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Novel QTL at chromosome 6p22 for alcohol consumption: Implications for the genetic liability of alcohol use disorders.

ABSTRACT: Linkage studies of alcoholism have implicated several chromosome regions, leading to the successful identification of susceptibility genes, including ADH4 and GABRA2 on chromosome 4. Quantitative endophenotypes that are potentially closer to gene action than clinical endpoints offer a means of obtaining more refined linkage signals of genes that predispose alcohol use disorders (AUD). In this study we examine a self-reported measure of the maximum number of drinks consumed in a 24-hr period (abbreviated Max Drinks), a significantly heritable phenotype (h(2) ?=?0.32?±?0.05; P?=?4.61?×?10(-14)) with a strong genetic correlation with AUD (?g ?=?0.99?±?0.13) for the San Antonio Family Study (n?=?1,203). Genome-wide SNPs were analyzed using variance components linkage methods in the program SOLAR, revealing a novel, genome-wide significant QTL (LOD?=?4.17; P?=?5.85?×?10(-6)) for Max Drinks at chromosome 6p22.3, a region with a number of compelling candidate genes implicated in neuronal function and psychiatric illness. Joint analysis of Max Drinks and AUD status shows that the QTL has a significant non-zero effect on diagnosis (P?=?4.04?×?10(-3)), accounting for 8.6% of the total variation. Significant SNP associations for Max Drinks were also identified at the linkage region, including one, rs7761213 (P?=?2.14?×?10(-4)), obtained for an independent sample of Chinese families. Thus, our study identifies a potential risk locus for AUD at 6p22.3, with significant pleiotropic effects on the heaviness of alcohol consumption that may not be population specific.

SUBMITTER: Kos MZ

PROVIDER: S-EPMC4172449 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Novel QTL at chromosome 6p22 for alcohol consumption: Implications for the genetic liability of alcohol use disorders.

Kos Mark Z MZ Glahn David C DC Carless Melanie A MA Olvera Rene R McKay D Reese DR Quillen Ellen E EE Gelernter Joel J Chen Xiang-Ding XD Deng Hong-Wen HW Kent Jack W JW Dyer Thomas D TD Göring Harald H H HH Curran Joanne E JE Duggirala Ravi R Blangero John J Almasy Laura L

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20140401 4

Linkage studies of alcoholism have implicated several chromosome regions, leading to the successful identification of susceptibility genes, including ADH4 and GABRA2 on chromosome 4. Quantitative endophenotypes that are potentially closer to gene action than clinical endpoints offer a means of obtaining more refined linkage signals of genes that predispose alcohol use disorders (AUD). In this study we examine a self-reported measure of the maximum number of drinks consumed in a 24-hr period (abb ...[more]

PMID: 24692236

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Project description:Humans show sex differences related to alcohol use disorders (AUD). Animal model research has the potential to provide important insight into how sex differences affect alcohol consumption, particularly because female animals frequently drink more than males. In previous work, inbred strains of the selectively bred alcohol-preferring (P) and non-preferring (NP) rat lines revealed a highly significant quantitative trait locus (QTL) on rat chromosome 4, with a logarithm of the odds score of 9.2 for alcohol consumption. Recently, interval-specific congenic strains (ISCS) were developed by backcrossing the congenic P.NP line to inbred P (iP) rats to further refine the chromosome 4 QTL region. Two ISCS sub-strains, ISCS-A and ISCS-B, were obtained with a narrowed QTL, where the smallest region of overlap consisted of 8.9 Mb in ISCS-B. Interestingly, we found that females from both ISCS lines consumed significantly less alcohol than female iP controls (p < 0.05), while no differences in alcohol consumption were observed between male ISCS and iP controls. RNA-sequencing was performed on the nucleus accumbens of alcohol-naïve female ISCS-B and iP rats, which revealed differentially expressed genes (DEG) with greater than 2-fold change and that were functionally relevant to behavior. These DEGs included down-regulation of Oxt, Asb4, Gabre, Gabrq, Chat, Slc5a7, Slc18a8, Slc10a4, and Ngfr, and up-regulation of Ttr, Msln, Mpzl2, Wnt6, Slc17a7, Aldh1a2, and Gstm2. Pathway analysis identified significant alterations in gene networks controlling nervous system development and function, as well as cell signaling, GABA and serotonin receptor signaling and G-protein coupled receptor signaling. In addition, ?-estradiol was identified as the most significant upstream regulator. The expression levels of estrogen-responsive genes that mapped to the QTL interval and have been previously associated with alcohol consumption were measured using RT-qPCR. We found that expression of the Adcyap1r1 gene, encoding the pituitary adenylate cyclase-activating polypeptide type 1 (PAC1) receptor, was upregulated in female ISCS-B compared to female iP controls, while no differences were exhibited in males. In addition, sequence variants in the Adcyap1r1 promoter region showed a differential response to estrogen stimulation in vitro. These findings demonstrate that rat chromosome 4 QTL contains genetic variants that respond to estrogen and are associated with female alcohol consumption.

Project description:BackgroundIndividuals differ in their sensitivity to alcohol's physiological effects, including blacking and passing out. Blackouts are periods of impaired memory formation when an individual engages in activities they later cannot recall, while passing out results in loss of consciousness.MethodsThe sample consisted of 3,292 adult twins from the Australian Twin Registry. Univariate twin analyses were conducted to examine the contributions of genetic and environmental influences to blacking and passing out occurrence and susceptibility (accounting for frequency of intoxication). Evidence for shared etiology of susceptibility to blacking and passing out was examined using bivariate twin analyses.ResultsAlthough blacking and passing out were strongly associated (odds ratio (OR) = 4.45, 95% confidence interval (CI): [3.85, 5.14]), the genetic epidemiology was quite different. Genetic (43%) and nonshared environmental (57%) influences contributed to liability for blackout occurrence. For passing out occurrence, there was evidence of sex differences. Among men, genetic (32%) and nonshared environmental (68%) influences contributed, whereas among women, there were shared (29%) and nonshared environmental (72%) influences. After accounting for frequency of intoxication, genetic influences on blackout susceptibility remained significant; in contrast, only nonshared environmental influences were significant for passing out susceptibility. There was evidence for overlapping genetic and nonshared environmental factors influencing susceptibility to blacking and passing out among men; among women, there were overlapping nonshared environmental influences.ConclusionsBlacking and passing out are 2 common sedative-like effects of heavy drinking, and people differ considerably in their susceptibility to these effects. This study suggests that differences in blackout susceptibility can be explained by genetic factors in both men and women, while differences in susceptibility to pass out after consuming alcohol may be attributable to environmental influences, particularly among women. These environmental factors may include changing social and cultural norms about alcohol use, drinking context, and the type(s) of alcohol consumed.

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Novel QTL at chromosome 6p22 for alcohol consumption: Implications for the genetic liability of alcohol use disorders.

Publications

Novel QTL at chromosome 6p22 for alcohol consumption: Implications for the genetic liability of alcohol use disorders.

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