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Hundreds of Genetic Variants Implicated in Tobacco, Alcohol Use

NEW YORK (GenomeWeb) – In a study published yesterday in Nature Genetics, an international team of researchers reported that 566 genetic variants in 406 loci may be associated with multiple stages of tobacco use as well as alcohol use, with 150 of those loci evidencing pleiotropic association.

In sample sizes of up to 1.2 million individuals, the researchers found that smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, and concluded that increased genetic risk for alcohol use is associated with lower disease risk. They also observed that genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission are all involved in tobacco and alcohol use.

Smoking initiation phenotypes included age of initiation of regular smoking and a binary phenotype indicating whether an individual had ever smoked regularly. Heaviness of smoking was measured with cigarettes per day. Smoking cessation was a binary variable contrasting current versus former smokers. Alcohol use was measured by drinks per week.

Alcohol use was not highly genetically correlated with the smoking phenotypes except for smoking initiation, the researchers said, suggesting that sequence variations affecting alcohol use and those affecting initiation of smoking overlap significantly. Smoking phenotypes were genetically correlated as expected with many behavioral, psychiatric, and medical phenotypes. Genetic variation associated with increased alcohol use was associated with greater levels of risky behavior and cannabis use, but with less risk of disease for almost all diseases.

Patterns of pleiotropy across phenotypes were highly diverse, with only three loci significantly associated with all five phenotypes. These three loci included associations implicating phosphodiesterase 4B (PDE4B) and cullin 3 (CUL3), the researchers said. PDE4B affects signal transduction and it is downregulated by chronic nicotine administration in rats. CUL3 has wide-ranging effects, including on ubiquination and protein degradation, and de novo mutations in CUL3 are associated with rare diseases affecting response to the mineralocorticoid aldosterone, which is also affected by smoking and is associated with alcohol use, they added.

In addition to testing for pleiotropy, the team also found 1,193 independent, genome-wide significantly associated common variants. Phenotypic variation accounted for by the initial 566 conditionally independent genome-wide significant variants from the initial GWAS ranged from 0.1 percent for smoking cessation to 2.3 percent for smoking initiation. SNP heritability calculated using linkage disequilibrium score regression ranged from 4.2 percent for drinks per week to 8 percent for cigarettes per day, the researchers noted.

"The results suggest that these phenotypes are highly polygenic and that the majority of the heritability is accounted for by variants below standard GWAS thresholds," the authors added.

Further analyses found cell and tissue enrichment across all five phenotypes within core histone marks from multiple central nervous system tissues. "Enrichment was observed in tissues from cortical and sub-cortical regions in the central nervous system. Structure and function of these regions have been robustly associated with individual differences in frequencies, magnitudes, and clinical characteristics of alcohol use, and substance use/misuse generally, in human imaging research," the team noted.

The researchers further noted that their results included "significant enrichment across phenotypes and histone marks in the hippocampus, inferior temporal pathways, dorsolateral and medial prefrontal cortex, caudate, and striatum," adding that alcohol and nicotine use affect dopaminergic and glutamatergic neurotransmission in these regions of the brain, "compromising reward-based learning and facilitating drug-seeking behavior."