Recent Advances in Genetic Studies of Alcohol Use Disorders

Multi-omics integration analysis identifies novel genes for alcoholism with potential link to neurodegenerative diseases

“…Alongside, the largest GWAS of typical alcohol intake (N=941,280) identified more than 200 independent genome-wide significant variants within or near more than 150 genes at 81 independent loci 11 . Despite a genetic correlation (SNP-rg) of 0.77 between PAU and DPW (less so for AUD and DPW, SNP-rg=0.67), genetic correlations between these aspects of alcohol involvement and other anthropometric, cardio-metabolic and psychiatric disorders revealed marked distinctions [10][11][12][13][14] . For instance, while AUD and PAU appear to be consistently associated with increased genetic liability for other psychiatric disorders and negatively with liability to educational achievement, DPW is genetically uncorrelated with most psychiatric disorders (except ADHD and tobacco use disorder) but correlated negatively with educational achievement and cardio-metabolic disease (which remains uncorrelated with PAU or AUD) [10][11][12][13][14] .…”

“…For instance, while AUD and PAU appear to be consistently associated with increased genetic liability for other psychiatric disorders and negatively with liability to educational achievement, DPW is genetically uncorrelated with most psychiatric disorders (except ADHD and tobacco use disorder) but correlated negatively with educational achievement and cardio-metabolic disease (which remains uncorrelated with PAU or AUD) [10][11][12][13][14] . These findings strongly hint at some common pathological underpinnings to AUD, PAU and other mental illnesses while genetic liability to DPW appears to be confounded with socio-economic correlates of alcohol use 10,11,13,14 .…”

“…Furthermore, positionally mapping a non-coding variant to the nearest gene often does not identify the causal gene(s) [15][16][17] . Indeed, most variants identified by GWAS reside within and affect the activity of regulatory elements (e.g., enhancers and promoters) that regulate the expression of target causal genes in specific cell types; the affected genes are often located at quite a distance from the risk variant/ regulatory element 13,15,16,18 . Several recent studies have integrated GWAS data with expression QTLs (eQTLs) using colocalization or integration methods to identify causal variants and genes associated with schizophrenia, Alzheimer's disease and many other complex disorders 13,15,16,18 .…”

“…Indeed, most variants identified by GWAS reside within and affect the activity of regulatory elements (e.g., enhancers and promoters) that regulate the expression of target causal genes in specific cell types; the affected genes are often located at quite a distance from the risk variant/ regulatory element 13,15,16,18 . Several recent studies have integrated GWAS data with expression QTLs (eQTLs) using colocalization or integration methods to identify causal variants and genes associated with schizophrenia, Alzheimer's disease and many other complex disorders 13,15,16,18 . While similar efforts have been targeted at AUD and DPW, they have predominantly relied on bulk mRNA expression data from the small number of brain tissue samples in GTEx 10-14 . In the current study, we used a multi-omics systems approach to identify causal variants and genes associated with AUD and DPW.…”

Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases

“…For example, the largest GWAS of typical alcohol intake (N = 941,280) identified more than 200 independent genome-wide significant variants within or near more than 150 genes at 81 independent loci 11 . Despite a genetic correlation (SNP-rg) of 0.77 between PAU and DPW (less so for AUD and DPW, SNP-rg=0.67), genetic correlations between these aspects of alcohol involvement and other anthropometric, cardio-metabolic, and psychiatric disorders revealed marked distinctions [10][11][12][13][14] . For instance, while AUD and PAU appear to be consistently associated with increased genetic liability for other psychiatric disorders and positively with liability to educational achievement, DPW is genetically uncorrelated with most psychiatric disorders (except ADHD and tobacco use disorder) but correlated negatively with educational achievement and cardio-metabolic disease (which remains uncorrelated with PAU or AUD) [10][11][12][13][14] .…”