We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.
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N-GWAMA and MA-GWAMA software is available at: https://github.com/baselmans/multivariate_GWAMA/
Summary Statistics excluding results from 23AndMe can be downloaded from https://surfdrive.surf.nl/files/index.php/s/Ow1qCDpFT421ZOO. The data transfer agreement with 23AndMe stipulates that we can publish effect sizes associated with 10,000 SNPs. These summary statistics can be downloaded from https://surfdrive.surf.nl/files/index.php/s/Ow1qCDpFT421ZOO. For 23AndMe dataset access, see https://research.23andme.com/dataset-access/. The Understanding Society data are distributed by the UK Data Service. The genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website at https://www.understandingsociety.ac.uk/. Genotype-trait data access for UKHLS is available by application to Metadac through http://www.metadac.ac.uk/.
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We thank all participants in the cohort studies. This work was supported by the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW grants 904‐61‐090, 985‐10‐002,904‐61‐193,480‐04‐004, 400‐05‐717, NWO‐bilateral agreement 463‐06‐001, NWO‐VENI 451‐04‐034, Addiction‐31160008, Middelgroot‐911‐09‐032, Spinozapremie 56‐464‐14192), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007), the VU University’s Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA), the European Science Council (ERC Advanced, 230374), the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH, R01D0042157‐01A). Part of the genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health (NIMH, MH081802) and by the Grand Opportunity grants 1RC2MH089951‐01 and 1RC2 MH089995‐01 from the NIMH. Part of the analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org/), which is financially supported by the Netherlands Scientific Organization (NWO 480‐05‐003), the Dutch Brain Foundation, and the department of Behavioural and Movement Sciences of the VU University Amsterdam. M.B. is/was financially supported by a senior fellowship of the (EMGO+) Institute for Health and Care and a VU University Research Chair position. This work is supported by an ERC consolidator grant (WELL-BEING 771057 PI Bartels). M.G.N. is supported by a ZonMw grant: ‘Genetics as a research tool: A natural experiment to elucidate the causal effects of social mobility on health’ (pnr: 531003014), ZonMw project: ‘Can sex- and gender-specific gene expression and epigenetics explain sex-differences in disease prevalence and etiology?’ (pnr:849200011) and grant R01AG054628 02S. Understanding Society is an initiative funded by the Economic and Social Research Council (ES/H029745/1) and various Government Departments, with scientific leadership by the Institute for Social and Economic Research, University of Essex, and survey delivery by NatCen Social Research and Kantar Public. The BIOS and SSGAC consortia are acknowledged as banner-coauthors for the key role their previous work played. A detailed description of their role and membership appears in the Supplementary Note.