Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression

Saskia P. Hagenaars, Jonathan R.I. Coleman, Shing Wan Choi, Héléna Gaspar, Mark J. Adams, David M. Howard, Karen Hodgson, Matthew Traylor, Tracy M. Air, Till F.M. Andlauer, Volker Arolt, Bernhard T. Baune, Elisabeth B. Binder, Douglas H.R. Blackwood, Dorret I. Boomsma, Archie Campbell, Micah Cearns, Darina Czamara, Udo Dannlowski, Katharina DomschkeEco J.C. de Geus, Steven P. Hamilton, Caroline Hayward, Ian B. Hickie, Jouke Jan Hottenga, Marcus Ising, Ian Jones, Lisa Jones, Zoltan Kutalik, Susanne Lucae, Nicholas G. Martin, Yuri Milaneschi, Bertram Mueller-Myhsok, Michael J. Owen, Sandosh Padmanabhan, Brenda W.J.H. Penninx, Giorgio Pistis, David J. Porteous, Martin Preisig, Stephan Ripke, Stanley I. Shyn, Patrick F. Sullivan, John B. Whitfield, Naomi R. Wray, Andrew M. McIntosh, Ian J. Deary, Gerome Breen, Cathryn M. Lewis*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

Original languageEnglish
Pages (from-to)309-330
Number of pages22
JournalAmerican Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume183
Issue number6
Early online date18 Jul 2020
DOIs
Publication statusPublished - Sept 2020

Funding

S. P. H. is funded by the Medical Research Council (MR/S0151132). CML is funding by the Medical Research Council (N015746/1). This study presents independent research supported by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. We thank participants and scientists involved in making the UK Biobank resource available ( http://www.ukbiobank.ac.uk/ ). UK Biobank data used in this study were obtained under approved application 16577. We are deeply indebted to the investigators who comprise the PGC, and to the hundreds of thousands of subjects who have shared their life experiences with PGC investigators. The PGC has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). Statistical analyses were carried out on the NL Genetic Cluster Computer ( http://www.geneticcluster.org/ ) hosted by SURFsara, and the King's Health Partners High Performance Compute Cluster funded with capital equipment grants from the GSTT Charity (TR130505) and Maudsley Charity (980). We would like to thank the research participants and employees of 23andMe for making this work possible. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL] Reference 104036/Z/14/Z). Ethics approval for the Generation Scotland was given by the NHS Tayside committee on research ethics (reference 15/ES/0040), and all participants provided written informed consent for the use of their data. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html . CM Lewis is a member of Myriad Neuroscience SAB. PF Sullivan is on the scientific advisory board for Pfizer, Inc., and the advisory committee for Lundbeck. All other authors reported no biomedical financial interest or potential conflicts of interest. The table below lists the funding that supported the primary studies analyzed in this article. In addition, PGC investigators received personal funding from the following sources. NR Wray award 1078901, 1087889, and 1113400, NHMRC, Australia. DI Boomsma award PAH/6635, KNAW Academy Professor Award, Netherlands. PF Sullivan award D0886501, Vetenskapsrådet, Sweden. AM McIntosh award 602450, European Union, UK; award BADiPS, NC3Rs, UK. C Hayward, Core funding, Medical Research Council, UK. S. P. H. is funded by the Medical Research Council (MR/S0151132). CML is funding by the Medical Research Council (N015746/1). This study presents independent research supported by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. We thank participants and scientists involved in making the UK Biobank resource available (http://www.ukbiobank.ac.uk/). UK Biobank data used in this study were obtained under approved application 16577. We are deeply indebted to the investigators who comprise the PGC, and to the hundreds of thousands of subjects who have shared their life experiences with PGC investigators. The PGC has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org/) hosted by SURFsara, and the King's Health Partners High Performance Compute Cluster funded with capital equipment grants from the GSTT Charity (TR130505) and Maudsley Charity (980). We would like to thank the research participants and employees of 23andMe for making this work possible. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award ?STratifying Resilience and Depression Longitudinally? [STRADL] Reference 104036/Z/14/Z). Ethics approval for the Generation Scotland was given by the NHS Tayside committee on research ethics (reference 15/ES/0040), and all participants provided written informed consent for the use of their data. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. CM Lewis is a member of Myriad Neuroscience SAB. PF Sullivan is on the scientific advisory board for Pfizer, Inc., and the advisory committee for Lundbeck. All other authors reported no biomedical financial interest or potential conflicts of interest. The table below lists the funding that supported the primary studies analyzed in this article. In addition, PGC investigators received personal funding from the following sources. NR Wray award 1078901, 1087889, and 1113400, NHMRC, Australia. DI Boomsma award PAH/6635, KNAW Academy Professor Award, Netherlands. PF Sullivan award D0886501, Vetenskapsr?det, Sweden. AM McIntosh award 602450, European Union, UK; award BADiPS, NC3Rs, UK. C Hayward, Core funding, Medical Research Council, UK. Study Lead investigator Award number Funder Country PGC PF Sullivan U01 MH109528 NIMH USA PGC A Agrawal U01 MH109532 NIDA USA PGC D Posthuma 480-05-003 Netherlands scientific organization Netherlands PGC D Posthuma ? Dutch Brain Foundation and the VU University Amsterdam Netherlands CoFaMS - Adelaide BT Baune APP1060524 NHMRC Australia Generation Scotland AM McIntosh 104036/Z/14/Z Wellcome Trust UK M?nster MDD cohort BT Baune N Health-F2-2008-222963 European Union Germany M?nster MDD cohort TG Schulze 01ZX1314K BMBF Integrament Germany M?nster MDD cohort TG Schulze Dr. Lisa Oehler foundation Germany M?nster MDD cohort TG Schulze SCHU 1603/5-1 German Research Foundation (DFG) Germany M?nster MDD cohort U Dannlowski FOR2107 DA1151/5-1; SFB- TRR58, Project C09 German Research Foundation (DFG) Germany M?nster MDD cohort U Dannlowski Dan3/012/17 Interdisciplinary Center for Clinical Research, Medical Faculty of University of M?nster Germany M?nster MDD cohort V Arolt N Health-F2-2008-222,963 European Union Germany NESDA BWJH Penninx ZonMW Geestkracht grant N.W.O. Netherlands NESDA BJWH Penninx 1RC2 MH089951; 1RC2 MH089995 NIH USA NTR DI Boomsma 1RC2 MH089951; 1RC2 MH089995 NIH Netherlands PsyColaus M Preisig 3200B0?105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401 Swiss National Science Foundation Switzerland QIMR NG Martin 941177, 971232, 3399450 and 443011 National Health and Medical Research Council Australia QIMR AC Heath AA07535, AA07728, andAA10249 NIAAA USA RADIANT C Lewis, G Breen G0701420 MRC UK RADIANT G Breen G0901245 MRC UK RADIANT G Breen U01 MH109528 NIMH UK STAR*D SP Hamilton R01 MH-072802 NIMH USA UK Biobank G Breen NIHR UK

