A genome wide search for alcoholism susceptibility genes

Hill, Shirley Y.; Shen, Sa; Zezza, Nicholas; Hoffman, Edward L.; Perlin, Mark W.; Allan, William P.

doi:10.1002/ajmg.b.30013

Cited by 96 publications

(119 citation statements)

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“…Probands and relatives with mental retardation or physical illness precluding participation were excluded. Complete details regarding participant selection may be seen in Hill et al [2004].…”

Section: Ascertainment and Diagnostic Assessmentmentioning

confidence: 99%

Section: Genotypingmentioning

confidence: 99%

“…PCR conditions were as described in Hill et al [2004]. Genotypes available for the present set of subjects included 25 STRs on Chromosome 11 that had been completed for a genome wide linkage study previously published [Hill et al, 2004]. Although significant IBD sharing had not been found in that effort, these genotypes were included with the present initiative to provide an opportunity for conducting a multipoint linkage analysis.…”

Section: Genotypingmentioning

confidence: 99%

“…Genotyping was available for a total of 21 STRs that had been part of our genome-wide analysis [Hill et al, 2004] and the 4 SNPs on Chromosome 11 that were the focus of interest. In order to eliminate markers in statistically significant LD with those within the DRD2 gene, all markers were evaluated for pair-wise LD using the ldmax routine from the GOLD software package [Abecasis and Cookson, 2000].…”

Section: Linkage Analysesmentioning

confidence: 99%

“…To investigate this hypothesis the A-241G and -141C Ins/Del polymorphisms were genotyped in the same set of families. Because these families had been included in a genome-wide linkage analysis [Hill et al, 2004], genotypes for microsatellites were available for further analyses. Also, previous genotyping had been done for the TaqI A and CA repeat polymorphisms from earlier work in our laboratory [Neiswanger et al, 1995;Hill et al, 1999] for a subset of individuals for whom the C957T, A-241G, and -141C Ins/Del genotyping was performed.…”

Section: Introductionmentioning

confidence: 99%

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Dopaminergic mutations: Within‐family association and linkage in multiplex alcohol dependence families

Hill

Hoffman

Zezza

et al. 2008

American J of Med Genetics Pt B

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Animal and human studies of addiction indicate that the D2 dopamine receptor (DRD2) plays a critical role in the mechanism of drug reward. D2 receptor density in the brains of alcoholics has been shown to be reduced relative to controls. Previous studies of DRD2 in association with alcohol dependence using variation in the TaqI A locus were highly controversial. Recently, a synonymous mutation, C957T, in the coding region of the human DRD2 gene has been identified which appears to have functional effects including alteration in receptor availability. In order to determine if susceptibility to alcohol dependence (AD) within multiplex alcohol dependence families would be altered by the C957T in the coding region of the D2 gene, within-family association was studied in members of Caucasian multiplex alcohol dependence families. Members of control families with no personal alcohol or substance dependence history were included for case/control comparisons. Analyses performed to detect within-family association showed evidence favoring an association for the C957T polymorphism (P = 0.038). Linkage analyses of polymorphisms in this region showed that only the C957T locus remained of interest (P = 0.015). Evidence for the C957T T allele having a role in AD susceptibility at the population level using a case/control comparison was statistically marginal (P = 0.062), but was consistent with the family data results. These results support a role for DRD2 as a susceptibility gene for alcohol dependence within multiplex families at high risk for developing alcohol dependence.

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Section: Ascertainment and Diagnostic Assessmentmentioning

confidence: 99%

Section: Genotypingmentioning

confidence: 99%

Section: Genotypingmentioning

confidence: 99%

Section: Linkage Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dopaminergic mutations: Within‐family association and linkage in multiplex alcohol dependence families

Hill

Hoffman

Zezza

et al. 2008

American J of Med Genetics Pt B

Self Cite

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Genome-wide Association Study of Alcohol Dependence

Treutlein¹,

Cichon²,

Ridinger³

et al. 2009

Arch Gen Psychiatry

367

318

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Context Identification of genes contributing to alcohol dependence will improve our understanding of the mechanisms underlying this disorder. Objective To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and follow-up study in a population of German male inpatients with an early age at onset. Design The GWAS included 487 male inpatients with DSM-IV alcohol dependence with an age at onset below 28 years and 1,358 population based control individuals. The follow-up study included 1,024 male inpatients and 996 age-matched male controls. All subjects were of German descent. The GWAS tested 524,396 single nucleotide polymorphisms (SNPs). All SNPs with p<10-4 were subjected to the follow-up study. In addition, nominally significant SNPs from those genes that had also shown expression changes in rat brains after chronic alcohol consumption were selected for the follow-up step. Results The GWAS produced 121 SNPs with nominal p<10-4. These, together with 19 additional SNPs from homologs of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, two closely linked intergenic SNPs met genome-wide significance (rs7590720 p=9.72×10-9; rs1344694 p=1.69×10-8). They are located on chromosome 2q35, a region which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including CDH13 and ADH1C genes which have been reported to be associated with alcohol dependence. Conclusion This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.

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