A systematic gene-based screen of chr4q22–q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts

Studies of alcohol dependence (AD) have consistently found evidence of linkage on chromosome 4q21–q32. A genome-wide linkage scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample also provided its strongest evidence of linkage on chromosome 4q22–q32 using an index of AD se...

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Bibliographic Details
Published in:Human molecular genetics 2010-06, Vol.19 (12), p.2497-2506
Main Authors: Kalsi, Gursharan, Kuo, Po-Hsiu, Aliev, Fazil, Alexander, Jeffry, McMichael, Omari, Patterson, Diana G., Walsh, Dermot, Zhao, Zhongming, Schuckit, Marc, Nurnberger, John, Edenberg, Howard, Kramer, John, Vladimirov, Vladimir, Prescott, Carol A., Dick, Danielle M., Kendler, Kenneth S., Riley, Brien P.
Format: Article
Language:English
Subjects:
Alcoholism - genetics
Alcoholism and acute alcohol poisoning
Association Studies
Biological and medical sciences
Chromosomes, Human, Pair 4 - genetics
Epidermal Growth Factor - genetics
Female
Fundamental and applied biological sciences. Psychology
Genetic Linkage
Genetic Predisposition to Disease
Genetics of eukaryotes. Biological and molecular evolution
Genome-Wide Association Study
Haplotypes
Humans
Intercellular Signaling Peptides and Proteins - genetics
Male
Medical sciences
Molecular and cellular biology
Polymorphism, Single Nucleotide
Toxicology
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Summary:Studies of alcohol dependence (AD) have consistently found evidence of linkage on chromosome 4q21–q32. A genome-wide linkage scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample also provided its strongest evidence of linkage on chromosome 4q22–q32 using an index of AD severity based on the count of DSM-IV AD symptoms (ADSX; LOD = 4.59). We conducted a systematic, gene-centric association study using 518 LD-tagging single nucleotide polymorphisms (SNPs) in the 65 known and predicted genes within the 1-LOD interval surrounding the linkage peak. Case-only regression analysis with the quantitative variable of ADSX was performed in the 562 genetically independent cases; nominal support for association was demonstrated by 32 tagging SNPs in 14 genes. We did not observe study-wide significance, but gene-wise correction for multiple testing with the Nyholt procedure yielded empirical evidence of association with two genes, DKK2 (dickkopf homolog 2) (P = 0.007) and EGF (epidermal growth factor) (P = 0.025) in the IASPSAD sample. Three SNPs in DKK2 (rs427983; rs419558; rs399087) demonstrated empirical significance. Assessment of possible replication in 847 cases of European descent from a large independent sample, the Collaborative Study of the Genetics of Alcoholism, yielded replication for DKK2 but not EGF. We observed genotypic and phenotypic replication for DKK2 with the three SNPs yielding significant association with ADSX in the IASPSAD sample. Haplotype-specific expression measurements in post-mortem tissue samples suggested a functional role for DKK2. This evidence notwithstanding, replication is needed before confidence can be placed in these findings.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddq112