Genome-wide analyses of smoking behaviors in schizophrenia: findings from the Psychiatric Genomics Consortium

Objective: While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia (SCZ) spectrum disorders are upwards of 60%. Several lines of evidence support a shared etiological basis for smoking and... [ view full abstract ]

Objective: While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia (SCZ) spectrum disorders are upwards of 60%. Several lines of evidence support a shared etiological basis for smoking and SCZ, including recent findings from genome-wide association studies (GWAS). However, few studies have considered whether genetic variants also influence smoking behavior among SCZ cases. Methods: We combined single nucleotide polymorphism (SNP) genotypes with self-reported nicotine-use and symptom data from the Psychiatric Genomics Consortium (PGC) study of SCZ. We evaluated whether polygenic risk scores (PRS) constructed from the results of the Tobacco and Genetics (TAG) meta-analyses of smoking behaviors are associated with SCZ risk, or predict these same outcomes in cases. Using genome-wide summary statistics for SCZ, and results from exploratory case-only GWAS of smoking initiation (SI) and cigarettes-smoked-per-day (CPD), we estimated the genetic correlation with TAG phenotypes. Results: We demonstrate significant genetic correlations of SCZ with SI (ρg=0.159; P=5.05×10-10), CPD (ρg=0.094; P=0.006), and age-of-onset of smoking (ρg=0.1; P=0.009) in the general population, and successfully replicate findings for SI and age-of-onset in an independent East-Asian cohort. Comparing SCZ-cases to the general population, we observe a significant positive genetic correlation for SI (ρg=0.624, P=0.002). Similarly, TAG-based PRS for SI and CPD were significantly associated with SI (P=3.49×10-5) and CPD (P=0.007) among cases. We also successfully replicated a novel SNP association with CPD among cases upstream of TMEM106B on chromosome 7 (rs148253479; P=3.18×10-8; N=3,520). Conclusion: We provide evidence of a partially shared genetic basis for SCZ and smoking behaviors, and for smoking behaviors among SCZ patients and the general population. Future research needs to address mechanisms underlying associations between these traits to aid both SCZ and smoking treatment and prevention efforts.