Conroy Judith, Cochrane Lynne, Anney Richard J L, Sutcliffe James S, Carthy Paula, Dunlop Adam, Mullarkey Marice, O'hici Bronagh, Green Andrew J, Ennis Sean, Gill Michael, Gallagher Louise
Neuropsychiatric Genetics Research Group, Trinity Centre for Health Sciences, Trinity College Dublin, Dublin, Ireland.
Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):535-44. doi: 10.1002/ajmg.b.30854.
Autism (OMIM %209850) is a neurodevelopmental disorder with a strong genetic component. We previously reported a de novo rearrangement of chromosome 2q31 in a patient with autism [Gallagher et al. (2003); J Autism Dev Disord 33(1):105-108]. Further cytogenetic analysis revealed this to be a 46,XY, t(9;2)(q31.1;q32.2q31.3) translocation. Association mapping with microsatellite and SNP markers of this translocated region on 2q revealed association with markers in Integrin alpha-4 (ITGA4; GeneID 3676). ITGA4 was tested for association in a sample of 179 trio-based families. SNP markers in exons 16 and 17 showed evidence of association. Mutation screening revealed a G to A synonymous variation in the last nucleotide of exon 16 (rs12690517), significantly associated with autism in the Irish sample (OR = 1.6; P = 0.04). The location of this SNP at a putative splice donor site may affect the splicing of the ITGA4 protein. Haplotype analysis showed significant overtransmission of haplotypes surrounding this marker. These markers were investigated in two additional samples, 102 families from Vanderbilt University (VT) (n = 102), and AGRE (n = 267). A non-significant trend towards overtransmission of the associated allele of rs12690517 in the Irish sample (OR = 1.2; P = 0.067) and haplotypes at the 3' end of ITGA4 was observed in the AGRE sample. The VT sample showed association with markers and haplotypes across the gene, but no association with the rs12690517 marker or its surrounding haplotypes. The combined sample showed evidence of association with rs12690517 (OR = 1.3; P = 0.008) and surrounding haplotypes. The findings indicate some evidence for the role of ITGA4 as candidate gene for autism.
自闭症（在线人类孟德尔遗传数据库编号%209850）是一种具有很强遗传因素的神经发育障碍疾病。我们之前报道过一名自闭症患者存在2号染色体q31区域的新生重排[加拉格尔等人（2003年）；《自闭症与发育障碍杂志》33(1):105 - 108]。进一步的细胞遗传学分析显示这是一种46,XY，t(9;2)(q31.1;q32.2q31.3)易位。对2号染色体上这个易位区域用微卫星和单核苷酸多态性（SNP）标记进行关联定位，发现与整合素α - 4（ITGA4；基因编号3676）中的标记存在关联。在179个基于三联体的家庭样本中对ITGA4进行关联检测。外显子16和17中的SNP标记显示出关联证据。突变筛查发现外显子16最后一个核苷酸处有一个从G到A的同义变异（rs12690517），在爱尔兰样本中与自闭症显著相关（比值比 = 1.6；P = 0.04）。这个SNP位于一个假定的剪接供体位点，可能会影响ITGA4蛋白的剪接。单倍型分析显示围绕这个标记的单倍型存在显著的过度传递。在另外两个样本中对这些标记进行了研究，一个是来自范德比尔特大学（VT）的102个家庭样本（n = 102），另一个是自闭症遗传资源交换库（AGRE）的样本（n = 267）。在爱尔兰样本中观察到rs12690517相关等位基因有不显著的过度传递趋势（比值比 = 1.2；P = 0.067），在AGRE样本中观察到ITGA4 3'端的单倍型有这种趋势。VT样本显示整个基因的标记和单倍型存在关联，但与rs12690517标记或其周围单倍型无关联。合并后的样本显示与rs12690517（比值比 = 1.3；P = 0.008）及其周围单倍型存在关联证据。这些发现表明有一些证据支持ITGA4作为自闭症候选基因的作用。
