Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence.
- Authors
- Xie, Pingxing; Kranzler, Henry R; Krauthammer, Michael; Cosgrove, Kelly P; Oslin, David; Anton, Raymond F; Farrer, Lindsay A; Picciotto, Marina R; Krystal, John H; Zhao, Hongyu; Gelernter, Joel
- Year
- 2011
- Journal
- Biological psychiatry
- PMID
- 21683344
- DOI
- 10.1016/j.biopsych.2011.04.017
- PMCID
- PMC3199609
BACKGROUND: Several studies report association of alpha-4 nicotinic acetylcholine receptors (encoded by CHRNA4) with nicotine dependence (ND). A meta-analysis of genomewide linkage studies for ND implicated a single chromosomal region, which includes CHRNA4, as genome-wide significant. METHODS: After establishing that common variants are unlikely to completely account for this linkage, we investigated the distribution of CHRNA4 rare variants by sequencing the coding exons and flanking intronic regions of CHRNA4 in 209 European American (EA) ND cases and 183 EA control subjects. Because most of the rare variants that we detected (and all nonsynonymous changes) were in Exon 5, we sequenced Exon 5 in an additional 1000 ND cases and 1000 non-ND comparison subjects, both of which included equal numbers of EAs and African Americans. RESULTS: Comparison subjects had a higher frequency of rare nonsynonymous variants in the Exon 5 region (encoding the large intercellular loop of the α4 subunit; Fisher's Exact Test p = .009; association test p = .009, odds ratio = .43; weighted-sum method p = .014), indicating a protective effect against ND. Considering data from the two stages combined and only nonsynonymous variants predicted to alter protein function, the association was stronger (Fisher's Exact Test p = .005; association test p = .008, odds ratio = .29; weighted-sum method p = .005). Single-photon emission computed tomography imaging results were consistent with functionality. CONCLUSIONS: CHRNA4 functional rare variants may reduce ND risk. This is the first demonstration that rare functional variants at a candidate locus protect against substance dependence to our knowledge, suggesting a novel mechanism of substance dependence heritability that is potentially of general importance.
Locations of CHRNA4 rare variants identified in the discovery and the test samples.(A) Schematic genomic structure of CHRNA4 spanning 17 Kb and 6 coding exons (dark boxes). Red arrows point to the identified rare nonsynonymous variants in the discovery samples; green arrows point to the identified rare synonymous variants in the discovery samples. The bars on the top show the PCR products. The dark grey region covering exon 5 was sequenced in the test samples.(B) Schematic depiction of the α4 nAChR subunit. Exon 5 was sequenced in the test samples, which encodes 114 amino acids of the extracellular domain, all of the first three transmembrane domains, and 256 amino acids of the cytoplasmic loop. Amino acids encoded by the gene regions not sequenced in the test stage are depicted in light grey. Red dots represent the amino acids affected by rare nonsynonymous variants identified in the test samples; green dots are those affected by rare synonymous variants identified in the test samples.
Rare variants found in the test samples, showing the locations of the rare variants and the distributions among cases and controls.
SPECT scans using 123-labeled 5-iodo-A-85380 ([123I]5-IA) for two nonsmoking rare variant carriers (S1 with a nonsynonymous rare variant and S2 with two synonymous variants) compared to their age-matched nonsmoking controls.(A) α4β2 nAChR availability (VT/fP) in cortical regions (average of parietal, frontal, anterior cingulate, temporal and occipital cortices), striatum (average of caudate and putamen) and cerebellum in S1 and S2 compared to age-matched controls (CON).(B) Parametric images (α4β2 nAChR availability, VT/fP) of S1, a 30-year-old female healthy nonsmoker and an age- and sex-matched control). The color bar shows corresponding VT/fP values.
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