Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence - PubMed (original) (raw)

doi: 10.1038/mp.2008.42. Epub 2008 Apr 15.

R Grucza, C Cruchaga, A L Hinrichs, S Bertelsen, J P Budde, L Fox, E Goldstein, O Reyes, N Saccone, S Saccone, X Xuei, K Bucholz, S Kuperman, J Nurnberger Jr, J P Rice, M Schuckit, J Tischfield, V Hesselbrock, B Porjesz, H J Edenberg, L J Bierut, A M Goate

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Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence

J C Wang et al. Mol Psychiatry. 2009 May.

Abstract

Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3'-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5-CHRNA3-CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.

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Figures

Figure 1

Figure 1

(a) Location of genotyped polymorphisms across the cluster of CHRNA5–CHRNA3–CHRNB4 genes. The dark boxes represent exons. The hatched boxes represent 5′- and 3′-UTRs; * represents coding single nucleotide polymorphisms (SNPs). Diagram is not drawn to scale. (b) Pair-wise linkage disequilibrium among polymorphisms in the region of CHRNA5–CHRNA3–CHRNB4 genes in COGA European-American data set. Numbers in boxes represent _r_2 value between variants.

Figure 2

Figure 2

Association of the single nucleotide polymorphism (SNP), 588765 with CHRNA5 mRNA expression. (a) The ΔRn vs cycle plot showing relative total expression of CHRNA5 (open circles and open squares) and GAPDH (solid circles and solid squares). Circles represent a sample homozygous for minor allele (TT) and squares represent a sample homozygous for major allele (CC). The level of expression was calculated from the _C_t value (the cycle at which the fluorescence intensity rises above a threshold) and was normalized by taking GAPDH as a reference. (b) Mann–Whitney _U_-statistic, two-tailed analysis of CHRNA5 total expression in subjects with homozygous for the major allele (CC), subjects with homozygous for the minor allele (TT) and heterozygous subjects (CT). y-Axis represents the relative expression level taking an arbitrary reference samples as 1. Mean±s.d. is shown; * indicates _P_-value < 0.05.

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