Genetic heterogeneity in depressive symptoms following the death of a spouse: Polygenic score analysis of the U.S. Health and retirement study

Benjamin W. Domingue*, Hexuan Liu, Aysu Okbay, Daniel W. Belsky

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Objective: Experience of stressful life events is associated with risk of depression. Yet many exposed individuals do not become depressed. A controversial hypothesis is that genetic factors influence vulnerability to depression following stress. This hypothesis is often tested with a "diathesisstress" model, in which genes confer excess vulnerability. The authors tested an alternative formulation of thismodel: genes may buffer against depressogenic effects of life stress. Method: The hypothesized genetic buffer was measured using a polygenic score derived from a published genomewide association study of subjective well-being. The authors tested whether married older adults who had higher polygenic scores were less vulnerable to depressive symptoms following the death of their spouse compared with agematched peers who had also lost their spouse and who had lower polygenic scores. Data were analyzed from 8,588 non-Hispanic white adults in the Health and Retirement Study (HRS), a population-representative longitudinal study of older adults in the United States. Results: HRS adults with higher well-being polygenic scores experienced fewer depressive symptoms during follow-up. Those who survived the death of their spouses (N=1,647) experienced a sharp increase in depressive symptoms following the death and returned toward baseline over the following 2 years. Having a higher well-being polygenic score buffered against increased depressive symptoms following a spouse's death. Conclusions: The effects were small, and the clinical relevance is uncertain, although polygenic score analyses may provide clues to behavioral pathways that can serve as therapeutic targets. Future studies of gene-environment interplay in depression may benefit from focus on genetics discovered for putative protective factors.

Original languageEnglish
Pages (from-to)963-970
Number of pages8
JournalAmerican Journal of Psychiatry
Issue number10
Early online date24 Mar 2017
Publication statusPublished - 1 Oct 2017


From the Stanford University Graduate School of Education, Stanford, Calif.; the School of Criminal Justice at the University of Cincinnati, Cincinnati; the Department of Complex Trait Genetics, Vrije Universiteit, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands; the Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, the Netherlands; and the Duke University School of Medicine, Department of Medicine, Division of Geriatrics, Duke University Social Science Research Institute, Duke University Center for the Study of Aging and Human Development, Durham, N.C. This study used data from the Health and Retirement Study, which is sponsored by the National Institute on Aging (grants NIA U01AG009740, RC2AG036495, and RC4AG039029) and conducted by the University of Michigan. Further support was provided by the NIH/NICHD-funded University of Colorado Population Center (R24HD066613). This research was facilitated by the Social Science Genetic Association Consortium. Dr. Okbay is supported by a European Research Council consolidator grant (647648 EdGe). Dr. Belsky is supported by an early-career research fellowship from the Jacobs Foundation, as well as National Institute on Aging grants R01AG032282, P30AG034424, and P30AG028716. All other authors report no financial relationships with commercial interests. Received Nov. 2, 2016; revision received Jan. 2, 2017; accepted Feb. 9, 2017; published online March 24, 2017.

FundersFunder number
NIH/NICHD-funded University of Colorado Population CenterR24HD066613
National Institute on AgingP30AG028716, R01AG032282, RC4AG039029, U01AG009740, RC2AG036495, P30AG034424
University of Michigan
European Research Council647648 EdGe
Jacobs Foundation


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