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Author Notes:

Saskia P Hagenaars, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8AF, UK. Email: saskia.hagenaars@kcl.ac.uk

Saskia P. Hagenaars, Cathryn M. Lewis designed the study, analyzed data, and interpreted the results. Jonathan R. I. Coleman, Shing Wan Choi, Héléna Gaspar, Mark J. Adams, David Howard, Karen Hodgson, Matthew Traylor contributed to data quality control and analysis pipelines. All other authors contributed study materials. All authors critically revised the manuscript and approved the final version.

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.

S. P. H. is funded by the Medical Research Council (MR/S0151132). CML is funding by the Medical Research Council (N015746/1).

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.

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.

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Research Funding:

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.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • Psychiatry
  • age at onset
  • cardio-metabolic disease
  • depression
  • genetics
  • polygenic risk scores
  • GENOME-WIDE ASSOCIATION
  • VASCULAR DEPRESSION
  • POLYGENIC RISK
  • METAANALYSIS
  • DISEASE
  • STROKE
  • OBESITY
  • HERITABILITY
  • SYMPTOMS
  • BIAS

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

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Journal Title:

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS

Volume:

Volume 183, Number 6

Publisher:

, Pages 309-330

Type of Work:

Article | Post-print: After Peer 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.
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