Genome-wide meta-analysis of common variant differences between men and women

Vesna Boraska; Ana Jerončić; Vincenza Colonna; Lorraine Southam; Dale R. Nyholt; Nigel William rayner; John R.B. Perry; Daniela Toniolo; Eva Albrecht; Wei Ang; Stefania Bandinelli; Maja Barbalic; Inês Barroso; Jacques S. Beckmann; Reiner Biffar; Dorret Boomsma; Harry Campbell; Tanguy Corre; Jeanette Erdmann; Tõnu Esko; Krista Fischer; Nora Franceschini; Timothy M. Frayling; Giorgia Girotto; Juan R. Gonzalez; Tamara B. Harris; Andrew C. Heath; Iris M. Heid; Wolfgang Hoffmann; Albert Hofman; Momoko Horikoshi; Jing Hua zhao; Anne U. Jackson; Jouke Jan Hottenga; Antti Jula; Mika Kähönen; Kay Tee Khaw; Lambertus A. Kiemeney; Norman Klopp; Zoltán Kutalik; Vasiliki Lagou; Lenore J. Launer; Terho Lehtimäki; Mathieu Lemire; Marja Liisa Lokki; Christina Loley; Jian'an Luan; Massimo Mangino; Irene Mateo leach; Sarah E. Medland; Evelin Mihailov; Grant W. Montgomery; Gerjan Navis; John Newnham; Markku S. Nieminen; Aarno Palotie; Kalliope Panoutsopoulou; Annette Peters; Nicola Pirastu; Ozren Polašek; Karola Rehnström; Samuli Ripatti; Graham R.S. Ritchie; Fernando Rivadeneira; Antonietta Robino; Nilesh J. Samani; So Youn Shin; Juha Sinisalo; Johannes H. Smit; Nicole Soranzo; Lisette Stolk; Dorine W. Swinkels; Toshiko Tanaka; Alexander Teumer; Anke Tönjes; Michela Traglia; Jaakko Tuomilehto; Armand Valsesia; Wiek H. Van gilst; Joyce B.J. Van meurs; Albert Vernon Smith; Jorma Viikari; Jacqueline M. Vink; Gerard Waeber; Nicole M. Warrington; Elisabeth Widen; Gonneke Willemsen; Alan F. Wright; Brent W. Zanke; Lina Zgaga; Michael Boehnke; Adamo Pio D'Adamo; Eco De geus; Ellen W. Demerath; Martin Den Heijer; Johan G. Eriksson; Luigi Ferrucci; Christian Gieger; Vilmundur Gudnason; Caroline Hayward; Christian Hengstenberg; Thomas J. Hudson; Marjo Riitta Järvelin; Manolis Kogevinas; Ruth J.F. Loos; Nicholas G. Martin; Andres Metspalu; Craig E. Pennell; Brenda W. Penninx; Markus Perola; Olli Raitakari; Veikko Salomaa; Stefan Schreiber; Heribert Schunkert; Tim D. Spector; Michael Stumvoll; André G. Uitterlinden; Sheila Ulivi; Pim Van der harst; Peter Vollenweider; Henry Völzke; Nicholas J. Wareham; H. Erich Wichmann; James F. Wilson; Igor Rudan; Yali Xue; Eleftheria Zeggini

doi:10.1093/hmg/dds304

Genome-wide meta-analysis of common variant differences between men and women

Vesna Boraska, Ana Jerončić, Vincenza Colonna, Lorraine Southam, Dale R. Nyholt, Nigel William rayner, John R.B. Perry, Daniela Toniolo, Eva Albrecht, Wei Ang, Stefania Bandinelli, Maja Barbalic, Inês Barroso, Jacques S. Beckmann, Reiner Biffar, Dorret Boomsma, Harry Campbell, Tanguy Corre, Jeanette Erdmann, Tõnu EskoKrista Fischer, Nora Franceschini, Timothy M. Frayling, Giorgia Girotto, Juan R. Gonzalez, Tamara B. Harris, Andrew C. Heath, Iris M. Heid, Wolfgang Hoffmann, Albert Hofman, Momoko Horikoshi, Jing Hua zhao, Anne U. Jackson, Jouke Jan Hottenga, Antti Jula, Mika Kähönen, Kay Tee Khaw, Lambertus A. Kiemeney, Norman Klopp, Zoltán Kutalik, Vasiliki Lagou, Lenore J. Launer, Terho Lehtimäki, Mathieu Lemire, Marja Liisa Lokki, Christina Loley, Jian'an Luan, Massimo Mangino, Irene Mateo leach, Sarah E. Medland, Evelin Mihailov, Grant W. Montgomery, Gerjan Navis, John Newnham, Markku S. Nieminen, Aarno Palotie, Kalliope Panoutsopoulou, Annette Peters, Nicola Pirastu, Ozren Polašek, Karola Rehnström, Samuli Ripatti, Graham R.S. Ritchie, Fernando Rivadeneira, Antonietta Robino, Nilesh J. Samani, So Youn Shin, Juha Sinisalo, Johannes H. Smit, Nicole Soranzo, Lisette Stolk, Dorine W. Swinkels, Toshiko Tanaka, Alexander Teumer, Anke Tönjes, Michela Traglia, Jaakko Tuomilehto, Armand Valsesia, Wiek H. Van gilst, Joyce B.J. Van meurs, Albert Vernon Smith, Jorma Viikari, Jacqueline M. Vink, Gerard Waeber, Nicole M. Warrington, Elisabeth Widen, Gonneke Willemsen, Alan F. Wright, Brent W. Zanke, Lina Zgaga, Michael Boehnke, Adamo Pio D'Adamo, Eco De geus, Ellen W. Demerath, Martin Den Heijer, Johan G. Eriksson, Luigi Ferrucci, Christian Gieger, Vilmundur Gudnason, Caroline Hayward, Christian Hengstenberg, Thomas J. Hudson, Marjo Riitta Järvelin, Manolis Kogevinas, Ruth J.F. Loos, Nicholas G. Martin, Andres Metspalu, Craig E. Pennell, Brenda W. Penninx, Markus Perola, Olli Raitakari, Veikko Salomaa, Stefan Schreiber, Heribert Schunkert, Tim D. Spector, Michael Stumvoll, André G. Uitterlinden, Sheila Ulivi, Pim Van der harst, Peter Vollenweider, Henry Völzke, Nicholas J. Wareham, H. Erich Wichmann, James F. Wilson, Igor Rudan, Yali Xue, Eleftheria Zeggini

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Abstract

The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10^-8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.

Original language	English
Article number	dds304
Pages (from-to)	4805-4815
Number of pages	11
Journal	Human molecular genetics
Volume	21
Issue number	21
DOIs	https://doi.org/10.1093/hmg/dds304
State	Published - Nov 2012

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10.1093/hmg/dds304

Cite this

Boraska, V., Jerončić, A., Colonna, V., Southam, L., Nyholt, D. R., William rayner, N., Perry, J. R. B., Toniolo, D., Albrecht, E., Ang, W., Bandinelli, S., Barbalic, M., Barroso, I., Beckmann, J. S., Biffar, R., Boomsma, D., Campbell, H., Corre, T., Erdmann, J., ... Zeggini, E. (2012). Genome-wide meta-analysis of common variant differences between men and women. Human molecular genetics, 21(21), 4805-4815. Article dds304. https://doi.org/10.1093/hmg/dds304

@article{d6cb096ac2b84665811d24bc8f2ec946,

title = "Genome-wide meta-analysis of common variant differences between men and women",

abstract = "The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10-8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.",

author = "Vesna Boraska and Ana Jeron{\v c}i{\'c} and Vincenza Colonna and Lorraine Southam and Nyholt, {Dale R.} and {William rayner}, Nigel and Perry, {John R.B.} and Daniela Toniolo and Eva Albrecht and Wei Ang and Stefania Bandinelli and Maja Barbalic and In{\^e}s Barroso and Beckmann, {Jacques S.} and Reiner Biffar and Dorret Boomsma and Harry Campbell and Tanguy Corre and Jeanette Erdmann and T{\~o}nu Esko and Krista Fischer and Nora Franceschini and Frayling, {Timothy M.} and Giorgia Girotto and Gonzalez, {Juan R.} and Harris, {Tamara B.} and Heath, {Andrew C.} and Heid, {Iris M.} and Wolfgang Hoffmann and Albert Hofman and Momoko Horikoshi and {Hua zhao}, Jing and Jackson, {Anne U.} and Hottenga, {Jouke Jan} and Antti Jula and Mika K{\"a}h{\"o}nen and Khaw, {Kay Tee} and Kiemeney, {Lambertus A.} and Norman Klopp and Zolt{\'a}n Kutalik and Vasiliki Lagou and Launer, {Lenore J.} and Terho Lehtim{\"a}ki and Mathieu Lemire and Lokki, {Marja Liisa} and Christina Loley and Jian'an Luan and Massimo Mangino and {Mateo leach}, Irene and Medland, {Sarah E.} and Evelin Mihailov and Montgomery, {Grant W.} and Gerjan Navis and John Newnham and Nieminen, {Markku S.} and Aarno Palotie and Kalliope Panoutsopoulou and Annette Peters and Nicola Pirastu and Ozren Pola{\v s}ek and Karola Rehnstr{\"o}m and Samuli Ripatti and Ritchie, {Graham R.S.} and Fernando Rivadeneira and Antonietta Robino and Samani, {Nilesh J.} and Shin, {So Youn} and Juha Sinisalo and Smit, {Johannes H.} and Nicole Soranzo and Lisette Stolk and Swinkels, {Dorine W.} and Toshiko Tanaka and Alexander Teumer and Anke T{\"o}njes and Michela Traglia and Jaakko Tuomilehto and Armand Valsesia and {Van gilst}, {Wiek H.} and {Van meurs}, {Joyce B.J.} and Smith, {Albert Vernon} and Jorma Viikari and Vink, {Jacqueline M.} and Gerard Waeber and Warrington, {Nicole M.} and Elisabeth Widen and Gonneke Willemsen and Wright, {Alan F.} and Zanke, {Brent W.} and Lina Zgaga and Michael Boehnke and D'Adamo, {Adamo Pio} and {De geus}, Eco and Demerath, {Ellen W.} and {Den Heijer}, Martin and Eriksson, {Johan G.} and Luigi Ferrucci and Christian Gieger and Vilmundur Gudnason and Caroline Hayward and Christian Hengstenberg and Hudson, {Thomas J.} and J{\"a}rvelin, {Marjo Riitta} and Manolis Kogevinas and Loos, {Ruth J.F.} and Martin, {Nicholas G.} and Andres Metspalu and Pennell, {Craig E.} and Penninx, {Brenda W.} and Markus Perola and Olli Raitakari and Veikko Salomaa and Stefan Schreiber and Heribert Schunkert and Spector, {Tim D.} and Michael Stumvoll and Uitterlinden, {Andr{\'e} G.} and Sheila Ulivi and {Van der harst}, Pim and Peter Vollenweider and Henry V{\"o}lzke and Wareham, {Nicholas J.} and Wichmann, {H. Erich} and Wilson, {James F.} and Igor Rudan and Yali Xue and Eleftheria Zeggini",

