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Multivariate genome-wide analyses of the well-being spectrum

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BIOS consortium, Baselmans, Bart M. L., Social Science Genetic Association Consortium, Jansen, Rick, Ip, Hill F., van Dongen, Jenny, Abdellaoui, Abdel, van de Weijer, Margot P., Bao, Yanchun, Smart, Melissa, Kumari, Meena, Willemsen, Gonneke, Hottenga, Jouke-Jan, Boomsma, Dorret I., de Geus, Eco J. C., Nivard, Michel G., Bartels, Meike·2019·Nature Genetics

DOI 10.1038/s41588-018-0320-8

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Abstract

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 (N obs = 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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Authors: BIOS consortium, Baselmans, B. M. L., Social Science Genetic Association Consortium, Jansen, R., Ip, H. F., van Dongen, J., Abdellaoui, A., van de Weijer, M. P., Bao, Y., Smart, M., Kumari, M., Willemsen, G., Hottenga, J.-J., Boomsma, D. I., de Geus, E. J. C., Nivard, M. G., & Bartels, M.
Affiliations: Amsterdam Public Health (NL)
Amsterdam Neuroscience (NL)
Vrije Universiteit Amsterdam (NL)
University of Essex (GB)
Corresponding author: Nivard, Michel G.
Bartels, Meike
ORCID: Baselmans, Bart M. L.
Jansen, Rick
Ip, Hill F.
van Dongen, Jenny
Abdellaoui, Abdel
Bao, Yanchun
Smart, Melissa
Willemsen, Gonneke
Hottenga, Jouke-Jan
Boomsma, Dorret I.
de Geus, Eco J. C.
Nivard, Michel G.
Bartels, Meike
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2019-01-14
Volume: 51
Issue: 3
Pages: 445-451
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/s41588-018-0320-8
OpenAlex: W2909650844
Cited by: 320
References: 60
Citations by year: 2026: 33 · 2025: 48 · 2024: 35 · 2023: 47 · 2022: 54 · 2021: 59 · 2020: 29 · 2019: 14
FWCI: 5.17
Type: journal article
Language: en
Open access: green
pure.amsterdamumc.nl
Licence: other-oa
www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
Pure Amsterdam UMC (acceptedVersion, other-oa)
Open Access at Essex (University of Essex) (acceptedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
VU Research Portal (submittedVersion, other-oa)
Warwick Research Archive Portal (University of Warwick) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: University of Essex
Wellcome Trust (213422/Z/18/Z)
ZonMw (849200011, Addiction‐31160008, Middelgroot‐911‐09‐032, 985-10-002, 400‐05‐717, 451‐04‐034, 463‐06‐001, 56-464-14192, 184.021.007, 904-61-193, 911‐09‐032, 1RC2 MH089995, 904-61-090, 531003014, 31160008, 480‐04‐004)
Vrije Universiteit Amsterdam
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (184021007, NWO 480‐05‐003, 463-06-001, 400‐05‐717, 480- 05-003, 904-61-193, 904-61-090, 311-60008, 56‐464‐14192, NWO-VENI 451-04-034, Addiction-31160008, Spinozapremie 56-464-14192, 451–04-034, 849200011, 985-10002, 480-04-004)
Avera Institute for Human Genetics
National Institutes of Health (R01D0042157-01A, 184.021.007, 451-04-034, 463-06-001, 1r01mh081802-01, 400-05-717)
Medical Research Council (MR/N01104X/1, MR/N01104X/2)
Economic and Social Research Council (ES/M008592/1, ES/M010341/1, ES/H029745/1, ES/S008349/1)
National Institute on Aging (R01AG054628)
National Institute of Mental Health (MH-081802, RC2MH089995, MH089995-01, RC2MH089951, MH089995)
H2020 European Research Council (771057)
FP7 Ideas: European Research Council (230374)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords: life satisfaction, positive affect, neuroticism, depressive symptoms, polygenic risk score, transcriptome-wide association study, methylome-wide association study, subiculum, GABAergic interneurons, brain gene expression
MeSH terms: Brain, Humans, Interneurons, Phenotype, Gene Expression, Genome, Human, Multivariate Analysis, Computational Biology, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Transcriptome

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