Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

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.

Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities

“…Fourth, we found that the two factors differ substantially in their associations with human well-being and disease. Our results expand upon recent phenome-wide association studies of genetic risk for major depressive disorder 33 and schizophrenia 34 , expanding the list of complex traits and medical phenotypes associated with mood and psychotic psychopathology. We also identified an interesting pattern of results in our genetic correlation and phenome-wide association analyses, where the factor comprising more common forms of mood disturbance (F1) had broader and often stronger negative associations with socioeconomic and health-related outcomes than the factor comprising rarer forms of serious mental illness (F2).…”

A large-scale genome-wide association study meta-analysis of cannabis use disorder

“…Genotyping and quality control of this sample have been described elsewhere. 41 A logistic regression model was fitted to each of 1335 case or control phenotypes that had at least 100 cases to estimate the odds of each diagnosis given the PRS for cannabis use disorder, after adjustment for sex, median age of the longitudinal electronic health record measurements, and the top ten ancestral principal controls. To explore whether pleiotropic effects of the PRS for cannabis use disorder were mediated by smoking behaviours, we did two phenotype-wide association study (PheWAS) sensitivity analyses: a PheWAS on summary statistics of cannabis use disorder that had been conditioned on the top smoking initiation loci using mtCOJO, 35 and a PheWAS using a diagnosis of tobacco use disorders as an additional covariate in the regression model, which is a conservative over-correction given the extremely high comorbidity expected between cannabis use disorder and tobacco use disorder.…”

Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

“…For each of the unrelated genotyped individuals of European ancestry from BioVU, we computed polygenic risk scores (PRS) for POU using the PRS-CS “auto” version [ 34 ]. Genotyping and quality control for this cohort have been extensively described [ 35 , 36 ].…”