note = "Funding Information: NTR1: Funding was obtained from the Netherlands Heart Foundation (90.313, 86.083 and 88.042), the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW): Genetic basis of anxiety and depression (904-61-090); Genetics of individual differences in smoking initiation and persistence (NWO 985-10-002); Resolving cause and effect in the association between exercise and well-being (904-61-193); Twin family database for behaviour genomics studies (480-04-004); Twin research focusing on behaviour (400-05-717); Genetic determinants of risk behaviour in relation to alcohol use and alcohol use disorder (Addiction-31160008); Genotype/phenotype database for behaviour genetic and genetic epidemiological studies (911-09-032); Spinozapremie (SPI 56-464-14192); CMSB: Center for Medical Systems Biology (NWO Genomics); NBIC/BioAssist/RK/2008.024); BBMRI –NL: Biobanking and Biomolecular Resources Research Infrastructure; the VU University: Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Foundation (ESF): Genomewide analyses of European twin and population cohorts (EU/ QLRT-2001-01254); European Community{\textquoteright}s Seventh Frame-work Program (FP7/2007-2013): ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC) Genetics of Mental Illness (230374); Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); Collaborative study of the genetics of DZ twinning (NIH R01D0042157-01A); the Genetic Association Information Network, a public–private partnership between the NIH and Pfizer Inc., Affymetrix Inc. and Abbott Laboratories. Funding Information: SORBS: We thank all those who participated in the study. Sincere thank is given to Peter Kovacs who was significantly involved in the planning and procedure of the Sorbs study. We also thank Knut Krohn (Microarray Core Facility of the Interdisciplinary Centre for Clinical Research, University of Leipzig) for the genotyping support and Inga Prokopenko and Nigel W. Rayner (WTCHG, University of Oxford, UK) for the excellent analytical and bioinformatics support. This work was supported by grants from the Interdisciplinary Centre for Clinical Research at the University of Leipzig (B27 to A.T.) from the German Diabetes Association (to A.T.), a Travel Grant from BIF (to A.T.) and by the DHFD, Diabetes Hilfs-und Forschungsfonds Deutschland. The work of Vasiliki Lagou was funded through the ENGAGE (European Network for Genetic and Genomic Epidemiology) Consortium, the European Community{\textquoteright}s Seventh Framework Programme (HEALTH-F4-2007-201413). Funding Information: RAINE: The authors are grateful to the Raine Study participants and their families and to the Raine Study research staff for cohort coordination and data collection. The authors gratefully acknowledge the NH&MRC for their long term contribution to funding the study over the last 20 years and also the following Institutions for providing funding for Core Management of the Raine Study: The University of Western Australia (UWA), Raine Medical Research Foundation, UWA Faculty of Medicine, Dentistry and Health Sciences, The Telethon Institute for Child Health Research and Women and Infants Research Foundation. The authors gratefully acknowledge the assistance of the Western Australian DNA Bank (National Health and Medical Research Council of Australia National Enabling Facility). The authors also acknowledge the support of the National Health and Medical Research Council of Australia (Grant ID 403981 and ID 003209) and the Canadian Institutes of Health Research (Grant ID MOP-82893). Funding Information: ECHRS-Spain: Spanish Ministry of Science and Innovation grant MTM2008-02457; Fondo de Investigaciones San-tarias grants 97/0035-01, 99/0034-01 and 99/0034-02; Hospital Universitario de Albacete; Consejeria de Sanidad; FWO (Fund for Scientific Research) grant G.0402.00; University of Antwerp; the Flemish Health Ministry; Sociedad Espa-{\~n}ola de Neumolog{\'i}a y Cirug{\'i}a Tor{\'a}cica (SEPAR), Public Health Service grant R01 HL62633-01; Consell Interdeparta-mental de Recerca i Innovaci{\'o} Tecnol{\`o}gica (CIRIT) grant 1999SGR 00241; Red Respira Instituto de Salud Carlos III (ISCIII). Funding Information: ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN26820 1100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN26820 1100010C, HHSN268201100011C, and HHSN2682011 00012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: AGES: The researchers are indebted to the participants for their willingness to participate in the study. This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. Funding Information: NESDA: Neuroscience Campus Amsterdam; EMGO+ Institute for Health and Care Research; NIMH R01 MH059160; Geestkracht program of ZonMW (10-000-1002); matching funds from universities and mental health care institutes involved in NESDA. Genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). Funding Information: SHIP: We thank all staff members and participants of the SHIP study, as well as all of the genotyping staff for generating the SHIP SNP data set. The genetic data analysis workflow was created using the Software InforSense. Genetic data were stored using the database Cach{\'e} (InterSystems). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network {\textquoteleft}Greifswald Approach to Individualized Medicine (GANI_MED){\textquoteright} funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlan-gen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the {\textquoteleft}Center of Knowledge Interchange{\textquoteright} program of the Siemens AG. Funding Information: CROATIA-Korcula: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum M{\"u}nchen, Neuherberg, Germany. The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), and Republic of Croatia Ministry of Science, Education and Sports research (108-1080315-0302). Funding Information: ORCADES: ORCADES DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). Funding Information: BLSA: The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. Funding Information: HBCS: Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland (Grant No. 120315 and 129287 to EW, 1129457 and 1216965 to KR, 120386 and 125876 to JGE), the Finnish Diabetes Research Society, Fol-kh{\"a}lsan Research Foundation, Novo Nordisk Foundation, Finska L{\"a}kares{\"a}llskapet, the European Science Foundation (EuroSTRESS), the Wellcome Trust (Grant No. 89061/Z/09/ Z and 089062/Z/09/Z), Samfundet Folkh{\"a}lsan, Finska L{\"a}kare-s{\"a}llskapet and the Signe and Ane Gyllenberg foundation. Funding Information: YFS: The Cardiovascular Risk in Young Finns study (YFS) is supported by the Academy of Finland (grant no. 117797, 121584 and 126925), the Social Insurance Institution of Finland, University Hospital Medical funds to Tampere, and Turku University Hospitals, the Finnish Foundation of Cardiovascular Research Emil Aaltonen Foundation (T.L), and Tampere Tuberculosis Foundation. Funding Information: RS: We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, and Lisbeth Herrera for their help in creating the GWAS database. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We would like to thank Dr. Tobias A. Knoch, Karol Estrada, Luc V. de Zeeuw, Anis Abu-seiris and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@Me-diGRID part of the German D-Grid for access to their grid resources. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI) – Netherlands Consortium of Healthy Aging (NCHA) project nr. 050-060-810, and funding from the European Commission (HEALTH-F2-2008-201865, GEFOS; HEALTH-F2-2008-35627, TREAT-OA). