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

Abstract

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.

Genome-wide association studies of maximum number of drinks

“…Previous genome linkage study identified chromosome 4 in the vicinity of the alcohol dehydrogenase (ADH) gene cluster (Saccone et al, 2000) while additional analyses of chromosome 4 showed modest evidence for both linkage and association. Recently, SNP rs7671475 in NDST4 showed a borderline association with AD (Kalsi et al, 2010). …”

Association Study ofDKK2Polymorphisms with Alcohol Dependence and Alcohol-Related Harm

“…Another study showed that through mRNA level measurement, such down-regulation of NF-jB was observed in the postmortem brain samples of chronic alcoholic patients (Okvist et al, 2007). These findings suggested a possible mechanism of how DKK2 might affect the risk level of alcoholism, which was also supported by the expression results from the study conducted with the Irish population (Kalsi et al, 2010). In particular, the researchers in the study reported that the haplotype consisting of rs427983, rs419558, rs419764, and rs447372 was associated with higher AD symptoms index (ADSX) and also led to a lower expression level of DKK2.…”

“…We suspect that rs17037102 was not studied in the previous report (Kalsi et al, 2010) because the SNP is considerably rarer in Caucasian than in Asian, according to the NCBI database. Although their study utilized 1,238 subjects of Irish descent, the subjects consisted of 591 probands, 620 affected siblings, and 27 first-degree relatives from 10 complex families, thus limiting the genetic diversity among them and omitting rs17037102 from the analysis.…”

“…Therefore, the genomic region of 4q22-q32, in which ADH is located, is of significant interest in the AD-related study. A recent study conducted a gene-based screening of 4q22-q32 region and identified a novel AD susceptibility gene, Dickkopf WNT signaling pathway inhibitor (DKK2), in Irish population (Kalsi et al, 2010). The study revealed that 3 single-nucleotide polymorphisms (SNPs) of DKK2, rs4279832, rs419558, and rs399087, were significantly associated with AD.…”

NCK2 Is Significantly Associated with Opiates Addiction in African‐Origin Men

“…GABRA2, CHRM2, ADH4, PKNOX2, GABRG3, TAS2R16, SNCA, OPRK1, and PDYN have all been associated with alcohol dependence with various degrees of replication [6–21]. Associations of other candidate alcohol dependence genes, such as KIAA0040, ALDH1A1, and MANBA [18, 20, 22–25], remain to be confirmed. Several groups reported CHRNA5, CHRNA3, CHRNB4, and CSMD1 to be associated with nicotine dependence [26–34].…”