Allelic variation within the putative autism spectrum disorder risk gene homeobox A1 and cerebellar maturation in typically developing children and adolescents.
Allelic variation within the putative autism spectrum disorder risk gene homeobox A1 and cerebellar maturation in typically developing children and adolescents.
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DOI：
10.1002/aur.238
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发表时间：
2012-04
期刊：
影响因子：
4.7
通讯作者：
Giedd, Jay N.
中科院分区：
文献类型：
--
作者：
Raznahan, Armin;Lee, Yohan;Vaituzis, Catherine;Tran, Lan;Mackie, Susan;Tiemeier, Henning;Clasen, Liv;Lalonde, Francois;Greenstein, Dede;Pierson, Ron;Giedd, Jay N.
众所周知，自闭症具有高度遗传性，并与包括小脑在内的几种大脑结构发育异常有关。先前的研究暗示，控制大脑后脑区域（如小脑）发育的基因可能会影响患自闭症的风险。这个基因被称为同源盒结构域A1 (HOXA1)，在HOXA1中，与自闭症有关的变异（A218G）被研究得最多，它位于一个对HOXA1蛋白功能很重要的基因区域。虽然我们知道自闭症似乎会影响大脑发育的动态，并且小脑的解剖结构会随着寿命的变化而不断变化，但我们不知道A218G基因型是否会随着时间的推移影响小脑的发育。我们在正常发育的对照组中研究了这个问题，他们在5岁到23岁之间共进行了296次重复的脑部结构扫描。在每次扫描中，通过手工测量多个小脑成分的体积，我们将这些体积的发育变化与A218G基因型联系起来。我们发现，在与自闭症有关的小脑部分，A218G基因型改变了小脑的生长速度。这首次表明，假定的ASD风险基因HOXA1具有改变与ASD神经生物学相关的小脑系统纵向发育的能力。同源盒a -1 （HOXA1）被认为是自闭症谱系障碍（ASD）的候选基因，因为它调节与自闭症神经生物学有关的后脑结构的胚胎学模式。与这一观点一致的是，HOXA1 - A218G （rs10951154）高度保守区域内的非同义性单核苷酸多态性与成年后期ASD风险和上后叶小脑解剖结构的横断面差异有关。尽管有证据表明ASD早期发病和发育动态的小脑参与，但对A218G基因型与小脑早期发育成熟之间的关系知之甚少。我们通过对116名5至23岁的健康个体进行296次纵向获得的结构磁共振成像脑部扫描来解决这个问题。采用混合模型比较年龄与a纯合子（AA）和G等位基因携带者（Gcar）半自动化小脑体积测量之间的关系。两组的小脑总容量在5岁至23岁之间均有所增加。然而，与AA组相比，Gcar组的这种变化加快了（基因型-年龄相互作用项，p=0.03），并受到双侧上后叶体积随年龄变化率的基因型依赖差异的驱动（p=0.002）。结果，尽管5岁时基因型组间上后叶体积没有显著差异（p=0.9），但到23岁时，Gcar组的上后叶体积比AA组大12% （p=0.002）。我们的研究结果表明，在这个假定的ASD风险基因中，常见的遗传变异有能力改变与ASD神经生物学相关的小脑系统的发育。
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. 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 neurobiology.
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