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. German MediGRID and Services@MediGRID are part of the German D-Grid and are both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G. Funding Information: org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. Funding Information: CROATIA-Split: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark. The CROATIA-Split study is funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). Funding Information: EGCUT: EGCUT received financial support from FP7 programs (ENGAGE, OPENGENE), targeted financial support from Estonian Government SF0180142s08, Estonian Research Roadmap through Estonian Ministry of Education and Research, Center of Excellence in Genomics (EXCEGEN) and University of Tartu (SP1GVARENG). The work of K.F. was supported by Estonian Science Foundation grant EstSF ETF9353. We acknowledge EGCUT technical personnel, especially Mr V. Soo and S. Smit. Data analyzes were carried out in part in the High Performance Computing Center of University of Tartu. Funding Information: ENGAGE: This research was supported through funds from The European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. Funding Information: InCHIANTI: We thank the Intramural Research Program of the NIH, National Institute on Aging who are responsible for the InCHIANTI samples. We also thank the InCHIANTI participants. The InCHIANTI study baseline (1998-2000) was supported as a {\textquoteleft}targeted project{\textquoteright} (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-ups 2 and 3 studies (2004-2010) were financed by the U.S. National Institute on Aging (Contract: N01-AG-5-0002); supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. JRBP is funded by a Sir Henry Wellcome Postdoctoral Fellowship (092447/Z/10/Z). Funding Information: CROATIA-Vis: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland, UK. The CROATIA-Vis study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants (108-1080315-0302). Funding Information: NTR2: Funding is acknowledged from the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW): Twin family database for behaviour genomics studies (480-04-004); Twin research focusing on behaviour (400-05-717); Genetic determinants of risk behaviour in relation to alcohol use (Addiction-31160008); Genotype/phenotype database for behaviour genetic and genetic epidemiological studies (911-09-032); Spinozapremie (SPI 56-464-14192); CMSB: Center for Medical Systems Biology (NWO Genomics); NBIC/BioAssist/RK/2008.024); BBMRI –NL: Biobanking and Biomolecular Resources Research Infrastructure; European Science Foundation (ESF): Genome-wide analyses of European twin and population cohorts (EU/QLRT-2001-01254); European Community{\textquoteright}s Seventh Framework Program (FP7/2007-2013): ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC) Genetics of Mental Illness (230374); Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06). Funding Information: QIMR: We thank the twins and their families for their participation. We also thank Dixie Statham, Ann Eldridge, Marlene Grace, Kerrie McAloney (sample collection); Anjali Henders, Megan Campbell, Lisa Bowdler and Steven Crooks (sample and DNA processing); Scott Gordon, David Smyth, Harry Beeby, and Daniel Park (IT support). We also acknowledge David Duffy, Peter Visscher, Margaret Wright, Pamela Madden and Wendy Slutske for their funding contributions. Genotype imputation was carried out on the Genetic Cluster Computer. Funding was provided by the Australian National Health and Medical Research Council (NHMRC grants 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498), the Australian Research Council (ARC grants A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), and the U.S. National Institutes of Health (NIH grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206). The Genetic Cluster Computer is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). G.W.M. was supported by an NHMRC Fellowship (619667), D.R.N. (FT0991022) and S.E.M. (FT110100548) were supported by an ARC Future Fellowship. Funding Information: TwinsUK: We thank the staff from the TwinsUK, the DNA Collections and Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation; Quality Control of the Twins UK cohort for genotyping (in particular Amy Chaney, Radhi Ravindrarajah, Douglas Simpkin, Cliff Hinds, and Thomas Dibling); Paul Martin and Simon Potter of the DNA and Genotyping Informatics teams for data handling; Le Centre National de G{\'e}notypage, France, led by Mark Lathrop, for genotyping; Duke University, North Carolina, USA, led by David Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie. The authors declare they have no conflicts of interest. The study was funded by the Wellcome Trust; European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-ENGAGE and the European Union FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and Framework 6 Project EUroClot. The study also receives support from the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy{\textquoteright}s & St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London. Funding Information: KORA: The KORA authors acknowledge the contribution of Peter Lichtner, Gertrud Eckstein, Guido Fischer and all members of the Helmholtz Center Munich genotyping staff for generating the SNP data, as well as all members of field staffs who were involved in the planning and conduction of the KORA Augsburg studies. The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. Funding Information: EPIC-Obesity: The EPIC Norfolk Study is funded by program grants from the Medical Research Council UK and Cancer Research UK. Funding Information: CoLaus: The authors express their gratitude to the participants in the Lausanne CoLaus study and to the investigators who have contributed to the recruitment. We would like to thank Drs Vincent Mooser and Dawn Waterworth from GlaxoSmithKline for helpful comments and for their continuous support for the CoLaus project. Part of the computation has been performed on the Vital-IT cluster (www.vita l-it.ch). We are grateful to Dr. Toby Johnson and Pr. Sven Bergmann for statistical discussions. The CoLaus study was supported by research grants from GlaxoSmithKline; the Faculty of Biology and Medicine of Lausanne, Switzerland; and the Swiss National Science Foundation (grant no:33CSCO-122661). G{\'e}rard Waeber and Peter Vollenwei-der received an unrestricted grant from GSK to build the CoLaus study. Funding Information: V.B. is supported by Unity Through Knowledge Fund CONNECTIVITY PROGRAM ({\textquoteleft}Gaining Experience{\textquoteright} Grant 2A), The National Foundation for Science, Higher Education and Technological Development of the Republic of Croatia (BRAIN GAIN—Postdoc fellowship) and the Wellcome Trust (098051). E.Z. is supported by the Wellcome Trust (098051). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust (098051). Funding Information: PREVEND: PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), The Netherlands Heart Foundation (Grant 2006B140, 2006T003), National Institutes of Health (grant LM010098, HL65234, HL67466, RR018787) and the EU project grant GENECURE (FP-6 LSHM CT 2006 037697). P.vd.H is supported by NWO VENI grant 91676170 and Dutch Inter University Cardiology Institute Netherlands (ICIN). Funding Information: GerMIFS: Supported by the Deutsche Forschungsge-meinschaft and the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus), the FP6 and FP7 EU funded integrated projects Cardiogenics (LSHM-CT-2006-037593) and ENGAGE (201413), and the bi-national BMBF/ANR funded project CARDomics (01KU0908A). Supported by the DZHK (Deutsches Zentrum f{\"u}r Herz-Kreislauf-Forschung – German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). Funding Information: INGI-VB: We thank the inhabitants of the VB that made this study possible, the local administrations, the Tortona and Genova archdiocese and the ASL-22, Novi Ligure (Al) for support. We also thank Cinzia Sala and Clara Camaschella for data collection supervision and organization of the clinical data collection, Fiammetta Vigan{\`o} for technical help, Corrado Masciullo and Massimiliano Cocca for building the analysis platform. The research was supported by funds from Compag-nia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy and Ministry of Health, Ricerca Finalizzata 2008 and Telethon, Italy to DT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: NBS: We thank the participants from the Municipality of Nijmegen for their continued support to the Nijmegen Biomedical Study. The study was partly funded by an investment grant of the Radboud University Nijmegen Medical Centre.",

