A New Genomewide Association Meta‐Analysis of Alcohol Dependence. (14th July 2015)

• Record Type: Journal Article
• Authors: Zuo, Lingjun; Tan, Yunlong; Zhang, Xiangyang; Wang, Xiaoping; Krystal, John; Tabakoff, Boris; Zhong, Chunlong; Luo, Xingguang
• Is Part Of: Alcoholism. Volume 39:Number 8(2015:Aug.)
• Page Start: 1388
• Page End: 1395
• Publication Date: 2015-07-14
• Subjects: Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.12786
• Languages: English
• ISSNs: 0145-6008

Abstract

<abstract abstract-type="main" id="acer12786-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="acer12786-sec-0001" sec-type="section"> <title>Background</title> <p>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.</p> </sec> <sec id="acer12786-sec-0002" sec-type="section"> <title>Methods</title> <p>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 <italic>p</italic>‐values. <italic>cis</italic>‐Acting expression of quantitative locus (<italic>cis</italic>‐eQTL) analysis of each risk variant in human tissues and RNA expression analysis of each risk gene in rat brain served as functional validation.</p> </sec> <sec id="acer12786-sec-0003" sec-type="section"> <title>Results</title> <p>In meta‐analysis of European American and European Australian cohorts, we found 10 top‐ranked single nucleotide polymorphisms (SNPs) (<italic>p</italic> < 10<sup>−6</sup>) that were associated with alcohol dependence. They included 6 at <italic>SERINC2</italic> (3.1 × 10<sup>−8</sup> ≤ <italic>p</italic> ≤ 9.6 × 10<sup>−8</sup>), 1 at <italic>STK40</italic> (<italic>p</italic> = 1.3 × 10<sup>−7</sup>), 2 at <italic>KIAA0040</italic> (3.3 × 10<sup>−7</sup> ≤ <italic>p</italic> ≤ 5.2 × 10<sup>−7</sup>), and 1 at <italic>IPO11</italic> (<italic>p</italic> = 6.9 × 10<sup>−7</sup>). In meta‐analysis of 2 African American cohorts, we found 2 top‐ranked SNPs including 1 at <italic>SLC6A11</italic> (<italic>p</italic> = 2.7 × 10<sup>−7</sup>) and 1 at <italic>CBLN2</italic> (<italic>p</italic> = 7.4 × 10<sup>−7</sup>). In meta‐analysis of all 4 cohorts, we found 2 top‐ranked SNPs in <italic>PTP4A1‐PHF3</italic> locus (6.0 × 10<sup>−7</sup> ≤ <italic>p</italic> ≤ 7.2 × 10<sup>−7</sup>). In an African American cohort only, we found 1 top‐ranked SNP at <italic>PLD1</italic> (<italic>p</italic> = 8.3 × 10<sup>−7</sup>; OR = 1.56). Many risk SNPs had positive <italic>cis</italic>‐eQTL signals, and all these risk genes except <italic>KIAA0040</italic> were found to express in both rat and mouse brains.</p> </sec> <sec id="acer12786-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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.</p> </sec> </abstract>