Allelic Variation Within the Putative Autism Spectrum Disorder Risk Gene H omeobox A 1 and Cerebellar Maturation in Typically Developing Children and Adolescents

“The absence of neurological or psychiatric illness was established through completion of a screening questionnaire (Child Behavior Checklist) and a structured diagnostic interview administered by a child psychiatrist [Giedd et al., 1999].”

“…quotient (FSIQ) of greater than 80 as determined using age-appropriate Wechsler Intelligence Scales including Wechsler Intelligence Scale for Children-Revised (WISC-R), Wechsler Adult Intelligence Scale-Revised (WAIS-R) and Wechsler Abbreviated Scale of Intelligence (WASI) [Shaw et al., 2006].”

“…HOXA1 as a candidate gene for ASD came from overlap in the hind-brain abnormalities seen in postmortem studies of people with idiopathic ASD [Bauman & Kemper, 2005], and hind-brain alterations in both animal HOXA1 knockout models, and postmortem studies of people with ASD in the context of…”

“…several cross-sectional reports suggest that cerebellar abnormalities in ASD may vary as a function of age [Cleavinger et al., 2008; Courchesne et al., 2001; Stanfield et al., 2008]—indicating that candidate cerebellar markers of ASD risk would be best studied using longitudinal study designs.”

“…from rhombomere 1) (Trainor & Krumlauf, 2000), recent evidence for more rostral HOXA1 expression suggests several mechanisms through which genetically determined variation in HOXA1 functioning could impact cerebellar development [McClintock et al., 2003; Wang & Zoghbi, 2001; Mark et al., 1993].”

“This is likely to reflect samplesize limitations because curvilinear volume changes in cerebellar volume have been identified in larger samples (Tiemeier et al., 2010).”

“In addition to arguing that HOXA1 may play a role in normal human cerebellar development, our findings raise the possibility that the tentative links that have been made between functional variation within HOXA1 signaling pathways and ASD risk [Rasalam et al., 2005] may be mediated by the capacity of HOXA1 to modify d…”

“This possibility has never been explored, but is supported by a recent observation that HOXA1 expression in human brain tissue varies dramatically as a function of age [Siegmund et al., 2007].”

“Theoretically, these two possibilities would be best distinguished by studying fully discordant monozygotic twin pairs, although this is not practically possible in ASD because of very high monozygotic concordance rates [Folstein & Rutter, 1977].”

“This argument is strengthened by the fact that our study localizes A218G genotype influences on cerebellar maturation to the superior posterior cerebellar lobe, which includes the cerebellar lobule that has most consistently shown abnormalities in ASD—lobule VI [Courchesne et al., 1994; Hashimoto et al., 1995; Kaufman…”

“…4 argues against the possibility that a functional HOXA1 polymorphism might modify cerebellar structures (which derive from rhombomere 1) (Trainor & Krumlauf, 2000), recent evidence for more rostral HOXA1 expression suggests several mechanisms through which genetically determined…”

“As was reported elsewhere [Mackie et al., 2007], for cerebellar lobes, initial intra- and inter-rater ICCs were greater than 0.”

“Subsequently, case-series of humans with rare HOXA1 mutations found that learning disability and ASD were central to the resulting syndrome, which was accompanied by radiological evidence of hind-brain malformation [Tischfield et al., 2005].”

“Segmentation was achieved using an artificial neural network (ANN) approach [Magnotta et al., 2002], which was “trained” on 30 different cerebella that had been manually segmented into the following structures: corpus medullare (cerebellar white matter and output nuclei), cerebellar vermis,…”

“In the recent years there has been increasing interest in using combinations of neuroimaging and genetics to delineate the biological pathways through which specific genetic variants may modify risk for heritable neurodevelopmental conditions [Hariri & Weinberger, 2003; Meyer-Lindenberg, 2010].”

“, 2000] or related traits [Chakrabarti et al., 2009] [although a different allele was implicated as imparting risk in each study, and several negative association studies also exist [Collins, Schroer, Bird, & Michaelis, 2003; Devlin et al.”

“This argument is strengthened by the fact that our study localizes A218G genotype influences on cerebellar maturation to the superior posterior cerebellar lobe, which includes the cerebellar lobule that has most consistently shown abnormalities in ASD—lobule VI [Courchesne et al., 1994; Hashimoto et al., 1995; Kaufman…”

“This argument is strengthened by the fact that our study localizes A218G genotype influences on cerebellar maturation to the superior posterior cerebellar lobe, which includes the cerebellar lobule that has most consistently shown abnormalities in ASD—lobule VI [Courchesne et al., 1994; Hashimoto et al., 1995; Kaufman…”

“shape cerebellar alterations in a developmentally dynamic manner within ASD is supported by evidence from twin and family neuroimaging studies demonstrating that the magnitude of genetic contribution may vary with age [Posthuma et al., 2000; Wallace et al., 2006].”

“This argument is strengthened by the fact that our study localizes A218G genotype influences on cerebellar maturation to the superior posterior cerebellar lobe, which includes the cerebellar lobule that has most consistently shown abnormalities in ASD—lobule VI [Courchesne et al., 1994; Hashimoto et al., 1995; Kaufman…”

“shape cerebellar alterations in a developmentally dynamic manner within ASD is supported by evidence from twin and family neuroimaging studies demonstrating that the magnitude of genetic contribution may vary with age [Posthuma et al., 2000; Wallace et al., 2006].”

“This paradigm has been used with some success in psychiatric conditions other than ASD [McIntosh et al., 2007; Raznahan et al., 2011], but comes with its own compilations.”

“To date however, relatively few studies have applied this approach to study putative risk genes for Autism Spectrum Disorder (ASD) [Raznahan et al., 2009, 2010; Wassink et al., 2007].”

