Lower levels of specific messenger RNA may increase risk for schizophrenia

Lower angiotensin-converting enzyme messenger RNA and protein levels were associated with increased schizophrenia risk, according to results of a Mendelian randomization study published in JAMA Psychiatry.

“Our study found that individuals who carry genetic variants associated with lower levels of the angiotensin-converting enzyme (ACE) gene and protein have increased liability to schizophrenia,” Sonia Shah, PhD, of the Institute for Molecular Biosciences at the University of Queensland in Australia, told Healio Psychiatry. “Therefore, drugs that also result in lower levels or activity of ACE, such as ACE inhibitors which are used to treat high blood pressure, may also do the same.”

Shah and colleagues sought to address the association between a single-nucleotide variant (SNV) and drug target gene expression. They analyzed quantitative trait loci (QTL) in blood samples and SNV-disease association from published case-control genome-wide association studies. They included data of 40,675 individuals with schizophrenia and 64,643 controls, 20,352 individuals with bipolar disorder and 31,358 controls, and 135,458 individuals with major depressive disorder and 344,901 controls. The researchers collected prefrontal cortex and cerebral spine fluid QTLs from some participants.

“One of the reasons why this study is different is because it uses genetic data to infer the effects of medication,” Shah said. “The gold standard approach would be to conduct a randomized clinical trial, but these are not always feasible. We now have access to very large genetic datasets, and by applying statistical methods, we can leverage this data to predict potential unknown beneficial or adverse effects of medication.”

Results showed an association between the ACE gene in blood and lower systolic blood pressure of 4 (95% CI, 2.7-5.3) mmHg with increased risk for schizophrenia (OR = 1.75; 95% CI, 1.28-2.38). In addition, the researchers noticed a comparable association between ACE expression in the prefrontal cortex (OR = 1.33; 95% CI, 1.13-1.56) and ACE protein levels in cerebral spinal fluid (OR per 1-SD decrease = 1.04; 95% CI, 1.01-1.07).

“I want to strongly emphasize that the evidence from genetic analyses alone is insufficient to justify any changes to prescription guidelines,” Shah said. “Individuals taking ACE inhibitors should not stop taking their medication, as these medications are very effective at controlling high blood pressure, as well as preventing and managing heart disease. But what our findings do warrant is further investigation into the role of ACE in schizophrenia and closer monitoring of individuals, especially those with schizophrenia, who may be on such medication.”