Archival ReportRare Nonsynonymous Variants in Alpha-4 Nicotinic Acetylcholine Receptor Gene Protect Against Nicotine Dependence
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Subjects
Subjects were recruited for linkage and association studies of the genetics of cocaine, opioid, and alcohol dependence (26, 27). The participants were recruited at five sites: the University of Connecticut Health Center (538 ND cases and 467 comparison subjects), Yale University School of Medicine (432 ND cases and 428 comparison subjects), the Medical University of South Carolina (54 ND cases and 255 comparison subjects), the University of Pennsylvania School of Medicine (133 ND cases and 16
Sequencing the Coding Exons of CHRNA4 in the Discovery Sample Set
We identified 31 unique single-nucleotide variants in the coding exons and flanking intronic regions of CHRNA4 in the discovery cohort. Of these variants, 21 were exonic, including eight types of single nucleotide polymorphisms (minor allele frequencies [MAF] > 5%) and 13 types of rare variants (MAF ≤ 1%, Figure 1A). None of the variants were found to have MAF between 1% and 5%. Six of the 13 rare variants identified were nonsynonymous substitutions, and all were missense mutations. Two
Discussion
In this study, we investigated the distribution of rare variants in CHRNA4 in more than 2000 ND cases and comparison subjects. Compared with cases, controls had a significantly higher frequency of rare nonsynonymous variants located in the Exon 5 region encoding the cytoplasmic loop of the α4 nAChR (FET p = .009; association test p = .009, OR = .43, 95% CI = .23–.81; WSM p = .014). Functional in silico analysis (PolyPhen) further demonstrated that the comparison subjects carried significantly
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Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use
2018, Drug and Alcohol DependenceCitation Excerpt :In contrast, for the detection of rare variants with a MAF of 0.001, we had sufficient power to detect variants with large effect sizes (i.e., Cohen’s d ≥ 1.17 for alcohol consumption and Cohen’s d ≥ 1.5 for tobacco use). Although our findings coupled with the power analysis suggest that rare genetic variants with large effect sizes do not play an important role, we cannot rule out the possibility that rare exonic variants with smaller effects contribute to the phenotypic variation in alcohol consumption and CPD, as previously suggested by candidate gene studies (Haller et al., 2012, 2014; Olfson et al., 2016; Thorgeirsson et al., 2016; Xie et al., 2011; Yang et al., 2015). Even though not all previously reported rare variants were tagged on the ExomeChip or passed our QC, several of these variants were included in our analyses, and several of the associated genes were analyzed with our gene-based tests.
Clinical Syndromes of Substance Use Disorder
2016, Genomics, Circuits, and Pathways in Clinical Neuropsychiatry