https://scholars.lib.ntu.edu.tw/handle/123456789/521115
標題: | 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 | 作者: | Kalsi G. PO-HSIU KUO Aliev F. Alexander J. McMichael O. Patterson D.G. Walsh D. Zhao Z. Schuckit M. Nurnberger J. Edenberg H. Kramer J. Vladimirov V. Prescott C.A. Dick D.M. Kendler K.S. HSIU-PO KUO |
公開日期: | 2010 | 卷: | 19 | 期: | 12 | 起(迄)頁: | 2497-2506 | 來源出版物: | Human Molecular Genetics | 摘要: | 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. ? The Author 2010. Published by Oxford University Press. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-77955312372&doi=10.1093%2fhmg%2fddq112&partnerID=40&md5=33c332276d2eb6d40560bc7455543abe https://scholars.lib.ntu.edu.tw/handle/123456789/521115 |
ISSN: | 0964-6906 | DOI: | 10.1093/hmg/ddq112 | SDG/關鍵字: | adh gene; alcoholism; article; chromosome 4q; controlled study; dkk2 gene; egf gene; gene; gene identification; genetic association; genetic risk; haplotype; human; Ireland; major clinical study; priority journal; regression analysis; risk assessment; single nucleotide polymorphism; Alcoholism; Chromosomes, Human, Pair 4; Epidermal Growth Factor; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Haplotypes; Humans; Intercellular Signaling Peptides and Proteins; Linkage (Genetics); Male; Polymorphism, Single Nucleotide |
顯示於: | 流行病學與預防醫學研究所 |
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