title: Allelic variation within the putative autism spectrum disorder risk gene homeobox A1 and cerebellar maturation in typically developing children and adolescents.
abstract: Homeobox A1 (HOXA1) has been proposed as a candidate gene for autism spectrum disorder (ASD) as it regulates embryological patterning of hind-brain structures implicated in autism neurobiology. In line with this notion, a nonsynonymous single nucleotide polymorphism within a highly conserved domain of HOXA1--A218G (rs10951154)--has been linked to both ASD risk, and cross-sectional differences in superior posterior lobar cerebellar anatomy in late adulthood. Despite evidence for early onset and developmentally dynamic cerebellar involvement in ASD, little is known of the relationship between A218G genotype and maturation of the cerebellum over early development. We addressed this issue using 296 longitudinally acquired structural magnetic resonance imaging brain scans from 116 healthy individuals between 5 and 23 years of age. Mixed models were used to compare the relationship between age and semi-automated measures of cerebellar volume in A-homozygotes (AA) and carriers of the G allele (Gcar). Total cerebellar volume increased between ages of 5 and 23 years in both groups. However, this was accelerated in the Gcar relative to the AA group (Genotype-by-age interaction term, P = 0.03), and driven by genotype-dependent differences in the rate of bilateral superior posterior lobar volume change with age (P = 0.002). Resultantly, although superior posterior lobar volume did not differ significantly between genotype groups at age 5 (P = 0.9), by age 23 it was 12% greater in Gcar than AA (P = 0.002). Our results suggest that common genetic variation within this putative ASD risk gene has the capacity to modify the development of cerebellar systems implicated in ASD neurobiology.
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. raznahana@mail.nih.gov
authors.forename: Armin
authors.initials: A
authors.lastname: Raznahan
authors.forename: Yohan
authors.initials: Y
authors.lastname: Lee
authors.forename: Catherine
authors.initials: C
authors.lastname: Vaituzis
authors.forename: Lan
authors.initials: L
authors.lastname: Tran
authors.forename: Susan
authors.initials: S
authors.lastname: Mackie
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.forename: Liv
authors.initials: L
authors.lastname: Clasen
authors.forename: Francois
authors.initials: F
authors.lastname: Lalonde
authors.forename: Dede
authors.initials: D
authors.lastname: Greenstein
authors.forename: Ron
authors.initials: R
authors.lastname: Pierson
authors.forename: Jay N
authors.initials: JN
authors.lastname: Giedd
mesh_terms: D000293:Adolescent; D002531:Cerebellum / Q000254:growth & development*; D002648:Child; D002657:Child Development; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D005260:Female; D005801:Genes, Homeobox / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein