title: Resequencing and association analysis of arylalkylamine N-acetyltransferase (AANAT) gene and its contribution to major depression susceptibility.
abstract: Circadian rhythms disruptions, including abnormalities of circadian phase position and melatonin secretion, have been described in major depression (MD). Arylalkylamine N-acetyltransferase (AANAT) is a key enzyme of the melatonin pathway involved in circadian oscillations of melatonin levels. We assessed the contribution of AANAT gene variability to susceptibility to MD considering common and rare genetic variations through a sequential sequencing and single nucleotide polymorphism (SNP)-based genotyping approach in a sample of 445 unrelated patients with MD (257 unipolar MD, 188 bipolar depression) and 440 community-based screened control subjects. We identified 17 sequence changes, thirteen of which represented novel sequence variations. We did not observe an over-representation of patients carrying rare variants compared with the healthy controls. Common variants (MAF > 2%) were included in a case-control association analysis that showed significant association after multiple testing correction of two SNPs located in the promoter region of AANAT with MD: rs3760138 (P = 0.00006) and rs4238989 (P = 0.005). Multimarker analysis found significant associations between two three-marker protective haplotypes and a susceptibility three-marker haplotype containing the rare alleles of rs3760138-rs4238989-rs8150 and MD. We present evidence of the association of genetic variability in the AANAT gene with susceptibility to MD. Our results support the hypothesis that the melatonin-signaling pathway and circadian clock mechanisms may contribute to the pathophysiology of MD.
authors.affiliation: CIBERSAM (CIBER en Salud Mental), Mood Disorders Clinical and Research Unit, Psychiatry Department, Bellvitge University Hospital, Idibell, Barcelona, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Soria
authors.forename: Erika
authors.initials: E
authors.lastname: Martínez-Amorós
authors.forename: Geòrgia
authors.initials: G
authors.lastname: Escaramís
authors.forename: Joaquín
authors.initials: J
authors.lastname: Valero
authors.forename: José M
authors.initials: JM
authors.lastname: Crespo
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gutiérrez-Zotes
authors.forename: Mònica
authors.initials: M
authors.lastname: Bayés
authors.forename: Lourdes
authors.initials: L
authors.lastname: Martorell
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vilella
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: José M
authors.initials: JM
authors.lastname: Menchón
authors.forename: Mònica
authors.initials: M
authors.lastname: Gratacòs
authors.forename: Mikel
authors.initials: M
authors.lastname: Urretavizcaya
mesh_terms: D000328:Adult; D000368:Aged; D047068:Arylalkylamine N-Acetyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D002940:Circadian Rhythm; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: C478879:AANAT protein, human; D047068:Arylalkylamine N-Acetyltransferase