year = "2012",

month = nov,

doi = "10.1093/hmg/dds304",

language = "English",

volume = "21",

pages = "4805--4815",

journal = "Human molecular genetics",

issn = "0964-6906",

number = "21",

}

Boraska, V, Jerončić, A, Colonna, V, Southam, L, Nyholt, DR, William rayner, N, Perry, JRB, Toniolo, D, Albrecht, E, Ang, W, Bandinelli, S, Barbalic, M, Barroso, I, Beckmann, JS, Biffar, R, Boomsma, D, Campbell, H, Corre, T, Erdmann, J, Esko, T, Fischer, K, Franceschini, N, Frayling, TM, Girotto, G, Gonzalez, JR, Harris, TB, Heath, AC, Heid, IM, Hoffmann, W, Hofman, A, Horikoshi, M, Hua zhao, J, Jackson, AU, Hottenga, JJ, Jula, A, Kähönen, M, Khaw, KT, Kiemeney, LA, Klopp, N, Kutalik, Z, Lagou, V, Launer, LJ, Lehtimäki, T, Lemire, M, Lokki, ML, Loley, C, Luan, J, Mangino, M, Mateo leach, I, Medland, SE, Mihailov, E, Montgomery, GW, Navis, G, Newnham, J, Nieminen, MS, Palotie, A, Panoutsopoulou, K, Peters, A, Pirastu, N, Polašek, O, Rehnström, K, Ripatti, S, Ritchie, GRS, Rivadeneira, F, Robino, A, Samani, NJ, Shin, SY, Sinisalo, J, Smit, JH, Soranzo, N, Stolk, L, Swinkels, DW, Tanaka, T, Teumer, A, Tönjes, A, Traglia, M, Tuomilehto, J, Valsesia, A, Van gilst, WH, Van meurs, JBJ, Smith, AV, Viikari, J, Vink, JM, Waeber, G, Warrington, NM, Widen, E, Willemsen, G, Wright, AF, Zanke, BW, Zgaga, L, Boehnke, M, D'Adamo, AP, De geus, E, Demerath, EW, Den Heijer, M, Eriksson, JG, Ferrucci, L, Gieger, C, Gudnason, V, Hayward, C, Hengstenberg, C, Hudson, TJ, Järvelin, MR, Kogevinas, M, Loos, RJF, Martin, NG, Metspalu, A, Pennell, CE, Penninx, BW, Perola, M, Raitakari, O, Salomaa, V, Schreiber, S, Schunkert, H, Spector, TD, Stumvoll, M, Uitterlinden, AG, Ulivi, S, Van der harst, P, Vollenweider, P, Völzke, H, Wareham, NJ, Wichmann, HE, Wilson, JF, Rudan, I, Xue, Y & Zeggini, E 2012, 'Genome-wide meta-analysis of common variant differences between men and women', Human molecular genetics, vol. 21, no. 21, dds304, pp. 4805-4815. https://doi.org/10.1093/hmg/dds304

TY - JOUR

T1 - Genome-wide meta-analysis of common variant differences between men and women

AU - Boraska, Vesna

AU - Jerončić, Ana

AU - Colonna, Vincenza

AU - Southam, Lorraine

AU - Nyholt, Dale R.

AU - William rayner, Nigel

AU - Perry, John R.B.

AU - Toniolo, Daniela

AU - Albrecht, Eva

AU - Ang, Wei

AU - Bandinelli, Stefania

AU - Barbalic, Maja

AU - Barroso, Inês

AU - Beckmann, Jacques S.

AU - Biffar, Reiner

AU - Boomsma, Dorret

AU - Campbell, Harry

AU - Corre, Tanguy

AU - Erdmann, Jeanette

AU - Esko, Tõnu

AU - Fischer, Krista

AU - Franceschini, Nora

AU - Frayling, Timothy M.

