Addictions Biology: Haplotype-Based Analysis for 130 Candidate Genes on a Single Array

Hodgkinson, Colin A.; Yuan, Qiaoping; Xu, Ke; Shen, Pei‐Hong; Heinz, Elizabeth; Lobos, Elizabeth A.; Binder, Elke; Cubells, Joe; Ehlers, Cindy L.; Gelernter, Joel; Mann, J. John; Riley, Brien P.; Roy, Alec; Tabakoff, Boris; Todd, Richard D.; Zhou, Zhifeng; Goldman, David

doi:10.1093/alcalc/agn032

Cited by 224 publications

(283 citation statements)

References 46 publications

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“…In our analyses of alcohol consumption, P values for these two SNPs were ≥0.5 in all analyses. We also examined association data within ±50 kb of 121 candidate autosomal genes for addictions (alcoholism, other addictions, and disorders of mood and anxiety) listed in a recent review (14). The SNP with the lowest P value for each of the 121 genes is shown in Table S6.…”

Section: Resultsmentioning

confidence: 99%

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

Schumann

Coin

Lourdusamy

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

259

258

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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.

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Section: Resultsmentioning

confidence: 99%

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

Schumann

Coin

Lourdusamy

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

259

258

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“…The samples were also genotyped for 150 ancestry informative markers (Hodgkinson et al, 2008), from which individual ethnic factor scores were computed (Supplementary Materials). The four ethnic factor scores explaining the highest variance (Table 2) were included as covariates in all genetic analyses to control population stratification.…”

Section: Genotypingmentioning

confidence: 99%

Effect of GABRA2 Genotype on Development of Incentive-Motivation Circuitry in a Sample Enriched for Alcoholism Risk

Heitzeg

Villafuerte

Weiland

et al. 2014

Neuropsychopharmacol

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Heightened reactivity of the incentive-motivation system has been proposed to underlie adolescent-typical risky behaviors, including problem alcohol involvement. However, even in adolescence considerable individual variation in these behaviors exists, which may have genetic underpinnings and be related to variations in risk for later alcohol use disorder (AUD). Variants in GABRA2 have been associated with adult alcohol dependence as well as phenotypic precursors, including impulsiveness and externalizing behaviors. We investigated the impact of GABRA2 on the developmental trajectory of nucleus accumbens (NAcc) activation during anticipation of monetary reward from childhood to young adulthood. Functional MRI during a monetary incentive delay task was collected in 175 participants, with the majority (n ¼ 151) undergoing repeated scanning at 1-to 2-year intervals. One group entered the study at age 8-13 years (n ¼ 76) and another entered at age 18-23 years (n ¼ 99). Most participants were children of alcoholics (79%) and thus at heightened risk for AUD. A total of 473 sessions were completed, covering ages 8-27 years. NAcc activation was heightened during adolescence compared with childhood and young adulthood. GABRA2 genotype (SNP rs279858) was associated with individual differences in NAcc activation specifically during adolescence, with the minor allele (G) associated with greater activation. Furthermore, NAcc activation mediated an effect of genotype on alcohol problems (n ¼ 104). This work demonstrates an impact of GABRA2 genotype on incentive-motivation neurocircuitry in adolescence, with implications for vulnerability to alcoholism. These findings represent an important step toward understanding the genetic and neural basis of individual differences in how risk for addiction unfolds across development.

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“…Ancestry informative markers (AIMs, n ¼ 2500) were extracted from the Illumina array to calculate ancestral proportions for all study participants (missing data for five subjects). Using methods described previously for an AIMs panel including 186 markers (Hodgkinson et al, 2008), which were not available for our data set, the ancestry assessment identified six ethnic factors (Africa, Europe, Asia, Far East Asia, Oceania, and Americas). For subjects who self-reported as Caucasian or white, the mean European factor score was 0.94 (median, 0.96) and the mean African factor score was 0.013 (median, 0.001).…”

Section: Human Association Studymentioning

confidence: 99%

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

Huang

Schwandt

Chester

et al. 2014

Neuropsychopharmacol

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Alcohol withdrawal is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a cochaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity.

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Addictions Biology: Haplotype-Based Analysis for 130 Candidate Genes on a Single Array

Cited by 224 publications

References 46 publications

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

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

Effect of GABRA2 Genotype on Development of Incentive-Motivation Circuitry in a Sample Enriched for Alcoholism Risk

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

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