Allelic Variation Within the Putative Autism Spectrum Disorder Risk Gene Homeobox A1 and Cerebellar Maturation in Typically Developing Children and Adolescents

Abstract

LAY ABSTRACT Autism is known to be highly heritable, and has been associated with abnormalities in the development of several brain structures, including the cerebellum. Previous research has hinted that a gene controlling the development of posterior brain regions such as the cerebellum, may influence risk for autism. This gene is called Homeobox Domain A1 (HOXA1), and the variant within HOXA1 that has been most studied in relation to autism (A218G) falls within a gene region that is important for HOXA1 protein functioning. Although we know that autism appear to influence the dynamics of brain development, and that cerebellar anatomy continues to change over the lifespan – we do not know if A218G genotype influences cerebellar development over time. We studied this issue in typically developing controls who had a total of 296 repeat structural brain scans taken between ages 5 and 23 years of age. The volume of multiple cerebellar components was measures by hand in each scan, and we related developmental changes in these volumes to A218G genotype. We found that, in a part of the cerebellum implicated in autism, A218G genotype modified the rate of cerebellar growth. This suggests for the first time that the putative ASD risk gene HOXA1 has the capacity to modify the longitudinal development of cerebellar systems implicated in ASD neurobiology. SCIENTIFIC ABSTRACT Homeobox-A-1 (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 non-synonymous 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 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...

Complex epigenetic regulation of Engrailed-2 (EN-2) homeobox gene in the autism cerebellum

“…Based on the findings reported here, EN-2 may now be included in the several candidate genes that have both genetic and epigenetic associations with autism including brain-derived neurotrophic factor, 50, 51 RELN, 52, 53 oxytocin, 54, 55 HOXA1, 56, 57 MeCP2, 58 and FXS . 59 In addition, five independent family-based studies have identified polymorphic variation in EN-2 as an autism susceptibility gene.…”

Behavioral, perceptual, and neural alterations in sensory and multisensory function in autism spectrum disorder

“…Thus, although efforts have been made to look at genotype-phenotype relations in ASD (Bruining et al, 2014; Chang et al, 2015; Schauder et al, 2015b; Veatch et al, 2014), and to relate structural and functional imaging features to either genotype or phenotype (Hedrick et al, 2012; Raznahan et al, 2012; Wiggins et al, 2012; Wiggins et al, 2014), little has been done to bridge across these three areas, and even less has been done to incorporate sensory features and sensory networks into these analyses. Although such work will be laborious and resource intensive, it will only be with such an integrated approach that we will be able to reveal new and important relationships that provide key insights into the marked heterogeneity that characterizes ASD.…”

Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics

“…To date, neuroimaging-genetics studies have taken two forms: studies of the effects of ASD-associated risk alleles on brain measures in neurotypical children, adolescents, and adults (eg, Clemm von Hohenberg et al, 2013; Dennis et al, Hedrick et al, 2012;Raznahan et al, 2012;Sauer et al, 2012;Tan et al, 2010;Voineskos et al, 2011;Whalley et al, 2011) and studies comparing the effects of ASD-associated risk alleles on children and adolescents with ASD compared with neurotypical controls (eg, Rudie et al, 2012a;. investigated the impact of the contactin-associated protein-like 2 (CNTNAP2) rs2710102, C risk allele on functional connectivity in children and adolescents with ASD.…”