AU - Girotto, Giorgia

AU - Gonzalez, Juan R.

AU - Harris, Tamara B.

AU - Heath, Andrew C.

AU - Heid, Iris M.

AU - Hoffmann, Wolfgang

AU - Hofman, Albert

AU - Horikoshi, Momoko

AU - Hua zhao, Jing

AU - Jackson, Anne U.

AU - Hottenga, Jouke Jan

AU - Jula, Antti

AU - Kähönen, Mika

AU - Khaw, Kay Tee

AU - Kiemeney, Lambertus A.

AU - Klopp, Norman

AU - Kutalik, Zoltán

AU - Lagou, Vasiliki

AU - Launer, Lenore J.

AU - Lehtimäki, Terho

AU - Lemire, Mathieu

AU - Lokki, Marja Liisa

AU - Loley, Christina

AU - Luan, Jian'an

AU - Mangino, Massimo

AU - Mateo leach, Irene

AU - Medland, Sarah E.

AU - Mihailov, Evelin

AU - Montgomery, Grant W.

AU - Navis, Gerjan

AU - Newnham, John

AU - Nieminen, Markku S.

AU - Palotie, Aarno

AU - Panoutsopoulou, Kalliope

AU - Peters, Annette

AU - Pirastu, Nicola

AU - Polašek, Ozren

AU - Rehnström, Karola

AU - Ripatti, Samuli

AU - Ritchie, Graham R.S.

AU - Rivadeneira, Fernando

AU - Robino, Antonietta

AU - Samani, Nilesh J.

AU - Shin, So Youn

AU - Sinisalo, Juha

AU - Smit, Johannes H.

AU - Soranzo, Nicole

AU - Stolk, Lisette

AU - Swinkels, Dorine W.

AU - Tanaka, Toshiko

AU - Teumer, Alexander

AU - Tönjes, Anke

AU - Traglia, Michela

AU - Tuomilehto, Jaakko

AU - Valsesia, Armand

AU - Van gilst, Wiek H.

AU - Van meurs, Joyce B.J.

AU - Smith, Albert Vernon

AU - Viikari, Jorma

AU - Vink, Jacqueline M.

AU - Waeber, Gerard

AU - Warrington, Nicole M.

AU - Widen, Elisabeth

AU - Willemsen, Gonneke

AU - Wright, Alan F.

AU - Zanke, Brent W.

AU - Zgaga, Lina

AU - Boehnke, Michael

AU - D'Adamo, Adamo Pio

AU - De geus, Eco

AU - Demerath, Ellen W.

AU - Den Heijer, Martin

AU - Eriksson, Johan G.

AU - Ferrucci, Luigi

AU - Gieger, Christian

AU - Gudnason, Vilmundur

AU - Hayward, Caroline

AU - Hengstenberg, Christian

AU - Hudson, Thomas J.

AU - Järvelin, Marjo Riitta

AU - Kogevinas, Manolis

AU - Loos, Ruth J.F.

AU - Martin, Nicholas G.

AU - Metspalu, Andres

AU - Pennell, Craig E.

AU - Penninx, Brenda W.

AU - Perola, Markus

AU - Raitakari, Olli

AU - Salomaa, Veikko

AU - Schreiber, Stefan

AU - Schunkert, Heribert

AU - Spector, Tim D.

AU - Stumvoll, Michael

AU - Uitterlinden, André G.

AU - Ulivi, Sheila

AU - Van der harst, Pim

AU - Vollenweider, Peter

AU - Völzke, Henry

AU - Wareham, Nicholas J.

AU - Wichmann, H. Erich

AU - Wilson, James F.

AU - Rudan, Igor

AU - Xue, Yali

AU - Zeggini, Eleftheria

N1 - Funding Information: NTR1: Funding was obtained from the Netherlands Heart Foundation (90.313, 86.083 and 88.042), the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW): Genetic basis of anxiety and depression (904-61-090); Genetics of individual differences in smoking initiation and persistence (NWO 985-10-002); Resolving cause and effect in the association between exercise and well-being (904-61-193); Twin family database for behaviour genomics studies (480-04-004); Twin research focusing on behaviour (400-05-717); Genetic determinants of risk behaviour in relation to alcohol use and alcohol use disorder (Addiction-31160008); Genotype/phenotype database for behaviour genetic and genetic epidemiological studies (911-09-032); Spinozapremie (SPI 56-464-14192); CMSB: Center for Medical Systems Biology (NWO Genomics); NBIC/BioAssist/RK/2008.024); BBMRI –NL: Biobanking and Biomolecular Resources Research Infrastructure; the VU University: Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Foundation (ESF): Genomewide analyses of European twin and population cohorts (EU/ QLRT-2001-01254); European Community’s Seventh Frame-work Program (FP7/2007-2013): ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC) Genetics of Mental Illness (230374); Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); Collaborative study of the genetics of DZ twinning (NIH R01D0042157-01A); the Genetic Association Information Network, a public–private partnership between the NIH and Pfizer Inc., Affymetrix Inc. and Abbott Laboratories. Funding Information: SORBS: We thank all those who participated in the study. Sincere thank is given to Peter Kovacs who was significantly involved in the planning and procedure of the Sorbs study. We also thank Knut Krohn (Microarray Core Facility of the Interdisciplinary Centre for Clinical Research, University of Leipzig) for the genotyping support and Inga Prokopenko and Nigel W. Rayner (WTCHG, University of Oxford, UK) for the excellent analytical and bioinformatics support. This work was supported by grants from the Interdisciplinary Centre for Clinical Research at the University of Leipzig (B27 to A.T.) from the German Diabetes Association (to A.T.), a Travel Grant from BIF (to A.T.) and by the DHFD, Diabetes Hilfs-und Forschungsfonds Deutschland. The work of Vasiliki Lagou was funded through the ENGAGE (European Network for Genetic and Genomic Epidemiology) Consortium, the European Community’s Seventh Framework Programme (HEALTH-F4-2007-201413). Funding Information: RAINE: The authors are grateful to the Raine Study participants and their families and to the Raine Study research staff for cohort coordination and data collection. The authors gratefully acknowledge the NH&MRC for their long term contribution to funding the study over the last 20 years and also the following Institutions for providing funding for Core Management of the Raine Study: The University of Western Australia (UWA), Raine Medical Research Foundation, UWA Faculty of Medicine, Dentistry and Health Sciences, The Telethon Institute for Child Health Research and Women and Infants Research Foundation. The authors gratefully acknowledge the assistance of the Western Australian DNA Bank (National Health and Medical Research Council of Australia National Enabling Facility). The authors also acknowledge the support of the National Health and Medical Research Council of Australia (Grant ID 403981 and ID 003209) and the Canadian Institutes of Health Research (Grant ID MOP-82893). Funding Information: ECHRS-Spain: Spanish Ministry of Science and Innovation grant MTM2008-02457; Fondo de Investigaciones San-tarias grants 97/0035-01, 99/0034-01 and 99/0034-02; Hospital Universitario de Albacete; Consejeria de Sanidad; FWO (Fund for Scientific Research) grant G.0402.00; University of Antwerp; the Flemish Health Ministry; Sociedad Espa-ñola de Neumología y Cirugía Torácica (SEPAR), Public Health Service grant R01 HL62633-01; Consell Interdeparta-mental de Recerca i Innovació Tecnològica (CIRIT) grant 1999SGR 00241; Red Respira Instituto de Salud Carlos III (ISCIII). Funding Information: ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN26820 1100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN26820 1100010C, HHSN268201100011C, and HHSN2682011 00012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: AGES: The researchers are indebted to the participants for their willingness to participate in the study. This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. Funding Information: NESDA: Neuroscience Campus Amsterdam; EMGO+ Institute for Health and Care Research; NIMH R01 MH059160; Geestkracht program of ZonMW (10-000-1002); matching funds from universities and mental health care institutes involved in NESDA. Genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). Funding Information: SHIP: We thank all staff members and participants of the SHIP study, as well as all of the genotyping staff for generating the SHIP SNP data set. The genetic data analysis workflow was created using the Software InforSense. Genetic data were stored using the database Caché (InterSystems). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlan-gen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG. Funding Information: CROATIA-Korcula: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), and Republic of Croatia Ministry of Science, Education and Sports research (108-1080315-0302). Funding Information: ORCADES: ORCADES DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). Funding Information: BLSA: The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. Funding Information: HBCS: Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland (Grant No. 120315 and 129287 to EW, 1129457 and 1216965 to KR, 120386 and 125876 to JGE), the Finnish Diabetes Research Society, Fol-khälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, the European Science Foundation (EuroSTRESS), the Wellcome Trust (Grant No. 89061/Z/09/ Z and 089062/Z/09/Z), Samfundet Folkhälsan, Finska Läkare-sällskapet and the Signe and Ane Gyllenberg foundation. Funding Information: YFS: The Cardiovascular Risk in Young Finns study (YFS) is supported by the Academy of Finland (grant no. 117797, 121584 and 126925), the Social Insurance Institution of Finland, University Hospital Medical funds to Tampere, and Turku University Hospitals, the Finnish Foundation of Cardiovascular Research Emil Aaltonen Foundation (T.L), and Tampere Tuberculosis Foundation. Funding Information: RS: We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, and Lisbeth Herrera for their help in creating the GWAS database. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We would like to thank Dr. Tobias A. Knoch, Karol Estrada, Luc V. de Zeeuw, Anis Abu-seiris and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@Me-diGRID part of the German D-Grid for access to their grid resources. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI) – Netherlands Consortium of Healthy Aging (NCHA) project nr. 050-060-810, and funding from the European Commission (HEALTH-F2-2008-201865, GEFOS; HEALTH-F2-2008-35627, TREAT-OA). