Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene ( AUTS2 ) in the regulation of alcohol consumption

Abstract

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene ( AUTS2 ) was associated with alcohol consumption at genome-wide significance ( P = 4 × 10 −8 to P = 4 × 10 −9 ). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples ( P = 0.026) and significant ( P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila ( P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males

“…14 We recently performed behavioural and neurobiological phenotyping of a Rasgrf2 -/-mouse strain in order to validate and extend upon our GWAS signal implicating RASGRF2 in alcohol consumption. 9 We found a significant reduction in both ethanol intake and preference in male (no significant dif ferences were found in female mice) Rasgrf2 -/-mice relative to wildtype controls, 10 which is in accordance with the male specific GWAS signal. 9 Male Rasgrf2 -/-mice also exhibited de creased mesolimbic dopamine neuron activity relative to con trols, which was accompanied by reduced ethanolinduced dopamine release in the NAcc.…”

“…7,8 The ex ploratory nature of GWAS is proving to be instrumental in fur thering our understanding of the precise mechanisms in the brain that regulate alcoholrelated phenotypes, particularly when combined with extensive followup functional work. In a recent GWAS metaanalysis of alcohol consumption (n > 20 000) we identified a novel malespecific signal in the RASGRF2 gene, 9 and in further support of this, a followup candidatebased analysis in a sample of male adolescents re vealed a significant association between a RASGRF2 polymor phism and frequency of binge drinking episodes.…”

Genetics of Alcohol Use Disorder

“…Benzer bir şekilde "SH3 domain binding protein" (5SH3BP5), "nuclear receptor subfamily 2 group C member 2" (NR2C2), "Plasminogen-like B2" (PLGLB2)'deki SNP'ler ve kromozom 5q'da bulunan IPO11-HRT1A bölgesindeki rs7445832 alkol ve nikotin birlikte bağımlılığı ile ilişkili bulunmuştur (71,77). 12 populasyon temelli örneklemden 26.316 kişinin dahil edildiği bir çalışmada AUT2 rs6943555 alkol tüketimi ile genom boyu anlamlı bulunmuştur (78). Baik ve arkadaşları 1.721 erkekten oluşan örneklemde kromozom 12q24'teki bazı SNP'leri yine alkol tüketimi ile genom boyu anlamlı bulmuşlardır.…”

Les addictions sous l’angle de la génétique

“…Cette étude a montré une association de la dépendance à l'alcool avec des marqueurs couvrant le gène GABRA2 (GABA A receptor, a2), qui code pour le récepteur 2 du GABA (g-aminobutyric acid), en accord avec l'hypothèse neurobiologique des effets de l'alcool [19]. L'année suivante, l'analyse GWAS de 26 316 personnes a identifié une association entre le variant rs6943555 du gène AUTS2 (autism susceptibility candidate 2), un possible régula-teur transcriptionnel neuronal exprimé dans plusieurs régions du cerveau, initialement identifié comme un gène de susceptibilité à l'autisme, et la consommation d'alcool, observation qui a été confirmée par l'analyse d'une deuxième cohorte de 21 185 individus [20]. L'allèle mineur A du rs6943555 est associé à une réduction de 5,5 % de la consommation d'alcool.…”

“…Cet allèle a un effet biologique, puisqu'il diminue la production de l'ARN messager AUTS2 de 20 à 50 % selon qu'il est présent à l'état hété-rozygote ou homozygote. Enfin, l'invalidation de ce gène dans un modèle animal réduit la sensibilité à l'alcool de ces animaux [20]. Un consortium allemand a montré, par des analyses pangénomiques, une association entre la dépendance à l'alcool et des polymorphismes dans le cluster de gènes codant pour les enzymes alcool déshydrogé-nases, dont ADH1B et ADH1C, chez 487 patients dépendants comparés à 1 358 sujets contrôles.…”