Multivariate genome-wide analyses of the well-being spectrum
Open accessAbstract
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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The prioritized SNP at CCDC71 is in strong LD with the lead SNP from a previous depressive symptoms meta-analysis (rs7617480, r2=0.83, D'=1.0).
“our prioritized SNP is in strong LD with that study’s lead SNP (current study rs7617480, r2=0.83, D’=1.0).32”
From Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions (2021) · cites this paper as [32]
In several GWASs of depression-related traits, TNKS was found to be associated with depression-related traits (p = 7.68 × 10−10), bipolar disorder (p = 3 × 10−6), and positive affect (p = 0.0003).
“In several genome-wide association studies (GWASs) of depression-related traits, TNKS was found to be associated with (p = 7.68 × 10−10)38, bipolar disorder (p = 3 × 10−6)39, and positive affect (p = 0.0003)40.”
From Methylome-wide change associated with response to electroconvulsive therapy in depressed patients (2021) · cites this paper as [40]
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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
- Venue
- Nature Genetics
- Published
- 2019-01-14
- Volume
- 51
- Issue
- 3
- Pages
- 445-451
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- 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 · 2017: 1
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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