Genome‐wide association discoveries of alcohol dependence. (November 2014)

• Record Type: Journal Article
• Authors: Zuo, Lingjun; Lu, Lingeng; Tan, Yunlong; Pan, Xinghua; Cai, Yiqiang; Wang, Xiaoping; Hong, Jiang; Zhong, Chunlong; Wang, Fei; Zhang, Xiang‐Yang; Vanderlinden, Lauren A.; Tabakoff, Boris; Luo, Xingguang
• Is Part Of: American journal on addictions. Volume 23:Number 6(2014:Nov./Dec.)
• Page Start: 526
• Page End: 539
• Publication Date: 2014-11
• Subjects: Substance abuse -- Periodicals; Substance abuse -- Treatment -- Periodicals; 616.86005
• DOI: 10.1111/j.1521-0391.2014.12147.x
• Languages: English
• ISSNs: 1055-0496

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ajad12147-sec-0001" sec-type="section"> <title>Objective</title> <p>To report the genome‐wide significant and/or replicable risk variants for alcohol dependence and explore their potential biological functions.</p> </sec> <sec id="ajad12147-sec-0002" sec-type="section"> <title>Methods</title> <p>We searched in PubMed for all genome‐wide association studies (GWASs) of alcohol dependence. The following three types of the results were extracted: genome‐wide significant associations in an individual sample, the combined samples, or the meta‐analysis (<italic>p</italic> < 5 × 10<sup>−8</sup>); top‐ranked associations in an individual sample (<italic>p</italic> < 10<sup>−5</sup>) that were nominally replicated in other samples (<italic>p</italic> < .05); and nominally replicable associations across at least three independent GWAS samples (<italic>p</italic> < .05). These results were meta‐analyzed. <italic>cis</italic>‐eQTLs in human, RNA expression in rat and mouse brains and bioinformatics properties of all of these risk variants were analyzed.</p> </sec> <sec id="ajad12147-sec-0003" sec-type="section"> <title>Results</title> <p>The variants located within the alcohol dehydrogenase (ADH) cluster were significantly associated with alcohol dependence at the genome‐wide level (<italic>p</italic> < 5 × 10<sup>−8</sup>) in at least one sample. Some associations with the <italic>ADH</italic> cluster were replicable across six independent GWAS samples. The variants located within or near <italic>SERINC2</italic>, <italic>KIAA0040</italic>, <italic>MREG–PECR</italic> or <italic>PKNOX2</italic> were significantly associated with alcohol dependence at the genome‐wide level (<italic>p</italic> < 5 × 10<sup>−8</sup>) in meta‐analysis or combined samples, and these associations were replicable across at least one sample. The associations with the variants within <italic>NRD1</italic>, <italic>GPD1L–CMTM8</italic> or <italic>MAP3K9–PCNX</italic> were suggestive (5 × 10<sup>−8</sup> < <italic>p</italic> < 10<sup>−5</sup>) in some samples, and nominally replicable in other samples. The associations with the variants at <italic>HTR7</italic> and <italic>OPA3</italic> were nominally replicable across at least three independent GWAS samples (10<sup>−5</sup> < <italic>p</italic> < .05). Some risk variants at the <italic>ADH</italic> cluster, <italic>SERINC2</italic>, <italic>KIAA0040</italic>, <italic>NRD1</italic>, and <italic>HTR7</italic> had potential biological functions.</p> </sec> <sec id="ajad12147-sec-0004" sec-type="section"> <title>Conclusion</title> <p>The most robust risk locus was the <italic>ADH</italic> cluster. <italic>SERINC2</italic>, <italic>KIAA0040</italic>, <italic>NRD1</italic>, and <italic>HTR7</italic> were also likely to play important roles in alcohol dependence. <italic>PKNOX2</italic>, <italic>MREG, PECR</italic>, <italic>GPD1L</italic>, <italic>CMTM8</italic>, <italic>MAP3K9</italic>, <italic>PCNX</italic>, and <italic>OPA3</italic> might play less important roles in risk for alcohol dependence based on the function analysis. This conclusion will significantly contribute to the post‐GWAS follow‐up studies on alcohol dependence. (Am J Addict 2014;23:526–539)</p> </sec> </abstract>