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Multivariate genome-wide analysis of education, socioeconomic status and brain phenome

Abstract

Socioeconomic status (SES) and education (EDU) are phenotypically associated with psychiatric disorders and behaviours. It remains unclear how these associations influence genetic risk for psychopathology, psychosocial factors and EDU and/or SES (EDU/SES) individually. Using information from >1 million individuals, we conditioned the genetic risk for psychiatric disorders, personality traits, brain imaging phenotypes and externalizing behaviours with genome-wide data for EDU/SES. Accounting for EDU/SES significantly affected the observed heritability of psychiatric traits, ranging from 2.44% h2 decrease for bipolar disorder to 14.2% h2 decrease for Tourette syndrome. Neuroticism h2 significantly increased by 20.23% after conditioning with SES. After EDU/SES conditioning, neuronal cell types were identified for risky behaviour (excitatory), major depression (inhibitory), schizophrenia (excitatory and γ-aminobutyric acid (GABA) mediated) and bipolar disorder (excitatory). Conditioning with EDU/SES also revealed unidirectional causality between brain morphology, psychopathology and psychosocial factors. Our results indicate that genetic discoveries related to psychopathology and psychosocial factors may be limited by genetic overlap with EDU/SES.

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Fig. 1: Trait inclusion genetic correlations.
Fig. 2: Heritability (h2) changes.
Fig. 3: Cell-type transcriptomic profile enrichments underlying psychopathology and psychosocial factors.
Fig. 4: Trait loading onto latent factors.
Fig. 5: Causal relationships masked by EDU and SES effects.
Fig. 6: LCV relationship network.

Data availability

All GWAS association data and analysis materials used in this study are publicly available for download by qualified researchers. All data used to make conclusions discussed in this study are provided as Supplementary Material.

Social Science Genetic Association Consortium: https://www.thessgac.org

Psychiatric Genomics Consortium: https://www.med.unc.edu/pgc/download-results/

UK Biobank: https://www.ukbiobank.ac.uk/register-apply/

23andMe: https://research.23andme.com/research-innovation-collaborations/

Brain Imaging Genetics: http://big.stats.ox.ac.uk

Code availability

Previously developed pipelines were used to produce the results for this study. No custom code was developed.

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Acknowledgements

The authors thank the research participants and employees of 23andMe Inc for making this work possible. This study was supported by the Simons Foundation Autism Research Initiative (SFARI Explorer Award 534858 (R.P.)), the American Foundation for Suicide Prevention (YIG-1-109-16 (R.P.)), the National Institutes of Health (R21 DC018098 (R.P.), R21 DA047527 (R.P.), F32 MH122058 (F.R.W.) and R01 MH117646 (T.L.)) and the National Center for PTSD of the U.S. Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Contributions

F.R.W and R.P. conceived the study design; F.R.W. generated and analysed all data; F.R.W., G.A.P., T.L., J.H.K., J.G. and R.P. contributed to data interpretation; F.R.W., G.A.P. and R.P. contributed to data visualization and presentation; F.R.W. drafted the original manuscript; F.R.W., G.A.P., T.L., J.H.K., J.G. and R.P. critically evaluated and revised the manuscript.

Corresponding author

Correspondence to Renato Polimanti.

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Competing interests

J.H.K. reports compensation as the editor of Biological Psychiatry and also serves on the Scientific Advisory Boards for Bioasis Technologies, Inc., Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), Cadent Therapeutics (Clinical Advisory Board), PsychoGenics, Inc, Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, and the Lohocla Research Corporation. He owns stock in ArRETT Neuroscience, Inc., Biohaven Pharmaceuticals, Sage Pharmaceuticals and Spring Care, Inc. and stock options in Biohaven Pharmaceuticals Medical Sciences, BlackThorn Therapeutics, Inc. and Storm Biosciences, Inc. He is co-inventor on multiple patents as listed below: (1) Seibyl J. P., Krystal J. H., Charney D. S. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. US patent 5,447,948 (1995); (2) Vladimir, C., Krystal, J. H., Sanacora, G. Glutamate modulating agents in the treatment of mental disorders, US patent 8,778,979 (2014); (3) Charney D., Krystal J. H., Manji H., Matthew S., Zarate C. Intranasal administration of ketamine to treat depression US patent application 14/197,767 (2014); (4) Zarate, C., Charney, D. S., Manji, H. K., Mathew, S. J., Krystal, J. H., Department of Veterans Affairs. Methods for treating suicidal ideation, US patent application no. 14/197,767 (2014); (5) Arias A., Petrakis I., Krystal J. H. Composition and methods to treat addiction. US patent application no. 61/973/961 (2014); (6) Chekroud, A., Gueorguieva, R., Krystal, J. H. Treatment selection for major depressive disorder (filing date 2016, USPTO docket number Y0087.70116US00). Provisional patent submission by Yale University: (7) Gihyun, Y., Petrakis I., Krystal, J. H. Compounds, compositions and methods for treating or preventing depression and other diseases. US provisional patent application no. 62/444,552 (filed 10 January 2017) by Yale University Office of Cooperative Research OCR 7088 US01: (8) Abdallah, C., Krystal, J. H., Duman, R., Sanacora, G. Combination therapy for treating or preventing depression or other mood diseases. US provisional patent application no. 047162-7177P1 (00754) filed on 20 August 2018 by Yale University Office of Cooperative Research OCR 7451 US01. J.G. is named as an inventor on PCT patent application 15/878,640 Genotype-guided dosing of opioid agonists, filed 24 January 2018. J.G. and R.P. are paid for their editorial work on the journal Complex Psychiatry. The other authors declare no competing interests.

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Wendt, F.R., Pathak, G.A., Lencz, T. et al. Multivariate genome-wide analysis of education, socioeconomic status and brain phenome. Nat Hum Behav (2020). https://doi.org/10.1038/s41562-020-00980-y

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