rs1042173

This review examines neurogenetic and neuropharmacological correlates of opioid use disorder (OUD) with emphasis on ancestry-specific genetic risk profiles. The paper identifies multiple genes involved in the reward pathway (DRD2, DRD3, DRD4, OPRM1, OPRK1, OPRD1, BDNF, NRXN3, COMT, SLC6A4, KCNC1, KCNG2) and their variants associated with OUD susceptibility and treatment response across different ethnic populations, highlighting critical research disparities where African Americans and Hispanics have been underrepresented in genetic association studies.

This association study examined 3,564 subjects from the SAGE dataset (2,428 European-American, 1,136 African-American) to determine associations between 88 variants in HTR3A, HTR3B, and SLC6A4 genes and alcohol, cocaine, and nicotine dependence. Individual SNP analysis found rs2066713 in SLC6A4 significantly associated with FTND in African-Americans (beta = -1.39, P = 1.6E-04). Haplotype analysis identified major haplotypes in HTR3B and HTR3A significantly associated with alcohol dependence and FTND. GMDR interaction analysis revealed significant SNP-by-SNP interactions within these three genes affecting multiple addictive phenotypes.

This case-control association study examined 22 SNPs in HTR3A, HTR3B, and SLC6A4 genes in relation to alcohol dependence in 500 cases and 280 controls of European descent. Low-frequency variants rs33940208 (HTR3A) and rs2276305 (HTR3B) showed protective effects (OR=0.212, P=0.004 and OR=0.261, P=0.016 respectively). Gene-by-gene interaction analyses revealed significant interactive effects among SLC6A4, HTR3A, and HTR3B variants on alcohol dependence risk (OR=2.71-3.095, P<0.001-2×10⁻⁴). Findings were replicated in 6,699 samples from the OZ-ALC-GWAS study.

This family-based association study examined parent-of-origin effects and allelic expression imbalance of the serotonin transporter (5HTT) gene in 312 nuclear families with bipolar disorder. The 3'UTR polymorphism G2651T (rs1042173) showed significant association with bipolar disorder (P=0.042), with the T allele being the risk allele (RR=1.346). Analysis of allele-specific mRNA expression in lymphoblastoid cells from 21 bipolar patients (13 suicide attempters, 8 non-attempters) revealed no significant differences in T/G expression ratios between groups, providing no evidence that differential allelic expression or genomic imprinting contributes to suicidal behavior in bipolar disorder.

Family-based association study of 290 Caucasian families investigating SLC6A4 and ITGB3 genes in autism, stratified by family history. While individual SNPs showed no significant associations after multiple testing correction, stratification by family history revealed nominally significant associations at rs2066713 (SLC6A4) in both positive and negative family history groups, and rs3809865 (ITGB3) in positive family history families. Gene-gene interaction analysis confirmed a significant interaction between rs2066713 (SLC6A4) and rs5918 (ITGB3, Leu33Pro) (p=0.014, survived multiple testing correction), suggesting family history is an important index of genetic heterogeneity in autism susceptibility.

Haplotype-tagging SNP analysis in 364 individuals from 152 ADHD families identified significant associations between commission errors and SNPs in the DRD2 gene (rs2075654, rs1079596) and between reaction time variability and a SNP in the NET gene (rs3785155). These findings suggest that commission errors and reaction time variability are valid ADHD endophenotypes linked to dopaminergic and noradrenergic pathways.