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Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence.

ABSTRACT: Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying P-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent P-value thresholds of 0.01-0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with P?

SUBMITTER: Yan J

PROVIDER: S-EPMC3664249 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence.

Yan Jia J Aliev Fazil F Webb Bradley T BT Kendler Kenneth S KS Williamson Vernell S VS Edenberg Howard J HJ Agrawal Arpana A Kos Mark Z MZ Almasy Laura L Nurnberger John I JI Schuckit Marc A MA Kramer John R JR Rice John P JP Kuperman Samuel S Goate Alison M AM Tischfield Jay A JA Porjesz Bernice B Dick Danielle M DM

Addiction biology 20130130 4

Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We create ...[more]

PMID: 23362995

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Project description:OBJECTIVE:To report the genome-wide significant and/or replicable risk variants for alcohol dependence and explore their potential biological functions. METHODS:We searched in PubMed for all genome-wide association studies (GWASs) of alcohol dependence. The following three types of the results were extracted: genome-wide significant associations in an individual sample, the combined samples, or the meta-analysis (p?<?5?×?10(-8) ); top-ranked associations in an individual sample (p?<?10(-5) ) that were nominally replicated in other samples (p?<?.05); and nominally replicable associations across at least three independent GWAS samples (p?<?.05). These results were meta-analyzed. cis-eQTLs in human, RNA expression in rat and mouse brains and bioinformatics properties of all of these risk variants were analyzed. RESULTS:The variants located within the alcohol dehydrogenase (ADH) cluster were significantly associated with alcohol dependence at the genome-wide level (p?<?5?×?10(-8) ) in at least one sample. Some associations with the ADH cluster were replicable across six independent GWAS samples. The variants located within or near SERINC2, KIAA0040, MREG-PECR or PKNOX2 were significantly associated with alcohol dependence at the genome-wide level (p?<?5?×?10(-8) ) in meta-analysis or combined samples, and these associations were replicable across at least one sample. The associations with the variants within NRD1, GPD1L-CMTM8 or MAP3K9-PCNX were suggestive (5?×?10(-8) ?<?p?<?10(-5) ) in some samples, and nominally replicable in other samples. The associations with the variants at HTR7 and OPA3 were nominally replicable across at least three independent GWAS samples (10(-5) ?<?p?<?.05). Some risk variants at the ADH cluster, SERINC2, KIAA0040, NRD1, and HTR7 had potential biological functions. CONCLUSION:The most robust risk locus was the ADH cluster. SERINC2, KIAA0040, NRD1, and HTR7 were also likely to play important roles in alcohol dependence. PKNOX2, MREG, PECR, GPD1L, CMTM8, MAP3K9, PCNX, and OPA3 might play less important roles in risk for alcohol dependence based on the function analysis. This conclusion will significantly contribute to the post-GWAS follow-up studies on alcohol dependence.

Project description:Alcohol dependence is a serious and common public health problem. It is well established that genetic factors play a major role in the development of this disorder. Identification of genes that contribute to alcohol dependence will improve our understanding of the mechanisms that underlie this disorder.To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and a follow-up study in a population of German male inpatients with an early age at onset.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 genes that had also shown expression changes in rat brains after long-term alcohol consumption were selected for the follow-up step.Five university hospitals in southern and central Germany.The GWAS included 487 male inpatients with alcohol dependence as defined by the DSM-IV and an age at onset younger than 28 years and 1358 population-based control individuals. The follow-up study included 1024 male inpatients and 996 age-matched male controls. All the participants were of German descent.Significant association findings in the GWAS and follow-up study with the same alleles.The GWAS produced 121 SNPs with nominal P < 10(-4). These, together with 19 additional SNPs from homologues 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, 2 closely linked intergenic SNPs met genome-wide significance (rs7590720, P = 9.72 x 10(-9); rs1344694, P = 1.69 x 10(-8)). They are located on chromosome region 2q35, which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including the CDH13 and ADH1C genes, that have been reported to be associated with alcohol dependence.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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Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence.

Publications

Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence.

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