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. German MediGRID and Services@MediGRID are part of the German D-Grid and are both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G. Funding Information: org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. Funding Information: CROATIA-Split: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark. The CROATIA-Split study is funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). Funding Information: EGCUT: EGCUT received financial support from FP7 programs (ENGAGE, OPENGENE), targeted financial support from Estonian Government SF0180142s08, Estonian Research Roadmap through Estonian Ministry of Education and Research, Center of Excellence in Genomics (EXCEGEN) and University of Tartu (SP1GVARENG). The work of K.F. was supported by Estonian Science Foundation grant EstSF ETF9353. We acknowledge EGCUT technical personnel, especially Mr V. Soo and S. Smit. Data analyzes were carried out in part in the High Performance Computing Center of University of Tartu. Funding Information: ENGAGE: This research was supported through funds from The European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. Funding Information: InCHIANTI: We thank the Intramural Research Program of the NIH, National Institute on Aging who are responsible for the InCHIANTI samples. We also thank the InCHIANTI participants. The InCHIANTI study baseline (1998-2000) was supported as a ‘targeted project’ (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-ups 2 and 3 studies (2004-2010) were financed by the U.S. National Institute on Aging (Contract: N01-AG-5-0002); supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. JRBP is funded by a Sir Henry Wellcome Postdoctoral Fellowship (092447/Z/10/Z). Funding Information: CROATIA-Vis: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland, UK. The CROATIA-Vis study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants (108-1080315-0302). Funding Information: NTR2: Funding is acknowledged from the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW): Twin family database for behaviour genomics studies (480-04-004); Twin research focusing on behaviour (400-05-717); Genetic determinants of risk behaviour in relation to alcohol use (Addiction-31160008); Genotype/phenotype database for behaviour genetic and genetic epidemiological studies (911-09-032); Spinozapremie (SPI 56-464-14192); CMSB: Center for Medical Systems Biology (NWO Genomics); NBIC/BioAssist/RK/2008.024); BBMRI –NL: Biobanking and Biomolecular Resources Research Infrastructure; European Science Foundation (ESF): Genome-wide analyses of European twin and population cohorts (EU/QLRT-2001-01254); European Community’s Seventh Framework Program (FP7/2007-2013): ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC) Genetics of Mental Illness (230374); Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06). Funding Information: QIMR: We thank the twins and their families for their participation. We also thank Dixie Statham, Ann Eldridge, Marlene Grace, Kerrie McAloney (sample collection); Anjali Henders, Megan Campbell, Lisa Bowdler and Steven Crooks (sample and DNA processing); Scott Gordon, David Smyth, Harry Beeby, and Daniel Park (IT support). We also acknowledge David Duffy, Peter Visscher, Margaret Wright, Pamela Madden and Wendy Slutske for their funding contributions. Genotype imputation was carried out on the Genetic Cluster Computer. Funding was provided by the Australian National Health and Medical Research Council (NHMRC grants 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498), the Australian Research Council (ARC grants A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), and the U.S. National Institutes of Health (NIH grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206). The Genetic Cluster Computer is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). G.W.M. was supported by an NHMRC Fellowship (619667), D.R.N. (FT0991022) and S.E.M. (FT110100548) were supported by an ARC Future Fellowship. Funding Information: TwinsUK: We thank the staff from the TwinsUK, the DNA Collections and Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation; Quality Control of the Twins UK cohort for genotyping (in particular Amy Chaney, Radhi Ravindrarajah, Douglas Simpkin, Cliff Hinds, and Thomas Dibling); Paul Martin and Simon Potter of the DNA and Genotyping Informatics teams for data handling; Le Centre National de Génotypage, France, led by Mark Lathrop, for genotyping; Duke University, North Carolina, USA, led by David Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie. The authors declare they have no conflicts of interest. The study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-ENGAGE and the European Union FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and Framework 6 Project EUroClot. The study also receives support from the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. Funding Information: KORA: The KORA authors acknowledge the contribution of Peter Lichtner, Gertrud Eckstein, Guido Fischer and all members of the Helmholtz Center Munich genotyping staff for generating the SNP data, as well as all members of field staffs who were involved in the planning and conduction of the KORA Augsburg studies. The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. Funding Information: EPIC-Obesity: The EPIC Norfolk Study is funded by program grants from the Medical Research Council UK and Cancer Research UK. Funding Information: CoLaus: The authors express their gratitude to the participants in the Lausanne CoLaus study and to the investigators who have contributed to the recruitment. We would like to thank Drs Vincent Mooser and Dawn Waterworth from GlaxoSmithKline for helpful comments and for their continuous support for the CoLaus project. Part of the computation has been performed on the Vital-IT cluster (www.vita l-it.ch). We are grateful to Dr. Toby Johnson and Pr. Sven Bergmann for statistical discussions. The CoLaus study was supported by research grants from GlaxoSmithKline; the Faculty of Biology and Medicine of Lausanne, Switzerland; and the Swiss National Science Foundation (grant no:33CSCO-122661). Gérard Waeber and Peter Vollenwei-der received an unrestricted grant from GSK to build the CoLaus study. Funding Information: V.B. is supported by Unity Through Knowledge Fund CONNECTIVITY PROGRAM (‘Gaining Experience’ Grant 2A), The National Foundation for Science, Higher Education and Technological Development of the Republic of Croatia (BRAIN GAIN—Postdoc fellowship) and the Wellcome Trust (098051). E.Z. is supported by the Wellcome Trust (098051). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust (098051). Funding Information: PREVEND: PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), The Netherlands Heart Foundation (Grant 2006B140, 2006T003), National Institutes of Health (grant LM010098, HL65234, HL67466, RR018787) and the EU project grant GENECURE (FP-6 LSHM CT 2006 037697). P.vd.H is supported by NWO VENI grant 91676170 and Dutch Inter University Cardiology Institute Netherlands (ICIN). Funding Information: GerMIFS: Supported by the Deutsche Forschungsge-meinschaft and the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus), the FP6 and FP7 EU funded integrated projects Cardiogenics (LSHM-CT-2006-037593) and ENGAGE (201413), and the bi-national BMBF/ANR funded project CARDomics (01KU0908A). Supported by the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung – German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). Funding Information: INGI-VB: We thank the inhabitants of the VB that made this study possible, the local administrations, the Tortona and Genova archdiocese and the ASL-22, Novi Ligure (Al) for support. We also thank Cinzia Sala and Clara Camaschella for data collection supervision and organization of the clinical data collection, Fiammetta Viganò for technical help, Corrado Masciullo and Massimiliano Cocca for building the analysis platform. The research was supported by funds from Compag-nia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy and Ministry of Health, Ricerca Finalizzata 2008 and Telethon, Italy to DT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: NBS: We thank the participants from the Municipality of Nijmegen for their continued support to the Nijmegen Biomedical Study. The study was partly funded by an investment grant of the Radboud University Nijmegen Medical Centre.

PY - 2012/11

Y1 - 2012/11

N2 - The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10-8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.

AB - The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10-8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.

UR - http://www.scopus.com/inward/record.url?scp=84867814813&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds304

DO - 10.1093/hmg/dds304

M3 - Article

C2 - 22843499

AN - SCOPUS:84867814813

SN - 0964-6906

VL - 21

SP - 4805

EP - 4815

JO - Human molecular genetics

JF - Human molecular genetics

IS - 21

M1 - dds304

ER -

Genome-wide meta-analysis of common variant differences between men and women

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