Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease
Year: 2019
Type: article
Study design: Observational Study
Abstract: Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04–1.18; P 8.43 × 10 −4 ) and 1.13 (95% CI, 1.07–1.20; P 4.51 × 10 −6 ) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03–1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95–1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99–1.14; P = 0.07) and 1.07 (1.01–1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.
Source: Molecular Psychiatry
Authors: Jessica Dennis, Julia Sealock, Rebecca T. Levinson, Eric Farber-Eger, Jacob Franco, Sarah Fong, Peter Straub, Donald Hucks, Wen-Liang Song, MacRae F. Linton, Pierre Fontanillas, Sarah L. Elson, Douglas Ruderfer, Abdel Abdellaoui, Sandra Sanchez-Roige, Abraham A. Palmer, Dorret I. Boomsma, Nancy J. Cox, Guanhua Chen, Jonathan D. Mosley, Quinn S. Wells, Lea K. Davis
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: U.S. Department of Health and Human Services, American Heart Association, Tobacco-Related Disease Research Program, Vanderbilt University, Vanderbilt University Medical Center, Government of Canada, National Institutes of Health, Canadian Institutes of Health Research, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Center for Research Resources, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities, CIHR Skin Research Training Centre
Awards: G1052397333, G1135917780, G115506582, G1182793083, G1243299691, G1460387277, G1527150935, G1537707606, Genomic and Phenomic Architecture of Heart Failure, G1691174148, G1706615277, G173303992, G185044200, G1941623656, G2043572114, G2178242675, G2308744219, G2481190194, G2564988809, G2650613164, G2818629771, G2893286242, G2994311132, G2998239322, G301743239, G3114902838, G3220087362, G3272238124, G3320368763, G332351177, G3410686264, G3462919067, Mental health and chronic disease: A psycheMERGE investigation into the shared biology underlying psychiatric disorders and their physical comorbidities, G3619590958, G3724712001, G4107354744, Using electronic health records linked to a DNA biobank to characterize relationships between mental and physical health, G4167445418, G4175770015, G4200864717, Social Regulation of Gene Expression, G4290769314, G4299203191, G4335719375, G4425699080, G4433008109, G4558225130, G457330776, Analysis, Validation and Resource Creation for Genome Sequencing of Complex Diseases, G4814458579, G4998334444, PsycheMERGE: Leveraging electronic health records and genomics for mental health research, G5074086979, G5125936451, G5253921404, G5588757656, Toward Obesity Precision Medicine: Promise of the Glucagon-Like Peptide 1 Receptor, G560889077, G563474107, G567847597, G5679716143, G5868276417, G6033034647, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, G6195637971, G622112995, G6263508347, Institutional Clinical and Translational Science Award, G6540056966, G6548750934, Delineating epidemiological and genetic factors associated with cardiac diastolic dysfunction, G7030178931, G7051404557, G7406331046, Macrophage SR-BI Regulates Autophagy, Angiogenin and tRNA-derived small RNAs, G7653134492, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G7955974312, G8012826751, Discovering Biology for Neuropsychiatric Diseases Through Omics Studies on Comorbidities, Social Regulation of Gene Expression, G8225907289, G8558577029, Center for Genetic Studies of Drug Abuse in Outbred Rats, G8654190048, G8831369200, G8899773733, Modular Automated -80C Sample Storage System, G9000001553, G9000011408, G9000018826, G9000033427, G9000043901, G9000075328, G9000117721, G9000161510, G9000213099, G9000256508, G9000300101, G931818222, G949362299, G959610197
OpenAlex ID: W2992440468