A genome-wide linkage and association scan reveals novel loci for autism.
A genome-wide linkage and association scan reveals novel loci for autism.
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虽然自闭症是一种高度遗传的神经发育障碍，但迄今为止，识别特定易感基因的尝试取得了有限的成功。全基因组关联研究（GWAS）使用了50万或更多的标记，特别是那些通过荟萃分析获得的样本量非常大的标记，在绘制其他复杂遗传性状的基因图谱方面取得了巨大成功（http：//www.genome.gov/26525384）。因此，我们在1,031个多发性自闭症家庭（1,553个受影响的后代）中使用50万个全基因组SNP进行了连锁和关联作图研究。我们确定了区域的暗示和显着的连锁染色体6 q27和20 p13，分别。最初的分析并没有产生全基因组的显著关联;然而，在其他家族中，对最高命中的基因分型揭示了染色体5 p15上的SNP（在SEMA 5A和TAS 2 R1之间）与自闭症显著相关（P = 2 × 10−7）。我们还证明了SEMA 5A的表达在自闭症患者的大脑中减少，进一步暗示SEMA 5A是自闭症易感基因。这里报道的连锁区域提供了罕见变异筛选的靶点，而单一新关联的发现证明了常见变异的作用。
Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies (GWAS) using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits (http://www.genome.gov/26525384). Consequently, we initiated a linkage and association mapping study using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed a SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10−7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening while the discovery of a single novel association demonstrates the action of common variants.
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