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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