baltimore
JR O'Connell
LF Bielak - University of Michigan
RJ Webster - Harry Perkins Institute of Medical Research
R Saxena
JM Stafford - Wake Forest University
BS Pourcain - University of Bristol
NJ Timpson - University of Bristol
P Salo - National Institute for Health and Welfare
SY Shin
N Amin - Erasmus University Rotterdam
AV Smith
G Li - University of Washington
N Verweij - University Medical Center Groningen
A Goel - University of Oxford
I Ford - Robertson Centre for Biostatistics
PCD Johnson
T Johnson - Queen Mary University of London
K Kapur - University of Lausanne
G Thorleifsson - deCODE Genetics
RJ Strawbridge - University of Glasgow
LJ Rasmussen-Torvik
T Esko - University of Tartu
E Mihailov - University of Tartu
T Fall - Science for Life Laboratory
RM Fraser - University of Edinburgh
A Mahajan - University of Oxford
S Kanoni - Queen Mary University of London
V Giedraitis - Uppsala University
ME Kleber - Heidelberg University
G Silbernagel - Medical University of Graz
J Meyer
M Müller-Nurasyid
A Ganna - Broad Institute
AP Sarin
L Yengo - University of Lille Nord de France
D Shungin - Umeå University
J Luan - University of Cambridge
M Horikoshi - University of Oxford
P An - Washington University in St. Louis
S Sanna - University Medical Center Groningen
Y Boettcher - Leipzig University
NW Rayner - University of Oxford
IM Nolte - University Medical Center Groningen
T Zemunik - University of Split
EV Iperen
P Kovacs - Leipzig University
ND Hastie - Western General Hospital
SH Wild - University of Edinburgh
S McLachlan - University of Edinburgh
S Campbell - Western General Hospital
O Polasek - University of Split
O Carlson - National Institutes of Health
J Egan - National Institutes of Health
W Kiess - Leipzig University
G Willemsen - VU University Amsterdam
J Kuusisto - University of Eastern Finland
M Laakso - University of Eastern Finland
M Dimitriou - Harokopio University of Athens
Andrew A. Hicks
R Rauramaa
S Bandinelli
B Thorand
Y Liu - Wake Forest University
I Miljkovic - University of Pittsburgh
L Lind - Uppsala University Hospital
A Doney
M Perola - National Institute for Health and Welfare
A Hingorani - University College London
M Kivimaki - University College London
M Kumari - University College London
AJ Bennett - University of Oxford
CJ Groves - University of Oxford
C Herder - University of Düsseldorf
HA Koistinen - National Institute for Health and Welfare
L Kinnunen - National Institute for Health and Welfare
U Faire
SJL Bakker
M Uusitupa - University of Eastern Finland
CNA Palmer
JW Jukema - Leiden University Medical Center
N Sattar - University of Glasgow
A Pouta - National Institute for Health and Welfare
H Snieder - University Medical Center Groningen
E Boerwinkle - University of Texas Health Science Center at Houston
JS Pankow - University of Minnesota
PK Magnusson - Karolinska Institutet
U Krus - Lund University
C Scapoli - University of Ferrara
EJCN de Geus
M Blüher - University of Southern California
BHR Wolffenbuttel
MA Province - Washington University in St. Louis
GR Abecasis - University of Michigan
JB Meigs - Broad Institute
GK Hovingh - Novo Nordisk
J Lindström - National Institute for Health and Welfare
JF Wilson - University of Edinburgh
AF Wright - Western General Hospital
GV Dedoussis - Harokopio University of Athens
SR Bornstein - Dresden University of Technology
PEH Schwarz
A Tönjes - Leipzig University
BR Winkelmann
BO Boehm - Nanyang Technological University
W März - Synlab
A Metspalu - University of Tartu
JF Price - University of Edinburgh
P Deloukas - Queen Mary University of London
A Körner - Harvard University
TA Lakka - University of Eastern Finland
SM Keinanen-Kiukaanniemi
TE Saaristo
RN Bergman - Cedars-Sinai Medical Center
J Tuomilehto
NJ Wareham - University of Cambridge
C Langenberg - University of Cambridge
S Männistö - National Institute for Health and Welfare
PW Franks - Umeå University
C Hayward - Western General Hospital
V Vitart - Western General Hospital
J Kaprio - University of Helsinki
S Visvikis-Siest
B Balkau - French Institute of Health and Medical Research
D Altshuler - Massachusetts Institute of Technology
I Rudan - University of Edinburgh
M Stumvoll - Leipzig University
H Campbell - University of Edinburgh
CM van Duijn - Erasmus University Rotterdam
C Gieger
T Illig - Medizinische Hochschule Hannover
L Ferrucci - National Institutes of Health
NL Pedersen - Karolinska Institutet
Peter P. Pramstaller - University of Lübeck
M Boehnke - University of Michigan
TM Frayling - University of Exeter
AR Shuldiner - University of Maryland, Baltimore
PA Peyser - University of Michigan
SLR Kardia
LJ Palmer - University of Adelaide
BW Penninx
P Meneton - French Institute of Health and Medical Research
TB Harris - National Institutes of Health
G Navis - University Medical Center Groningen
PV Harst
GD Smith - University of Bristol
NG Forouhi - University of Cambridge
RJF Loos
V Salomaa - National Institute for Health and Welfare
N Soranzo - Wellcome Trust
DI Boomsma - VU University Amsterdam
L Groop - University of Helsinki
T Tuomi
A Hofman - Harvard University
PB Munroe - Queen Mary University of London
V Gudnason - University of Iceland
DS Siscovick - University of Washington
H Watkins - University of Oxford
C Lecoeur - University of Lille Nord de France
P Vollenweider
A Franco-Cereceda
P Eriksson - Karolinska University Hospital
MR Jarvelin
K Stefansson - University of Iceland
A Hamsten - Karolinska University Hospital
G Nicholson - University of Oxford
F Karpe - National Institute for Health Research
ET Dermitzakis - University of Geneva
CM Lindgren
MI McCarthy
P Froguel - Imperial College London
MA Kaakinen - University of Surrey
V Lyssenko - University of Bergen
RM Watanabe - University of Southern California
E Ingelsson - Cardiovascular Institute of the South
JC Florez - Harvard University
J Dupuis - Boston University
I Barroso - University of Cambridge
AP Morris
I Prokopenko
Publication Details: Nature Communications, Vol.12(1)
ISSN: 2041-1723
EISSN: 2041-1723
Series / Volume: 12
Publisher: Nature Research
Identifiers: (EURAC)22886139
991006218094701241
Web of Science ID: PW1JB
Copyright: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Academic Unit: Institute for Biomedicine
Language: English
Resource Type: Journal article
Local Fields: Scientific
Author Names String: 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, Strawbridge RJ, Rasmussen-Torvik LJ, Esko T, Mihailov E, Fall T, Fraser RM, Mahajan A, Kanoni S, Giedraitis V, Kleber ME, Silbernagel G, Meyer J, Müller-Nurasyid M, Ganna A, Sarin AP, Yengo L, Shungin D, Luan J, Horikoshi M, An P, Sanna S, Boettcher Y, Rayner NW, Nolte IM, Zemunik T, Iperen EV, Kovacs P, Hastie ND, Wild SH, McLachlan S, Campbell S, Polasek O, Carlson O, Egan J, Kiess W, Willemsen G, Kuusisto J, Laakso M, Dimitriou M, Hicks AA, Rauramaa R, Bandinelli S, Thorand B, Liu Y, Miljkovic I, Lind L, Doney A, Perola M, Hingorani A, Kivimaki M, Kumari M, Bennett AJ, Groves CJ, Herder C, Koistinen HA, Kinnunen L, Faire U, Bakker SJL, Uusitupa M, Palmer CNA, Jukema JW, Sattar N, Pouta A, Snieder H, Boerwinkle E, Pankow JS, Magnusson PK, Krus U, Scapoli C, de Geus EJCN, Blüher M, Wolffenbuttel BHR, Province MA, Abecasis GR, Meigs JB, Hovingh GK, Lindström J, Wilson JF, Wright AF, Dedoussis GV, Bornstein SR, Schwarz PEH, Tönjes A, Winkelmann BR, Boehm BO, März W, Metspalu A, Price JF, Deloukas P, Körner A, Lakka TA, Keinanen-Kiukaanniemi SM, Saaristo TE, Bergman RN, Tuomilehto J, Wareham NJ, Langenberg C, Männistö S, Franks PW, Hayward C, Vitart V, Kaprio J, Visvikis-Siest S, Balkau B, Altshuler D, Rudan I, Stumvoll M, Campbell H, van Duijn CM, Gieger C, Illig T, Ferrucci L, Pedersen NL, Pramstaller PP, Boehnke M, Frayling TM, Shuldiner AR, Peyser PA, Kardia SLR, Palmer LJ, Penninx BW, Meneton P, Harris TB, Navis G, Harst PV, Smith GD, Forouhi NG, Loos RJF, Salomaa V, Soranzo N, Boomsma DI, Groop L, Tuomi T, Hofman A, Munroe PB, Gudnason V, Siscovick DS, Watkins H, Lecoeur C, Vollenweider P, Franco-Cereceda A, Eriksson P, Jarvelin MR, Stefansson K, Hamsten A, Nicholson G, Karpe F, Dermitzakis ET, Lindgren CM, McCarthy MI, Froguel P, Kaakinen MA, Lyssenko V, Watanabe RM, Ingelsson E, Florez JC, Dupuis J, Barroso I, Morris AP, Prokopenko I

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