Conciatori Monica, Stodgell Christopher J, Hyman Susan L, O'Bara Melanie, Militerni Roberto, Bravaccio Carmela, Trillo Simona, Montecchi Francesco, Schneider Cindy, Melmed Raun, Elia Maurizio, Crawford Lori, Spence Sarah J, Muscarella Lucianna, Guarnieri Vito, D'Agruma Leonardo, Quattrone Alessandro, Zelante Leopoldo, Rabinowitz Daniel, Pascucci Tiziana, Puglisi-Allegra Stefano, Reichelt Karl-Ludvig, Rodier Patricia M, Persico Antonio M
Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Via Longoni 83, I-00155 Rome, Italy.
Biol Psychiatry. 2004 Feb 15;55(4):413-9. doi: 10.1016/j.biopsych.2003.10.005.
The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism.
We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios.
A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype.
The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.
HOXA1基因在脑干和颅骨形态发生中起主要作用。先前已发现HOXA1 A218G多态性的G等位基因与自闭症有关。
我们进行了病例对照和基于家系的关联分析，将127例自闭症患者与174名种族匹配的对照进行对比，并在189个完整三联体中评估等位基因传递不平衡情况。
使用病例对照（基因型和等位基因的卡方值分别为chi(2)=8.96和5.71，1自由度，p<.005和<.025）和基于家系的（传递/不平衡检验chi(2)=8.80，1自由度，p<.005）关联分析，发现与自闭症相关的是A等位基因，而非G等位基因。与166例携带A/A基因型的患者相比，31例携带一个或两个G等位基因拷贝的患者头围的中位数显著更大（第95百分位数对第82.5百分位数，p<.05），个体间变异性显著降低（p<.0001）。
HOXA1 A218G多态性解释了自闭症患者头围约5%的变异，据我们所知，这是第一个已知的对颅骨形态有显著贡献的基因变异。目前正在研究这一发现的疾病特异性。基因连锁/关联研究中的非重复性可能部分源于由头围形态学定义的内表型的不均匀分布。
