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A New Genomewide Association Meta‐Analysis of Alcohol Dependence
Author(s) -
Zuo Lingjun,
Tan Yunlong,
Zhang Xiangyang,
Wang Xiaoping,
Krystal John,
Tabakoff Boris,
Zhong Chunlong,
Luo Xingguang
Publication year - 2015
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12786
Subject(s) - meta analysis , cohort , single nucleotide polymorphism , expression quantitative trait loci , oncology , cohort study , genetics , genome wide association study , proband , medicine , biology , genotype , gene , mutation
Background Conventional meta‐analysis based on genetic markers may be less powerful for heterogeneous samples. In this study, we introduced a new meta‐analysis for 4 genomewide association studies on alcohol dependence that integrated the information of putative causal variants. Methods A total of 12,481 subjects in 4 independent cohorts were analyzed, including 1 European American cohort (1,409 cases with alcohol dependence and 1,518 controls), 1 European Australian cohort (a total of 6,438 family subjects with 1,645 probands), 1 African American cohort from SAGE + COGA (681 cases and 508 controls), and 1 African American cohort from Yale (1,429 cases and 498 controls). The genomewide association analysis was conducted for each cohort, and then, a new meta‐analysis was performed to derive the combined p ‐values. cis ‐Acting expression of quantitative locus ( cis ‐eQTL) analysis of each risk variant in human tissues and RNA expression analysis of each risk gene in rat brain served as functional validation. Results In meta‐analysis of European American and European Australian cohorts, we found 10 top‐ranked single nucleotide polymorphisms (SNPs) ( p < 10 −6 ) that were associated with alcohol dependence. They included 6 at SERINC 2 (3.1 × 10 −8 ≤ p ≤ 9.6 × 10 −8 ), 1 at STK 40 ( p = 1.3 × 10 −7 ), 2 at KIAA 0040 (3.3 × 10 −7 ≤ p ≤ 5.2 × 10 −7 ), and 1 at IPO 11 ( p = 6.9 × 10 −7 ). In meta‐analysis of 2 African American cohorts, we found 2 top‐ranked SNP s including 1 at SLC 6A11 ( p = 2.7 × 10 −7 ) and 1 at CBLN 2 ( p = 7.4 × 10 −7 ). In meta‐analysis of all 4 cohorts, we found 2 top‐ranked SNP s in PTP 4A1‐ PHF 3 locus (6.0 × 10 −7 ≤ p ≤ 7.2 × 10 −7 ). In an African American cohort only, we found 1 top‐ranked SNP at PLD 1 ( p = 8.3 × 10 −7 ; OR = 1.56). Many risk SNP s had positive cis ‐eQTL signals, and all these risk genes except KIAA 0040 were found to express in both rat and mouse brains. Conclusions We found multiple genes that were significantly or suggestively associated with alcohol dependence. They are among the most appropriate for follow‐up as contributors to risk for alcohol dependence.