GABA_A receptor polymorphisms in alcohol use disorder in the GWAS era

Abstract

Alcohol use disorder (AUD) is a chronic, relapsing, neuro-psychiatric illness of high prevalence and with a serious public health impact worldwide. It is complex and polygenic, with a heritability of about 50%, and influenced by environmental causal heterogeneity. Risk factors associated with its etiology have a genetic component. GABA (γ-aminobutyric acid) is a major inhibitory neurotransmitter in mammalian brain. GABA_A receptors are believed to mediate some of the physiological and behavioral actions of alcohol. In this critical review, relevant genetic terms and type and methodology of the genetic studies are briefly explained. Postulated candidate genes that encode subunits of GABA_A receptors, with all the reported SNPs, are presented. Genetic studies and meta-analyses examining polymorphisms of the GABA_A receptor and their association with AUD predisposition are presented. The data are critically examined with reference to recent GWAS studies that failed to show relations between GABA_A receptors and AUD. Restrictions and perspectives of the different findings are discussed.

Appendix

Table 3 DSM-III-R: criteria for alcohol dependence and alcohol abuse

Table 4 DSM-IV-TR: criteria for alcohol dependence and alcohol abuse

Table 5 DSM-5: alcohol use disorder

Glossary

Allele-polymorphism-SNPS-missense variants

Inter-individual variations of DNA that can be found in genes and non-coding areas of DNA are called alleles. A distinct region of DNA for which several alleles can be found is called polymorphic; the region can also be called polymorphism. The exchange of a single nucleotide in the DNA is the origin of single nucleotide polymorphisms (SNPs). Only a minority of SNPs (probably around 10%) are thought to affect protein function and are called functional or synonymous variants. Non-synonymous SNPs or missense variants cause a single amino acid (AA) substitution within a protein sequence and may or may not lead to altered protein function.

Candidate gene association studies

Studies designed to test candidate genes within chromosomal regions identified through linkage studies or based on plausibility of unrelated individuals. The candidate gene analysis verifies if certain alleles of the gene are associated with a disease, a special trait or a symptom. A gene is considered a candidate gene because the genes’ function might be related to the pathophysiology of the disease or because the gene lies in a chromosomal region that has already been linked to the disorder by linkage analysis. These studies can detect small increases in genetic risk variants associated with a disorder.

COGA Study

Collaborative Studies on Genetics of Alcoholism (COGA) was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) since 1989, to identify the specific genes that can influence a person’s likelihood of developing alcoholism. More than 2255 extended families and more than 17,702 individuals have been included in this database. A repository of cell lines from these individuals that serve as a permanent source of DNA for genetic studies has been established.

Genetic linkage studies

Studies of entire families in which several members are affected by the phenotype of interest. Specific genomic regions or the hole genome of all individuals are scanned using microsatellite markers (nucleotide tandem repeats in DNA sequences which have been mapped to known regions of the genome) or SNPs. It is examined whether specific alleles of the used markers are more often found in people with the disorder than in people without it. If the tested markers are in close physical proximity to a gene of physiological relevance to the examined disease, affected siblings are expected to share more identical alleles of the certain marker. Then linkage is assumed. Parametric (for monogenetic diseases) and non-parametric (for polygenetic diseases, like AUD) linkage analyses are the statistical tests used to test for significant linkage. Linkage is statistically quantified.

Genome-wide association studies

Genome-wide association studies (GWAS) entail the extensive parallel genotyping of several hundreds of thousands up to 2 million genomic markers, simultaneously in cases and controls, typically SNPs, which cover the majority of common genetic variation across the human genome. GWAS are performed in large, generally unrelated, populations in which either qualitative or quantitative phenotypic data are available. Genetic association is identified when an allele or genotype is associated with a phenotype at a specific significance threshold, which takes into account the need for multiple testing and is typically set at p < 5 × 10⁻⁸. It is recommended that large populations are studied to ensure that GWAS are adequately powered. These studies are hypothesis-generating in that they are not based on a priori hypotheses. GWAS are a useful approach for identifying genetic risk variants in complex polygenic disorders (like AUD).

Haplotype

A combination of alleles at different loci on the same chromosome.

Linkage disequilibrium

The excess and complementary deficit of combinations of alleles at two different loci, which is based on rarity of meiotic recombination between loci on the same chromosome. That is, the alleles are tightly correlated.

Locus-based linkage

The detection of locus-to-locus or locus-to-phenotype genetic linkage. This is generally accomplished by detecting a lack of meiotic recombination in families in which alleles at one locus are observed to be in coupling (co-transmitted) or repulsion (not co-transmitted) with alleles at a second locus.

Polygenicity

A model of genetic determinism in which many alleles function in combination to produce a phenotype.

Quantitative trait locus (QTL)

QTL is a section of DNA (the locus) which correlates with variation in a phenotype (the quantitative trait). Usually the QTL is linked to, or contains, the genes which control that phenotype. QTLs are mapped by identifying which molecular markers (such as SNPs) correlate with an observed trait. This is often an early step in identifying and sequencing the actual genes that cause the trait variation.