Association of Antihypertensive Drug Target Genes With Psychiatric Disorders

Importance: Observational studies have reported associations between antihypertensive medication and psychiatric disorders, although the reported direction of association appears to be dependent on drug class. Objective: To estimate the potential effect of different antihypertensive drug classes on schizophrenia, bipolar disorder, and major depressive disorder. Design, Setting, and Participants: This 2-sample mendelian randomization study assessed the association between a single-nucleotide variant (SNV) and drug target gene expression derived from existing expression quantitative trait loci (eQTL) data in blood (sample 1) and the SNV-disease association from published case-control genome-wide association studies (sample 2). Significant associations were corroborated using published brain eQTL and protein QTL data. Participants included 40 675 patients with schizophrenia and 64 643 controls, 20 352 patients with bipolar disorder and 31 358 controls, and 135 458 patients with major depressive disorder and 344 901 controls. Blood eQTL levels were measured in 31 684 individuals from 37 cohorts (eQTLGen consortium); prefrontal cortex eQTLs were measured from the PsychENCODE resource in 1387 individuals; and protein QTLs were measured in cerebral spinal fluid from 544 individuals and plasma from 818 individuals. Data were collected from October 4, 2019, to June 1, 2020, and analyzed from October 14, 2019, to June 6, 2020. Exposures: Expression levels of antihypertensive drug target genes as proxies for drug exposure, and genetic variants robustly associated with the expression of these genes as mendelian randomization instruments. Main Outcomes and Measures: Risk for schizophrenia, bipolar disorder, and major depressive disorder. Results: A 1-SD lower expression of the angiotensin-converting enzyme (ACE) gene in blood was associated with lower systolic blood pressure of 4.0 (95% CI, 2.7-5.3) mm Hg, but increased risk of schizophrenia (odds ratio [OR], 1.75; 95% CI, 1.28-2.38; P = 3.95 × 10-4). A concordant direction of association was also observed between ACE expression in prefrontal cortex (OR, 1.33; 95% CI, 1.13-1.56) and ACE protein levels in cerebral spinal fluid (OR per 1-SD decrease, 1.12; 95% CI, 1.05-1.19) and plasma (OR per 1-SD decrease, 1.04; 95% CI, 1.01-1.07). We found no evidence for an association between genetically estimated SBP and schizophrenia risk. Conclusions and Relevance: Findings suggest an adverse association of lower ACE messenger RNA and protein levels with schizophrenia risk. These findings warrant greater pharmacovigilance and further investigation into the effect of ACE inhibitors, particularly those that are centrally acting, on psychiatric symptoms in patients with schizophrenia, as well as the role of ACE inhibitor use in late-onset schizophrenia.