Beyond genome‐wide significance: integrative approaches to the interpretation and extension of GWAS findings for alcohol use disorder

Abstract

Alcohol use disorder (AUD) is a heritable complex behavior. Due to the highly polygenic nature of AUD, identifying genetic variants that comprise this heritable variation has proved to be challenging. With the exception of functional variants in alcohol metabolizing genes (e.g. ADH1B and ALDH2), few other candidate loci have been confidently linked to AUD. Genome-wide association studies (GWAS) of AUD and other alcohol-related phenotypes have either produced few hits with genome-wide significance or have failed to replicate on further study. These issues reinforce the complex nature of the genetic underpinnings for AUD and suggest that both GWAS studies with larger samples and additional analysis approaches that better harness the nominally significant loci in existing GWAS are needed. Here, we review approaches of interest in the post-GWAS era, including in silico functional analyses; functional partitioning of single nucleotide polymorphism heritability; aggregation of signal into genes and gene networks; and validation of identified loci, genes and gene networks in postmortem brain tissue and across species. These integrative approaches hold promise to illuminate our understanding of the biological basis of AUD; however, we recognize that the main challenge continues to be the extremely polygenic nature of AUD, which necessitates large samples to identify multiple loci associated with AUD liability.

Studying alcohol use disorder using Drosophila melanogaster in the era of ‘Big Data’

“…GWAS studies have limitations, including the inability to predict transcriptional changes in response to alcohol exposure and chronic use [9, 15, 17, 80, 97]. Transcriptome analysis has shed light on this research area.…”

“…In recent decades research has moved away from one-gene models towards models that encompass multiple contributing gene effects [1, 5, 13, 14]. This new understanding was facilitated by genome-wide association studies (GWAS) coupled with the fine genome mapping tools now available, and by transcriptional studies [14, 15]. However, human population studies are hampered by the long time course of AUD’s development and a patient’s unknown environmental factors.…”

Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

“…For example, it is unclear if phenotypes such as altered gross and cellular structure and gene expression in the brains of AUD patients contribute to AUDs or are merely a byproduct of their existence [ 20 , 21 , 22 , 23 ]. (7) Human genomic analyses often yield candidate gene sets that share remarkably little overlap with similar human studies [ 24 , 25 , 26 ]. Even when unambiguous candidates are established, their biological significance is often unclear.…”

Common genetic substrates of alcohol and substance use disorder severity revealed by pleiotropy detection against GWAS catalog in two populations

“…Alcohol use disorders (AUD) and other substance use disorders (SUD) are complex diseases, and like many other complex diseases, are postulated to have polygenic mode of inheritance and are often comorbid with other disorders. [1][2][3][4] Rates of AUD and SUD also vary across ethnic groups and populations. 5 For instance, select American Indian (AI) tribes have been shown to have significantly higher rates of AUD than the general population in the United States.…”

“…Alcohol use disorders (AUD) and other substance use disorders (SUD) are complex diseases, and like many other complex diseases, are postulated to have polygenic mode of inheritance and are often comorbid with other disorders 1–4 . Rates of AUD and SUD also vary across ethnic groups and populations 5 .…”