Genome-Wide Association Study of Alcohol Dependence Implicates KIAA0040 on Chromosome 1q

Abstract

Previous studies using SAGE (the Study of Addiction: Genetics and Environment) and COGA (the Collaborative Study on the Genetics of Alcoholism) genome-wide association study (GWAS) data sets reported several risk loci for alcohol dependence (AD), which have not yet been well replicated independently or confirmed by functional studies. We combined these two data sets, now publicly available, to increase the study power, in order to identify replicable, functional, and significant risk regions for AD. A total of 4116 subjects (1409 European-American (EA) cases with AD, 1518 EA controls, 681 African-American (AA) cases, and 508 AA controls) underwent association analysis. An additional 443 subjects underwent expression quantitative trait locus (eQTL) analysis. Genome-wide association analysis was performed in EAs to identify significant risk genes. All available markers in the genome-wide significant risk genes were tested in AAs for associations with AD, and in six HapMap populations and two European samples for associations with gene expression levels. We identified a unique genome-wide significant geneFKIAA0040Fthat was enriched with many replicable risk SNPs for AD, all of which had significant cis-acting regulatory effects. The distributions of Àlog(p) values for SNP-disease and SNP-expression associations for all markers in the TNN-KIAA0040 region were consistent across EAs, AAs, and five HapMap populations (0.369prp0.824; 2.8 Â 10 À9 ppp0.032). The most significant SNPs in these populations were in high LD, concentrating in KIAA0040. Finally, expression of KIAA0040 was significantly (1.2 Â 10 À11 ppp1.5 Â 10 À6) associated with the expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with AD. We concluded that KIAA0040 might harbor a causal variant for AD and thus might directly contribute to risk for this disorder. KIAA0040 might also contribute to the risk of AD via neurotransmitter systems or metabolic pathways that have previously been implicated in the pathophysiology of AD. Alternatively, KIAA0040 might regulate the risk via some interactions with flanking genes TNN and TNR. TNN is involved in neurite outgrowth and cell migration in hippocampal explants, and TNR is an extracellular matrix protein expressed primarily in the central nervous system.

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

“…Another voltage gated K + channel identified through GWAS explora tion was KCND2 that encodes for the K V 4.2 channel that regulate rapidly inactivating Atype K + current (I A ). A SNP in KCND2 was found in the top ten SNPs associated with alcohol and nicotine dependence and alcohol dependence alone [104][105][106]. And finally, an SNP in the KCNMA1 gene, which encodes the α1 subunit of K Ca 1.1 was significantly associated with the develop ment of alcohol dependence [89,90] and subjective response to alcohol [107].…”

Rare SERINC2 variants are specific for alcohol dependence in individuals of European descent

“…Interestingly, the NKAIN1 gene at 1p35.2, which encodes the member protein NKAIN1 from the same family as NKAIN2, is closely located to the serine incorporator 2 gene ( SERINC2 ) that was a top-ranked risk gene (p=2.3×10 −7 ) for alcohol dependence reported by one of our recent GWASs [9]. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF) < 0.05] in the NKAIN1-SERINC2 region, in order to confirm our previous GWAS finding that was based on common variant analysis (MAF > 0.05).…”

Genetics of Alcohol Use Disorder

“…Alkol ve nikotin komorbiditesi için "MAP/microtubule affinity regulating kinase 1" (MARK1) yakınındaki rs753030, "DEAD box helicase 6" (DDX6) yakınıdaki rs1784300 ve KIAA1409'daki rs12882384 polimorfizmleri genom çapı anlamlı olarak bulunmuştur (68). Benzer bir şekilde "SH3 domain binding protein" (5SH3BP5), "nuclear receptor subfamily 2 group C member 2" (NR2C2), "Plasminogen-like B2" (PLGLB2)'deki SNP'ler ve kromozom 5q'da bulunan IPO11-HRT1A bölgesindeki rs7445832 alkol ve nikotin birlikte bağımlılığı ile ilişkili bulunmuştur (71,77). 12 populasyon temelli örneklemden 26.316 kişinin dahil edildiği bir çalışmada AUT2 rs6943555 alkol tüketimi ile genom boyu anlamlı bulunmuştur (78).…”