Journal Article

Genetic proxies for antihypertensive drugs and mental disorders: Mendelian randomization study in European and East Asian populations

Fan, Bohan, Zhao, Jie V.

2024

Overview

Background Mental disorders are among the top causes of disease burden worldwide. Existing evidence regarding the repurposing of antihypertensives for mental disorders treatment is conflicting and cannot establish causation. Methods We used Mendelian randomization to assess the effects of angiotensin-converting-enzyme inhibitors (ACEIs), beta blockers (BBs), and calcium channel blockers (CCBs) on risk of bipolar disorder (BD), major depression disorder (MDD), and schizophrenia (SCZ). We used published genetic variants which are in antihypertensive drugs target genes and correspond to systolic blood pressure (SBP) in Europeans and East Asians, and applied them to summary statistics of BD (cases = 41,917; controls = 371,549 in Europeans), MDD (cases = 170,756; controls = 329,443 in Europeans and cases = 15,771; controls = 178,777 in East Asians), and SCZ (cases = 53,386; controls = 77,258 in Europeans and cases = 22,778; controls = 35,362 in East Asians) from the Psychiatric Genomics Consortium. We used inverse variance weighting with MR-Egger, weighted median, weighted mode, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. We performed gene-specific analysis and utilized various methods to address potential pleiotropy. Results After multiple testing correction, genetically proxied ACEIs were associated with an increased risk of SCZ in Europeans (odds ratio (OR) per 5 mmHg lower in SBP 2.10, 95% CI 1.54 to 2.87) and East Asians (OR per 5 mmHg lower in SBP 2.51, 95% CI 1.38 to 4.58). Genetically proxied BBs were not associated with any mental disorders in both populations. Genetically proxied CCBs showed no benefits on mental disorders. Conclusions Antihypertensive drugs have no protection for mental disorders but potential harm. Their long-term use among hypertensive patients with, or with high susceptibility to, psychiatric illness needs careful evaluation.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Angiotensin / Angiotensin-Converting Enzyme Inhibitors / Antihypertensive Agents - therapeutic use / Antihypertensive drugs / Antihypertensives / Asian people / Biomedicine / Bipolar disorder / Blood pressure / Calcium Channel Blockers / Calcium channels / Data analysis / Depressive Disorder, Major - drug therapy / Depressive Disorder, Major - genetics / Diagnosis / Disease susceptibility / Dosage and administration / Drug therapy / East Asian People / Enzyme inhibitors / European People / Genetic diversity / Genetic variance / Genome-Wide Association Study / Humans / Medicine / Medicine & Public Health / Mendelian randomization / Mendelian Randomization Analysis / Mental depression / Mental Disorders / Mental illness / Outliers (statistics) / Patient outcomes / Peptidyl-dipeptidase A / Pleiotropy / Population genetics / Populations / Randomization / Research Article / Schizophrenia / Statistical analysis