Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence.
Previous findings have demonstrated that variants in nicotinic receptor genes are associated with nicotine, alcohol and cocaine dependence. Because of the substantial comorbidity, it has often been unclear whether a variant is associated with multiple substances or whether the association is actually with a single substance. To investigate the possible contribution of rare variants to the development of substance dependencies other than nicotine dependence, specifically alcohol and cocaine dependence, we undertook pooled sequencing of the coding regions and flanking sequence of CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 in 287 African American and 1028 European American individuals from the Collaborative Study of the Genetics of Alcoholism (COGA). All members of families for whom any individual was sequenced (2504 African Americans and 7318 European Americans) were then genotyped for all variants identified by sequencing. For each gene, we then tested for association using FamSKAT. For European Americans, we find increased DSM-IV cocaine dependence symptoms (FamSKAT P = 2 × 10(-4)) and increased DSM-IV alcohol dependence symptoms (FamSKAT P = 5 × 10(-4)) among carriers of missense variants in CHRNB3. Additionally, one variant (rs149775276; H329Y) shows association with both cocaine dependence symptoms (P = 7.4 × 10(-5), β = 2.04) and alcohol dependence symptoms (P = 2.6 × 10(-4), β = 2.04). For African Americans, we find decreased cocaine dependence symptoms among carriers of missense variants in CHRNA3 (FamSKAT P = 0.005). Replication in an independent sample supports the role of rare variants in CHRNB3 and alcohol dependence (P = 0.006). These are the first results to implicate rare variants in CHRNB3 or CHRNA3 in risk for alcohol dependence or cocaine dependence.
Department of Psychiatry and.
Gabe
G
Haller
Manav
M
Kapoor
John
J
Budde
Xiaoling
X
Xuei
Howard
H
Edenberg
John
J
Nurnberger
John
J
Kramer
Andy
A
Brooks
Jay
J
Tischfield
Laura
L
Almasy
Arpana
A
Agrawal
Kathleen
K
Bucholz
John
J
Rice
Nancy
N
Saccone
Laura
L
Bierut
Alison
A
Goate
D001741:Black or African American / Q000235:genetics; D016022:Case-Control Studies; D019970:Cocaine-Related Disorders / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*; D044465:White People / Q000235:genetics
D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C470410:CHRNA6 protein, human; C539371:CHRNB3 protein, human; C447159:CHRNB4 protein, human