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

Abstract

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.

The shared genetic architecture of smoking behaviours and psychiatric disorders: Evidence from a population-based longitudinal study in England

“…It is further feasible that single genetic markers for schizophrenia, bipolar disorders, major depression, and intelligence of large effect, rather than an aggerate of common genetic markers of small effect, in uences the risk of smoking initiations in the general population. For example, one of the robust schizophrenia associated loci identi ed by a large genome-wide association study meta-analysis [17] has been found in a gene cluster encoding neuronal nicotinic acetylcholine receptors (nAChR), which is linked to heaviness of smoking in the general population [10,39]. However, by design, polygenic scores do not capture other structural variants beyond common genetic markers of relatively small effects, such as rare variants, poorly tagged or multiple independent variants, gene-by-gene interactions and gene-environment correlations [40].…”

A polygenic approach to the association between smoking and schizophrenia

“…Interestingly, genome‐wide association studies (GWAS) revealed that the CHRNA5–CHRNA3–CHRNB4 cluster on chromosome 15, coding for neuronal nicotinic acetylcholine receptor subunits, is associated with schizophrenia and different smoking traits 9–13 . Consequently, the reason for the high prevalence of smoking in SzP is currently under debate, and the consideration of tobacco as a risk factor for schizophrenia is becoming strongly supported 14–16 .…”

“…7,8 Interestingly, genome-wide association studies (GWAS) revealed that the CHRNA5-CHRNA3-CHRNB4 cluster on chromosome 15, coding for neuronal nicotinic acetylcholine receptor subunits, is associated with schizophrenia and different smoking traits. [9][10][11][12][13] Consequently, the reason for the high prevalence of smoking in SzP is currently under debate, and the consideration of tobacco as a risk factor for schizophrenia is becoming strongly supported. [14][15][16] Mendelian randomization (MR) studies, which use genetic variants associated with the risk factor of interest as instrumental variables to assess causality, are an alternative to observational studies.…”

Polygenic risk scores for late smoking initiation associated with the risk of schizophrenia

“…In contrast, among the GWASs of smoking-related phenotypes from the TAG, only an association between a genomic locus on 15q25 and smoking quantity has been revealed in smoking GWASs 16 . We found that genome-wide significant single-nucleotide polymorphisms (SNPs) on 15q25 shared between schizophrenia and smoking quantity contributed to a common pathophysiology underlying these phenotypes via altered CHRNA5 expression in the brain 23 .…”