“To date, three independent groups have linked a common nonsynonymous mutation with an evolutionarily conserved HOXA1 exon to risk for ASD [Conciatori et al., 2004; Ingram et al., 2000] or related traits [Chakrabarti et al., 2009] [although a different allele was implicated as imparting risk in each…”

“All measures of cerebellar anatomy were derived using the semiautomated method described in Pierson et al. [Pierson et al., 2002].”

“The best-replicated finding in these studies is abnormality within lobule VI of the cerebellum [Mitchell et al., 2009; Stanfield et al., 2008; Webb et al., 2009]— arguing that a regional approach to measurement of cerebellar anatomy in ASD is desirable.”

“HOXA1 is one of a family of evolutionarily conserved genes that govern morphogenesis and cellular differentiation of the central nervous system through their function as transcription factors [Akin & Nazarali, 2005].”

“Next we distinguished vermal and non-vermal (i.e., cereballar hemispheres) structures given evidence for a difference in their embryonic origins [Yachnis & Rorke, 1999].”

“This paradigm has been used with some success in psychiatric conditions other than ASD [McIntosh et al., 2007; Raznahan et al., 2011], but comes with its own compilations.”

“To date however, relatively few studies have applied this approach to study putative risk genes for Autism Spectrum Disorder (ASD) (Raznahan et al., 2010; Raznahan et al., 2009; Wassink et al., 2007).”

“This paradigm has been used with some success in psychiatric conditions other than ASD [McIntosh et al., 2007; Raznahan et al., 2011], but comes with its own compilations.”

“In the recent years there has been increasing interest in using combinations of neuroimaging and genetics to delineate the biological pathways through which specific genetic variants may modify risk for heritable neurodevelopmental conditions [Hariri & Weinberger, 2003; Meyer-Lindenberg, 2010].”

“It has been established that conversion of cells into lymphoblastoid lines does not cause errors into SNP genotyping [Herbeck et al., 2009].”

“…traits [Chakrabarti et al., 2009] [although a different allele was implicated as imparting risk in each study, and several negative association studies also exist [Collins, Schroer, Bird, & Michaelis, 2003; Devlin et al., 2002; Romano et al., 2003; Sen et al., 2007; Talebizadeh et al., 2002].”

“…traits [Chakrabarti et al., 2009] [although a different allele was implicated as imparting risk in each study, and several negative association studies also exist [Collins, Schroer, Bird, & Michaelis, 2003; Devlin et al., 2002; Romano et al., 2003; Sen et al., 2007; Talebizadeh et al., 2002].”

“This hypothesis is in keeping with existing evidence for developmentally dynamic relationships between A218G genotype and another anatomical index of relevance to the central nervous system—head circumference [Conciatori et al., 2004; Muscarella et al., 2007].”

“Furthermore, several cross-sectional reports suggest that cerebellar abnormalities in ASD may vary as a function of age [Cleavinger et al., 2008; Courchesne et al., 2001; Stanfield et al., 2008]—indicating that candidate cerebellar markers of ASD risk would be best studied using longitudinal study…”

“Although there are no published studies that directly test A218G functionality, sequence variation within this polyhistidine domain is known to result in increased cell death and impaired neuronal differentiation—suggesting that allelic variation at A218G may impact HOXA1 functioning and brain development [Paraguison…”

“…traits [Chakrabarti et al., 2009] [although a different allele was implicated as imparting risk in each study, and several negative association studies also exist [Collins, Schroer, Bird, & Michaelis, 2003; Devlin et al., 2002; Romano et al., 2003; Sen et al., 2007; Talebizadeh et al., 2002].”

“…A218G functionality, sequence variation within this polyhistidine domain is known to result in increased cell death and impaired neuronal differentiation—suggesting that allelic variation at A218G may impact HOXA1 functioning and brain development [Paraguison et al., 2005; Paraguison et al., 2007].”

“While the canonical understanding that HOXA1 expression is restricted to hind-brain regions including and caudal to rhombomere 4 argues against the possibility that a functional HOXA1 polymorphism might modify cerebellar structures (which derive from rhombomere 1) (Trainor & Krumlauf, 2000), recent evidence for more r…”

“Cross-sectional analyses in two independent groups of healthy adults in the sixth decade of life have also linked A218G genotype to superior posterior lobar volume, although G carriers had volumetric reductions compared with A homozygotes [Canu et al., 2009].”

“…traits [Chakrabarti et al., 2009] [although a different allele was implicated as imparting risk in each study, and several negative association studies also exist [Collins, Schroer, Bird, & Michaelis, 2003; Devlin et al., 2002; Romano et al., 2003; Sen et al., 2007; Talebizadeh et al., 2002].”

“…2 (CNTNAP2) (Scott-Van Zeeland et al., 2010a; Tan et al., 2010; Dennis et al., 2011; Whalley et al., 2011); homeobox A1 (HOXA1) (Canu et al., 2009; Raznahan et al., 2012); MET receptor tyrosine kinase (MET) (Hedrick et al., 2012), oxytocin receptor (OXT) (Inoue et al., 2010), and brain-derived…”

“…REVIEWS 2011; 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…”

“a decade, as it regulates embryological patterning of hindbrain structures implicated in autism neurobiology [56].”

“…phenotypes, raising the possibility that they may be involved in brain development (Shaw et al. 2007; Reiman et al. 2009; Furman et al. 2011; Tognin et al. 2011; Darki et al. 2012; Hedrick et al. 2012; Raznahan et al. 2012; Forbes et al. 2012; Ziermans et al. 2012; Knickmeyer et al. 2013).”

“Of interest, mutations and allelic variants within the human HOXA1 gene have been linked to ASD risk (Ingram et al., 2000, Raznahan et al., 2012, Tischfield et al., 2005).”