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Genetic architecture and socio-environmental risk factors for major depressive disorder in Nepal

Published online by Cambridge University Press:  16 September 2024

Karmel W. Choi Open the ORCID record for Karmel W. Choi [Opens in a new window] ,
Justin D. Tubbs ,
Younga H. Lee ,
Yixuan He ,
Kristin Tsuo ,
Mary T. Yohannes ,
Lethukuthula L. Nkambule ,
Emily Madsen ,
Dirgha J. Ghimire  and
Sabrina Hermosilla
...Show all authors
Karmel W. Choi*
Affiliation:
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA
Justin D. Tubbs*
Affiliation:
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA
Younga H. Lee
Affiliation:
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA
Yixuan He
Affiliation:
Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Kristin Tsuo
Affiliation:
Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Mary T. Yohannes
Affiliation:
Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
Lethukuthula L. Nkambule
Affiliation:
Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
Emily Madsen
Affiliation:
Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Dirgha J. Ghimire
Affiliation:
Population Studies Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
Sabrina Hermosilla
Affiliation:
Population Studies Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA Department of Population and Family Health, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA
Tian Ge
Affiliation:
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA
Alicia R. Martin
Affiliation:
Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
William G. Axinn
Affiliation:
Population Studies Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
Jordan W. Smoller*
Affiliation:
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA
*
Corresponding author: Karmel W. Choi; Email: kwchoi@mgh.harvard.edu; Justin D. Tubbs; Email: jtubbs@mgh.harvard.edu; Jordan W. Smoller; Email: jsmoller@mgh.harvard.edu
Corresponding author: Karmel W. Choi; Email: kwchoi@mgh.harvard.edu; Justin D. Tubbs; Email: jtubbs@mgh.harvard.edu; Jordan W. Smoller; Email: jsmoller@mgh.harvard.edu
Corresponding author: Karmel W. Choi; Email: kwchoi@mgh.harvard.edu; Justin D. Tubbs; Email: jtubbs@mgh.harvard.edu; Jordan W. Smoller; Email: jsmoller@mgh.harvard.edu
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Abstract

Background

Major depressive disorder (MDD) is the leading cause of disability globally, with moderate heritability and well-established socio-environmental risk factors. Genetic studies have been mostly restricted to European settings, with polygenic scores (PGS) demonstrating low portability across diverse global populations.

Methods

This study examines genetic architecture, polygenic prediction, and socio-environmental correlates of MDD in a family-based sample of 10 032 individuals from Nepal with array genotyping data. We used genome-based restricted maximum likelihood to estimate heritability, applied S-LDXR to estimate the cross-ancestry genetic correlation between Nepalese and European samples, and modeled PGS trained on a GWAS meta-analysis of European and East Asian ancestry samples.

Results

We estimated the narrow-sense heritability of lifetime MDD in Nepal to be 0.26 (95% CI 0.18–0.34, p = 8.5 × 10−6). Our analysis was underpowered to estimate the cross-ancestry genetic correlation (rg = 0.26, 95% CI −0.29 to 0.81). MDD risk was associated with higher age (beta = 0.071, 95% CI 0.06–0.08), female sex (beta = 0.160, 95% CI 0.15–0.17), and childhood exposure to potentially traumatic events (beta = 0.050, 95% CI 0.03–0.07), while neither the depression PGS (beta = 0.004, 95% CI −0.004 to 0.01) or its interaction with childhood trauma (beta = 0.007, 95% CI −0.01 to 0.03) were strongly associated with MDD.

Conclusions

Estimates of lifetime MDD heritability in this Nepalese sample were similar to previous European ancestry samples, but PGS trained on European data did not predict MDD in this sample. This may be due to differences in ancestry-linked causal variants, differences in depression phenotyping between the training and target data, or setting-specific environmental factors that modulate genetic effects. Additional research among under-represented global populations will ensure equitable translation of genomic findings.

Keywords

depressiongene-environmentgeneticsglobal mental healthheritabilityNepalpolygenic scorestrauma
Type
Original Article
Information
Psychological Medicine , First View , pp. 1 - 9
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Copyright
Copyright © The Author(s), 2024. Published by Cambridge University Press

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Footnotes

*

These authors share joint first-authorship.

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