title: Single nucleotide polymorphisms in the REG-CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample.
abstract: Impulsivity is a multi-faceted construct that, while characterized by a set of correlated dimensions, is centered around a core definition that involves acting suddenly in an unplanned manner without consideration for the consequences of such behavior. Several psychiatric disorders include impulsivity as a criterion, and thus it has been suggested that it may link a number of different behavioral disorders, including substance abuse. Native Americans (NA) experience some of the highest rates of substance abuse of all the US ethnic groups. The described analyses used data from a low-coverage whole genome sequence scan to conduct a genome-wide association study (GWAS) of an impulsivity phenotype in an American Indian community sample (n = 658). Demographic and clinical information were obtained using a semi-structured interview. Impulsivity was assessed using a scale derived from the Maudsley personality inventory that combines both novelty seeking and lack of planning items. The impulsivity score was tested for association with each variant adjusted for demographic variables, and corrected for ancestry and kinship, using emmax. Simulations were conducted to calculate empirical P-values. Genome-wide significant findings were observed for a variant 50-kb upstream from catenin cadherin-associated protein, alpha 2 (CTNNA2), a neuronal-specific catenin, in the REG gene cluster. A meta-analysis of GWAS had previously identified common variants in CTNNA2 as being associated with excitement seeking. A second locus upstream of nei endonuclease VIII-like 3 (NEIL3) on chromosome 4 also achieved genome-wide significance. The association between sequence variants in these regions suggests their potential roles in the genetic regulation of this phenotype in this population.
authors.affiliation: The Scripps Research Institute, Molecular and Cellular Neuroscience Department, La Jolla, CA.
authors.forename: C L
authors.initials: CL
authors.lastname: Ehlers
authors.affiliation: Department of Psychological Sciences, University of Missouri, Columbia, MO.
authors.forename: I R
authors.initials: IR
authors.lastname: Gizer
authors.affiliation: Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: C
authors.initials: C
authors.lastname: Bizon
authors.affiliation: Department of Psychological Sciences, University of Missouri, Columbia, MO.
authors.forename: W
authors.initials: W
authors.lastname: Slutske
authors.affiliation: The Scripps Research Institute, Molecular and Cellular Neuroscience Department, La Jolla, CA.|J Craig Venter Institute, Human Biology, La Jolla, CA.
authors.forename: Q
authors.initials: Q
authors.lastname: Peng
authors.affiliation: J Craig Venter Institute, Human Biology, La Jolla, CA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Schork
authors.affiliation: Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC.|Department of Genetics and Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Wilhelmsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D006801:Humans; D007175:Impulsive Behavior; D007198:Indians, North American / Q000235:genetics*; D051847:Lithostathine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009699:N-Glycosyl Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051178:alpha Catenin / Q000235:genetics
chemical_list: C079671:CTNNA2 protein, human; D051847:Lithostathine; C497617:REG1A protein, human; D051178:alpha Catenin; D009699:N-Glycosyl Hydrolases; C468764:NEIL3 protein, human
keywords: American Indian; Native American; association analyses; catenin cadherin-associated protein; chromosome 2; genetics; impulsivity; single nucleotide polymorphisms; substance dependence; whole genome sequencing