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

Gursharan Kalsi, Po Hsiu Kuo, Fazil Aliev, Jeffry Alexander, Omari McMichael, Diana G. Patterson, Dermot Walsh, Zhongming Zhao, Marc Schuckit, John Jr Nurnberger, Howard Edenberg, John Kramer, Vladimir Vladimirov, Carol A. Prescott, Danielle M. Dick, Kenneth S. Kendler, Brien P. Riley

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 5 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 5 0.007) and EGF (epidermal growth factor) (P 5 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.

Original languageEnglish (US)
Article numberddq112
Pages (from-to)2497-2506
Number of pages10
JournalHuman molecular genetics
Volume19
Issue number12
DOIs
StatePublished - Jun 15 2010

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Alcoholism
Single Nucleotide Polymorphism
Genes
Epidermal Growth Factor
Chromosomes
Diagnostic and Statistical Manual of Mental Disorders
Haplotypes
Regression Analysis
Genome

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

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. / Kalsi, Gursharan; Kuo, Po Hsiu; Aliev, Fazil; Alexander, Jeffry; McMichael, Omari; Patterson, Diana G.; Walsh, Dermot; Zhao, Zhongming; Schuckit, Marc; Nurnberger, John Jr; Edenberg, Howard; Kramer, John; Vladimirov, Vladimir; Prescott, Carol A.; Dick, Danielle M.; Kendler, Kenneth S.; Riley, Brien P.

In: Human molecular genetics, Vol. 19, No. 12, ddq112, 15.06.2010, p. 2497-2506.

Research output: Contribution to journalArticle

Kalsi, G, Kuo, PH, Aliev, F, Alexander, J, McMichael, O, Patterson, DG, Walsh, D, Zhao, Z, Schuckit, M, Nurnberger, JJ, Edenberg, H, Kramer, J, Vladimirov, V, Prescott, CA, Dick, DM, Kendler, KS & Riley, BP 2010, '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', Human molecular genetics, vol. 19, no. 12, ddq112, pp. 2497-2506. https://doi.org/10.1093/hmg/ddq112
Kalsi, Gursharan ; Kuo, Po Hsiu ; Aliev, Fazil ; Alexander, Jeffry ; McMichael, Omari ; Patterson, Diana G. ; Walsh, Dermot ; Zhao, Zhongming ; Schuckit, Marc ; Nurnberger, John Jr ; Edenberg, Howard ; Kramer, John ; Vladimirov, Vladimir ; Prescott, Carol A. ; Dick, Danielle M. ; Kendler, Kenneth S. ; Riley, Brien P. / 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. In: Human molecular genetics. 2010 ; Vol. 19, No. 12. pp. 2497-2506.
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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 5 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 5 0.007) and EGF (epidermal growth factor) (P 5 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.",
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AU - McMichael, Omari

AU - Patterson, Diana G.

AU - Walsh, Dermot

AU - Zhao, Zhongming

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AU - Kramer, John

AU - Vladimirov, Vladimir

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