New Insight Into Genetic Link Between Schizophrenia and CVD
TOPLINE:
There is an extensive genetic overlap between schizophrenia and smoking, but there are also schizophrenia genes that may protect against obesity, illustrating the bidirectional effects of shared loci across cardiovascular disease (CVD) risk factors, results of new research suggest.
METHODOLOGY:
Genome-wide association studies (GWAS) have detected several loci associated with CVD risk factors, including body mass index (BMI), waist-to-hip ratio, type 2 diabetes, lipids, and blood pressure, with increasing evidence suggesting genetic overlap between such risk factors and schizophrenia.
Researchers obtained what they call an “unprecedently large” set of GWAS samples, including schizophrenia (53,386 patients and 77,258 controls) and various CVD risk factors.
They used analytic approaches to identify genetic links between schizophrenia and CVD risk factors, including bivariate causal mixture model (MiXeR), which estimates the number of shared genetic variants between pairs of phenotypes, and conditional and conjunctional false discovery rate (condFDR and conjFDR), to identify specific genetic loci; these approaches can identify genetic overlap regardless of the effect directions.
TAKEAWAY:
Using MiXeR, the study showed that several genetic variants underlying schizophrenia also influence CVD phenotypes, particularly risk factors of smoking and BMI.
A total of 825 distinct loci were jointly associated with schizophrenia and CVD phenotypes at conjFDR <0.05.
Most of the loci shared with smoking were in line with positive genetic correlations; the authors noted individuals with schizophrenia are more nicotine dependent than the general population, and they experience greater reinforcing effects of nicotine and worse withdrawal symptoms during abstinence than the general population.
The overlapping loci with BMI had effect directions consistent with negative genetic correlations, suggesting people with schizophrenia are genetically predisposed to lower BMI; this is in line with evidence of low BMI being a risk factor for schizophrenia, although obesity is more common in people with schizophrenia.
There was a pattern of mixed effect directions among loci jointly associated with schizophrenia and lipids, blood pressure, type 2 diabetes, waist-to-hip ratio, and coronary artery disease, which may reflect variation in genetic susceptibility to CVD across subgroups of schizophrenia.
IN PRACTICE:
The new results “shed light” on biological pathways associated with comorbidity between CVD and schizophrenia, said the authors, adding future work could provide insights into mechanisms underlying the comorbidity and could facilitate development of antipsychotics with lower metabolic side effects, which could help prevent comorbid CVD, “thereby helping to mitigate a major clinical and health care problem.”
SOURCE:
The study was led by Linn Rødevand, PhD, Norwegian Center for Mental Disorders Research, Division of Mental Health and Addiction, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Norway, and colleagues. It was published online September 27 in the American Journal of Psychiatry.
LIMITATIONS:
Methods used in the study are limited by uncertainties in translating genetic loci to causal variants, which restricts the biological interpretation of the shared genetic variants. Among other methodological limitations are that discrepancies between the linkage disequilibrium structure of the samples used for the GWAS and that of the reference panel may have biased estimates underlying MiXeR.
DISCLOSURES:
The study received support from the Research Council of Norway, Norwegian Health Association, South-East Norway Regional Health Authority, and the European Union. Rødevand reports no relevant financial relationships. See the original article for disclosures of other authors.
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