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Genetic loci shared between major depression and intelligence with mixed directions of effect

Nature Human Behaviour volume 5, pages 795–801 (2021)Cite this article

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Abstract

Genome-wide association studies (GWAS) have identified several common genetic variants influencing major depression and general cognitive abilities, but little is known about whether the two share any of their genetic aetiology. Here we investigate shared genomic architectures between major depression (MD) and general intelligence (INT) with the MiXeR statistical tool and their overlapping susceptibility loci with conjunctional false discovery rate (conjFDR), which evaluate the level of overlap in genetic variants and improve the power for gene discovery between two phenotypes. We analysed GWAS data on MD (n = 480,359) and INT (n = 269,867) to characterize polygenic architecture and identify genetic loci shared between these phenotypes. Despite non-significant genetic correlation (rg = −0.0148, P = 0.50), we observed large polygenic overlap and identified 92 loci shared between MD and INT at conjFDR < 0.05. Among the shared loci, 69 and 64 are new for MD and INT, respectively. Our study demonstrates polygenic overlap between these phenotypes with a balanced mixture of effect.

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Fig. 1: Venn diagram showing the estimated number of causal variants shared (grey) between INT and MD and those unique (colours) to each.
Fig. 2: Conditional quantile–quantile plots.
Fig. 3: Common genetic variants jointly associated with MD and INT at conjFDR < 0.05.
Fig. 4: Distribution of the annotation for all SNPs jointly associated between major depression and intelligence at conjFDR < 0.10, including functional consequences of SNPs.
Fig. 5: Gene expression levels in human brain tissues.

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Data availability

Data used in this article were obtained from the UK Biobank (https://www.ukbiobank.ac.uk/), the Psychiatric Genomics Consortium (https://www.med.unc.edu/pgc/) and 23andMe (https://www.23andme.com/).

Code availability

The codes for MiXeR and conditional and conjunctional FDR analyses are publicly available at https://github.com/precimed/mixer and https://github.com/precimed/pleiofdr/, respectively.

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Acknowledgements

We would like to thank the research participants and the Major Depression Working Group of the Psychiatric Genomics Consortium, 23andMe and Intelligence cohorts for making their GWAS summary statistics available. We gratefully acknowledge support from the American National Institutes of Health (NS057198, EB00790), the European Union’s Horizon2020 Research and Innovation Action Grant No. 847776 CoMorMent, the Research Council of Norway (229129, 213837, 248778, 273291, 223273), the South-East Norway Regional Health Authority (2017-112) and K.G. Jebsen Stiftelsen (SKGJ-MED-008).

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Authors and Affiliations

  1. NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    Shahram Bahrami, Alexey Shadrin, Oleksandr Frei, Kevin S. O’Connell, Francesco Bettella, Florian Krull, Guy Hindley, Torill Ueland, Nils Eiel Steen, Olav B. Smeland & Ole A. Andreassen

  2. Department of Radiology, University of California, San Diego, La Jolla, CA, USA

    Chun C. Fan & Anders M. Dale

  3. Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA

    Chun C. Fan

  4. Division of Psychiatric Treatment Research, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Jan I. Røssberg

  5. Multimodal Imaging Laboratory, University of California, San Diego, La Jolla, CA, USA

    Anders M. Dale

  6. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    Anders M. Dale & Ole A. Andreassen

  7. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    Anders M. Dale

  8. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    Srdjan Djurovic

  9. NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway

    Srdjan Djurovic

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Contributions

S.B. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design was carried out by S.B. and O.A.A. Acquisition, analysis or interpretation of data was performed by S.B., A.S., O.F., K.S.O'C., O.B.S., F.B., F.K., C.C.F., A.M.D. and O.A.A. Drafting of the manuscript was carried out by S.B., A.S., O.B.S. and O.A.A. Critical revision of the manuscript for important intellectual content was undertaken by S.B., O.B.S., J.I.R., G.H., T.U., S.D., N.E.S. and O.A.A. Statistical analysis was performed by S.B. and A.S. O.A.A. obtained funding and provided administrative, technical and material support. Study supervision was provided by S.B. and O.A.A. All authors approved the final manuscript.

Corresponding authors

Correspondence to Shahram Bahrami or Ole A. Andreassen.

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Competing interests

O.A.A. has received speaker’s honorarium from Lundbeck and is a consultant to HealthLytix. A.M.D is a founder of and holds equity in CorTechs Labs, Inc. and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by University of California, San Diego in accordance with its conflict of interest policies. The other authors declare no competing interests.

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Bahrami, S., Shadrin, A., Frei, O. et al. Genetic loci shared between major depression and intelligence with mixed directions of effect. Nat Hum Behav 5, 795–801 (2021). https://doi.org/10.1038/s41562-020-01031-2

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