Identifying Of The Genetic Pleiotropic Gene For Smoking And Alcohol Drinking

Persistent smoking and excessive alcohol drinking are major public health problem worldwide. Alcohol dependence(AD) and nicotine dependence(ND) is the two major factors of morbidity and mortality. Both alcohol dependence and nicotine dependence are environmentally and genetically influenced complex disorders that exhibit a high degree of comorbidity. Epidemiological studies have shown that a relationship between smoking and drinking, but the nature of these associations is not well understood. Genome-wide association studies(GWAS) have been successful in identifying single nucleotide polymorphisms(SNPs) associated with alcohol and nicotine dependence. However, at existing sample sizes, these variants explain only part of the estimated heritability.Here, we use a genetic pleiotropy-informed conditional false discovery rate(FDR) method on GWAS summary statistics data to to systematically interrogate the potentially shared genetic basis between smoking behaviors(age of smoking initiation,smoking initiation and smoking quantity- cigarettes per day) and alcohol drinking behaviors(alcohol drinking, alcohol consumption). We computed stratified Q–Q curves of data to show enrichment of SNPs associated with smoking behaviors as a function of association with alcohol drinking behaviors and vice versa. The stratified Q-Q plots revealed strong polygenic pleiotropic enrichment between alcohol drinking and CPD, smoking initiation, with somewhat deficient enrichment with age of smoking initiation. Another stratified Q-Q plots revealed general polygenic pleiotropic enrichment between alcohol consumption and smoking initiation. A less clear pleiotropic enrichment was seen for CPD, but there was no evidence for enrichment in age of smoking initiation.In the present study we leveraged the power of GWAS data from independent smoking behaviors and alcohol drinking behaviors samples. Applying the conditional FDR method, we identified 17 loci associated with smoking behaviors and 35 loci associated with alcohol drinking behaviors below the conditional FDR level of 0.05. And we identified 14 loci were associated with both smoking and alcohol drinking(conjunction FDR ≤0.05). Of these, four SNPs(rs6265, rs11783438, rs1564499 and rs11784248) were located in BDNF, CSMD1, ADAMTS7, and SGCZ respectively. Several SNPs in these four genes have been discovered to show borderline association with smoking behaviors in larger samples using standard GWAS analytical methods. Thus, our study validated these SNPs with borderline association discovered in considerably larger samples and discovered these SNPs might be pleiotropic for smoking behaviors and alcohol drinking behaviors. The remaining 10 loci would not have been identified in the current sample without the use of the pleiotropy-informed stratified FDR method. It is possible that some of the loci identified in the current study might not be pleiotropic but rather underlie common aspects of the alcohol and nicotine dependence. This can be investigated in samples with more detailed phenotypes and additional experimental work is needed to further elucidate the biological underpinnings of these findings.In conclusion, applying the pleiotropy-informed conditional FDR method combining GWAS of two associated phenotypes, we found several new common gene variants associated with smoking behaviors and alcohol drinking that were not identified in the original analysis using traditional GWAS methods. Our results implicate potential shared pathological mechanisms between nicotine dependence and alcohol dependence and may have implications for therapeutic trials involving alcohol and nicotine dependence.