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The impact of assortative mating, participation bias and socioeconomic status on the polygenic risk of behavioural and psychiatric traits

Nature Human Behaviour (2024)Cite this article

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Abstract

To investigate assortative mating (AM), participation bias and socioeconomic status (SES) with respect to the genetics of behavioural and psychiatric traits, we estimated AM signatures using gametic phase disequilibrium and within-spouses and within-siblings polygenic risk score correlation analyses, also performing a SES conditional analysis. The cross-method meta-analysis identified AM genetic signatures for multiple alcohol-related phenotypes, bipolar disorder, major depressive disorder, schizophrenia and Tourette syndrome. Here, after SES conditioning, we observed changes in the AM genetic signatures for maximum habitual alcohol intake, frequency of drinking alcohol and Tourette syndrome. We also observed significant gametic phase disequilibrium differences between UK Biobank mental health questionnaire responders versus non-responders for major depressive disorder and alcohol use disorder. These results highlight the impact of AM, participation bias and SES on the polygenic risk of behavioural and psychiatric traits, particularly in alcohol-related traits.

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Fig. 1: Genetic signatures of AM across behavioural traits and psychiatric disorders after Bonferroni multiple testing correction.
Fig. 2: Genetic signatures of AM across UKB MHQ traits after Bonferroni multiple testing correction.
Fig. 3: Genetic signatures of AM across behavioural traits and psychiatric disorders with significant changes after SES conditioning.

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Data availability

All results used to make conclusions discussed in this study are provided as Supplementary Material. All GWAS data are publicly available on their respective websites: UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access); Psychiatric Genomics Consortium (https://pgc.unc.edu/for-researchers/download-results/); Million Veteran Program (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v8.p1); Pan-UK Biobank (https://pan.ukbb.broadinstitute.org/).

Code availability

The majority of the analyses were conducted using previously developed tools. These were described in Methods with their corresponding references. Custom R scripts developed for the simulation analysis and for estimating expected cross-method results are available on Zenodo (https://doi.org/10.5281/zenodo.10476703).

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Acknowledgements

We thank the participants and the investigators involved in the UK Biobank, Million Veteran Program and the Psychiatric Genomics Consortium for making their data publicly available. This research was conducted using the UK Biobank Resource (application reference number 58146). The authors acknowledge support from the National Institutes of Health (R21 DC018098, R33 DA047527 and RF1 MH132337 to R.P. and K99 AG078503 to G.A.P.), One Mind (Rising Star Award to R.P.) and the American Foundation for Suicide Prevention (PDF-1-022-21 to B.C.-M.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.

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Author notes

  1. These authors contributed equally: Loic Yengo, Renato Polimanti.

Authors and Affiliations

  1. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    Brenda Cabrera-Mendoza, Frank R. Wendt, Gita A. Pathak & Renato Polimanti

  2. VA CT Healthcare System, West Haven, CT, USA

    Brenda Cabrera-Mendoza, Frank R. Wendt, Gita A. Pathak & Renato Polimanti

  3. Department of Anthropology, University of Toronto, Toronto, Ontario, Canada

    Frank R. Wendt

  4. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    Frank R. Wendt

  5. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

    Loic Yengo

  6. Wu Tsai Institute, Yale University, New Haven, CT, USA

    Renato Polimanti

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Contributions

B.C.-M., L.Y. and R.P. designed this study. B.C.-M. conducted the analysis. B.C.-M. and R.P. wrote the paper. F.R.W., G.A.P. and L.Y. critically revised the paper. All authors contributed to interpretation of the data. L.Y. and R.P. contributed equally to this work and jointly supervised the study.

Corresponding authors

Correspondence to Loic Yengo or Renato Polimanti.

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Competing interests

R.P. is paid for their editorial work on the journal Complex Psychiatry and reports a research grant from Alkermes. The other authors declare no competing interests.

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Nature Human Behaviour thanks Lea Davis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary methods and Fig. 1.

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Supplementary Tables 1–21.

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Cabrera-Mendoza, B., Wendt, F.R., Pathak, G.A. et al. The impact of assortative mating, participation bias and socioeconomic status on the polygenic risk of behavioural and psychiatric traits. Nat Hum Behav (2024). https://doi.org/10.1038/s41562-024-01828-5

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