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Hum Genet (2013) 132:11651176 DOI 10.1007/s00439-013-1319-y
ORIGINAL INVESTIGATION
Association, interaction, and replication analysis of genes encoding serotonin transporter and 5-HT3 receptor subunits
A and B in alcohol dependence
Chamindi Seneviratne Jason Franklin Katherine Beckett Jennie Z. Ma
Nassima Ait-Daoud Thomas J. Payne Bankole A. Johnson Ming D. Li
Received: 17 January 2013 / Accepted: 26 May 2013 / Published online: 12 June 2013 Springer-Verlag Berlin Heidelberg 2013
Abstract On the basis of the converging evidence showing regulation of drinking behavior by 5-HT3AB
receptors and the serotonin transporter, we hypothesized that the interactive effects of genetic variations in the genes HTR3A, HTR3B, and SLC6A4 confer greater susceptibility to alcohol dependence (AD) than do their effects individually. We examined the associations of AD with 22 SNPs across HTR3A, HTR3B, and two functional variants in SLC6A4 in 500 AD and 280 healthy control individuals of European descent. We found that the alleles of the low-frequency SNPs rs33940208:T in HTR3A and rs2276305:A in HTR3B were inversely and nominally signicantly associated with AD with odds ratio (OR) and 95 % condence interval of 0.212 and 0.073, 0.616 (P = 0.004) and0.261 and 0.088, 0.777 (P = 0.016), respectively. Further, our gene-by-gene interaction analysis revealed that two four-variant models that differed by only one SNP carried a risk for AD (empirical P \ 1 9 10-6 for prediction
accuracy of the two models based on 106 permutations). Subsequent analysis of these two interaction models revealed an OR of 2.71 and 2.80, respectively, for AD (P \ 0.001) in carriers of genotype combinations 50-HTT
LPR:LL/LS(SLC6A4)rs1042173:TT/TG(SLC6A4)rs117 6744:AC(HTR3B)rs3782025:AG(HTR3B) and 50-HTTL
PR:LL/LS(SLC6A4)rs10160548:GT/TT(HTR3A)rs1176 744:AC(HTR3B)rs3782025:AG(HTR3B). Combining all ve genotypes resulted in an OR of 3.095 (P =2.0 9 10-4) for AD. Inspired by these ndings, we conducted the analysis in an independent sample, OZ-ALCGWAS (N = 6699), obtained from the NIH dbGAP database, which conrmed the ndings, not only for all three risk genotype combinations (Z = 4.384, P = 1.0 9 10-5;
Z = 3.155, P = 1.6 9 10-3; and Z = 3.389, P = 7.0 9 10-4, respectively), but also protective effects for rs33940208:T (v2 = 3.316, P = 0.0686) and rs2276305:A (v2 = 7.224, P = 0.007). These ndings reveal signicant interactive effects among variants in SLC6A4HTR3A HTR3B affecting AD. Further studies are...