Year: 2024
Type: article
Study design: Observational Study
Abstract: Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS). However, the impact of rare coding variants on depression remains poorly understood. Here, we present whole-exome sequencing analyses of depression with seven different definitions based on survey, questionnaire, and electronic health records in 320,356 UK Biobank participants. We showed that the burden of rare damaging coding variants in loss-of-function intolerant genes is significantly associated with risk of depression with various definitions. We compared the rare and common genetic architecture across depression definitions by genetic correlation and showed different genetic relationships between definitions across common and rare variants. In addition, we demonstrated that the effects of rare damaging coding variant burden and polygenic risk score on depression risk are additive. The gene set burden analyses revealed overlapping rare genetic variant components with developmental disorder, autism, and schizophrenia. Our study provides insights into the contribution of rare coding variants, separately and in conjunction with common variants, on depression with various definitions and their genetic relationships with neurodevelopmental disorders.
Source: Nature Communications
Institutions: Biogen (United States), Broad Institute, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Autism & Developmental Medicine Institute, Geisinger Health System, Vrije Universiteit Amsterdam, Northwell Health, Feinstein Institute for Medical Research, Institute of Mental Health, Zucker Hillside Hospital, GlaxoSmithKline (United States), Vanderbilt University Medical Center, Yale University, VA Connecticut Healthcare System, University of California San Diego, VA San Diego Healthcare System, Hofstra University, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
OpenAlex ID: W4392162661