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Thursday, March 25, 2010

A SYSTEMATIC GENE-BASED SCREEN OF CHR4q22-q32 IDENTIFIES ASSOCIATION OF A NOVEL SUSCEPTIBILITY GENE, DKK2, WITH THE QUANTITATIVE TRAIT OF ALCOHOL DEPE


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 alcohol dependence severity based on the count of DSM-IV alcohol dependence 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 tSNPs 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. 3 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 3 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.

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