FundersFunder number
Chief Scientist Office of the Scottish Government Health DirectoratesCZD/16/6
Dutch Brain Foundation
GSTTTR130505
Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
Myriad Neuroscience SAB1078901, 1087889, 1113400
NIHR UK
VU University Amsterdam Netherlands CoFaMS
Vetenskapsr?det602450
National Institutes of Health33CS30-148401, 3200B0-118308, 105993, 33CS30-139468, 33CSCO-122661
National Institute of Mental Health
National Institute on Drug AbuseU01 MH1095320, U01 MH109528
National Institute on Alcohol Abuse and AlcoholismR01AA007535
Wellcome Trust104036/Z/14/Z
Maudsley Charity
Medical Research CouncilMR/S0151132, N015746/1
National Institute for Health Research
Scottish Funding CouncilHR03006
King's College London16577
National Health and Medical Research CouncilPAH/6635, AA07728, AA07535
Deutsche Forschungsgemeinschaft1RC2 MH089951, 1RC2 MH089995, SFB- TRR58, FOR2107 DA1151/5-1
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung971232, 3399450, 443011
Koninklijke Nederlandse Akademie van WetenschappenD0886501
Bundesministerium für Bildung und ForschungSCHU 1603/5-1
National Centre for the Replacement Refinement and Reduction of Animals in Research

    Keywords

    • age at onset
    • cardio-metabolic disease
    • depression
    • genetics
    • polygenic risk scores

    Cohort Studies

    • Netherlands Twin Register (NTR)

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