title: Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search.
abstract: The caudate is a subcortical brain structure implicated in many common neurological and psychiatric disorders. To identify specific genes associated with variations in caudate volume, structural magnetic resonance imaging and genome-wide genotypes were acquired from two large cohorts, the Alzheimer's Disease NeuroImaging Initiative (ADNI; N=734) and the Brisbane Adolescent/Young Adult Longitudinal Twin Study (BLTS; N=464). In a preliminary analysis of heritability, around 90% of the variation in caudate volume was due to genetic factors. We then conducted genome-wide association to find common variants that contribute to this relatively high heritability. Replicated genetic association was found for the right caudate volume at single-nucleotide polymorphism rs163030 in the ADNI discovery sample (P=2.36 × 10⁻⁶) and in the BLTS replication sample (P=0.012). This genetic variation accounted for 2.79 and 1.61% of the trait variance, respectively. The peak of association was found in and around two genes, WDR41 and PDE8B, involved in dopamine signaling and development. In addition, a previously identified mutation in PDE8B causes a rare autosomal-dominant type of striatal degeneration. Searching across both samples offers a rigorous way to screen for genes consistently influencing brain structure at different stages of life. Variants identified here may be relevant to common disorders affecting the caudate.
authors.affiliation: Department of Neurology, Laboratory of Neuro Imaging, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Stein
authors.forename: D P
authors.initials: DP
authors.lastname: Hibar
authors.forename: S K
authors.initials: SK
authors.lastname: Madsen
authors.forename: M
authors.initials: M
authors.lastname: Khamis
authors.forename: K L
authors.initials: KL
authors.lastname: McMahon
authors.forename: G I
authors.initials: GI
authors.lastname: de Zubicaray
authors.forename: N K
authors.initials: NK
authors.lastname: Hansell
authors.forename: G W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.forename: M J
authors.initials: MJ
authors.lastname: Wright
authors.forename: A J
authors.initials: AJ
authors.lastname: Saykin
authors.forename: C R
authors.initials: CR
authors.lastname: Jack
authors.forename: M W
authors.initials: MW
authors.lastname: Weiner
authors.forename: A W
authors.initials: AW
authors.lastname: Toga
authors.forename: P M
authors.initials: PM
authors.lastname: Thompson
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics; D000328:Adult; D000367:Age Factors; D000368:Aged; D002421:Caudate Nucleus / Q000033:anatomy & histology*; D004298:Dopamine / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods / Q000706:statistics & numerical data*; D005838:Genotype; D040941:Heredity / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D059906:Neuroimaging / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide
chemical_list: D015105:3',5'-Cyclic-AMP Phosphodiesterases; C468781:PDE8B protein, human; D004298:Dopamine