title: Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence.
abstract: Common SNPs in nicotinic acetylcholine receptor genes (CHRN genes) have been associated with drug behaviors and personality traits, but the influence of rare genetic variants is not well characterized. The goal of this project was to identify novel rare variants in CHRN genes in the Center for Antisocial Drug Dependence (CADD) and Genetics of Antisocial Drug Dependence (GADD) samples and to determine if low frequency variants are associated with antisocial drug dependence. Two samples of 114 and 200 individuals were selected using a case/control design including the tails of the phenotypic distribution of antisocial drug dependence. The capture, sequencing, and analysis of all variants in 16 CHRN genes (CHRNA1-7, 9, 10, CHRNB1-4, CHRND, CHRNG, CHRNE) were performed independently for each subject in each sample. Sequencing reads were aligned to the human reference sequence using BWA prior to variant calling with the Genome Analysis ToolKit (GATK). Low frequency variants (minor allele frequency < 0.05) were analyzed using SKAT-O and C-alpha to examine the distribution of rare variants among cases and controls. In our larger sample, the region containing the CHRNA6/CHRNB3 gene cluster was significantly associated with disease status using both SKAT-O and C-alpha (unadjusted p values <0.05). More low frequency variants in the CHRNA6/CHRNB3 gene region were observed in cases compared to controls. These data support a role for genetic variants in CHRN genes and antisocial drug behaviors.
authors.affiliation: Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Kamens
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, 447 UCB, Boulder, CO, 80309, USA.
authors.forename: Robin P
authors.initials: RP
authors.lastname: Corley
authors.affiliation: BioFrontiers Institute, University of Colorado, Boulder, CO, USA.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Richmond
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, 447 UCB, Boulder, CO, 80309, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Darlington
authors.affiliation: BioFrontiers Institute, University of Colorado, Boulder, CO, USA.|Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Dowell
authors.affiliation: Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Hopfer
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, 447 UCB, Boulder, CO, 80309, USA.|Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Stallings
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, 447 UCB, Boulder, CO, 80309, USA.|Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Hewitt
authors.affiliation: Department of Psychology and Psychiatry, University of California San Diego, San Diego, CA, USA.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Brown
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, 447 UCB, Boulder, CO, 80309, USA. marissa.ehringer@colorado.edu.|Department of Integrative Physiology, University of Colorado, Boulder, CO, USA. marissa.ehringer@colorado.edu.
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Ehringer
mesh_terms: D000293:Adolescent; D000987:Antisocial Personality Disorder; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D011786:Quality Control; D011978:Receptors, Nicotinic / Q000235:genetics*; D012984:Software; D055815:Young Adult
chemical_list: C470410:CHRNA6 protein, human; C539371:CHRNB3 protein, human; D011978:Receptors, Nicotinic
keywords: Antisocial drug dependence; Association; Low frequency variants; Nicotinic acetylcholine receptor; Sequence