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Genome-Wide Variants Shared Between Smoking Quantity and Schizophrenia on 15q25 Are Associated With CHRNA5 Expression in the Brain.

Cigarette smokers with schizophrenia consume more cigarettes than smokers in the general population. Schizophrenia and smoking quantity may have shared genetic liability. Genome-wide association studies (GWASs) of schizophrenia and smoking quantity have highlighted a biological pleiotropy in which a robust 15q25 locus affects both traits. To identify the genetic variants shared between these traits on 15q25, we used summary statistics from large-scale GWAS meta-analyses of schizophrenia in the Psychiatric Genomics Consortium 2 and smoking quantity assessed by cigarettes smoked per day in the Tobacco and Genetics Consortium. To evaluate the regulatory potential of the shared genetic variants, expression quantitative trait loci analysis in 10 postmortem brain regions was performed using the BRAINEAC dataset in 134 neuropathologically normal individuals. Twenty-two genetic variants on 15q25 were associated with both smoking quantity and schizophrenia at the genome-wide significance level (P < 5.00 × 10-8). Major alleles of all variants were associated with higher smoking quantity and risk of schizophrenia. These genetic variants were associated with PSMA4, CHRNA3, and CHRNB4 expression in specific brain regions (lowest P = 4.81 × 10-4) and with CHRNA5 expression in multiple brain regions (lowest P = 8.70 × 10-6). Risk-associated major alleles of these variants were commonly associated with higher expression in several brain regions, excluding the medulla, at the transcript level. In addition, the risk-associated major allele at rs637137 was associated with higher CHRNA5 expression at the specific exon level in multiple brain regions (lowest P = 2.37 × 10-5). Our findings suggest that genome-wide variants shared between smoking quantity and schizophrenia contribute to a common pathophysiology underlying these traits involving altered CHRNA5 expression in the brain.