Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes.
Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes.
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DOI：
10.1186/1471-2350-5-12
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发表时间：
2004-05-05
影响因子：
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通讯作者：
Haines JL
中科院分区：
文献类型：
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作者：
Hutcheson HB;Olson LM;Bradford Y;Folstein SE;Santangelo SL;Sutcliffe JS;Haines JL
大量的研究支持自闭症与基因有关。此外，来自各种基因组筛选的结果暗示染色体7q31上的一个区域具有自闭症易感性变体。我们以前缩小这34 cM的区域到一个3 cM的关键区域（位于D7S496和D7S2418之间）使用自闭症（CLSA）7号染色体连锁家族的合作连锁研究。这个区间包含约4.5 Mb的基因组DNA，编码超过50个已知和预测的基因。在这个区域的四个候选基因（NRCAM，LRRN 3，KIAA0716和LAMB 1）被选择用于检查，基于它们与这些家族中与自闭症最一致的共分离标记（D7S1817）的接近度，它们的组织表达模式，以及与自闭症的可能生物学相关性。对30个7q31连锁家系的36个内含子和外显子单核苷酸多态性（SNPs）和这4个候选基因内及周围的1个微卫星标记进行了基因分型。使用多个SNP以提供尽可能完整的覆盖，因为连锁不平衡可以在基因内甚至非常短的距离上显著变化。这些数据的分析使用系谱不平衡检验单标记和多位点似然比检验。正如预期的那样，连锁不平衡发生在这些基因中的每一个，但我们没有观察到显着的LD跨基因。NRCAM、LRRN 3或KIAA0716的多态性均未给出p < 0.05，表明这些基因中没有一个与7号染色体连锁家族的这一子集中的自闭症易感性相关。然而，对于LAMB1，等位基因关联分析揭示了正关联的暗示性证据，包括一个单独的SNP（p = 0.02）和跨基因的三个单独的双SNP单倍型（p = 0.007、0.012和0.012）。NRCAM、LRRN3、KIAA0716不太可能参与自闭症。有一些证据表明LAMB1基因或其附近的变异可能与自闭症有关。
A substantial body of research supports a genetic involvement in autism. Furthermore, results from various genomic screens implicate a region on chromosome 7q31 as harboring an autism susceptibility variant. We previously narrowed this 34 cM region to a 3 cM critical region (located between D7S496 and D7S2418) using the Collaborative Linkage Study of Autism (CLSA) chromosome 7 linked families. This interval encompasses about 4.5 Mb of genomic DNA and encodes over fifty known and predicted genes. Four candidate genes (NRCAM, LRRN3, KIAA0716, and LAMB1) in this region were chosen for examination based on their proximity to the marker most consistently cosegregating with autism in these families (D7S1817), their tissue expression patterns, and likely biological relevance to autism. Thirty-six intronic and exonic single nucleotide polymorphisms (SNPs) and one microsatellite marker within and around these four candidate genes were genotyped in 30 chromosome 7q31 linked families. Multiple SNPs were used to provide as complete coverage as possible since linkage disequilibrium can vary dramatically across even very short distances within a gene. Analyses of these data used the Pedigree Disequilibrium Test for single markers and a multilocus likelihood ratio test. As expected, linkage disequilibrium occurred within each of these genes but we did not observe significant LD across genes. None of the polymorphisms in NRCAM, LRRN3, or KIAA0716 gave p < 0.05 suggesting that none of these genes is associated with autism susceptibility in this subset of chromosome 7-linked families. However, with LAMB1, the allelic association analysis revealed suggestive evidence for a positive association, including one individual SNP (p = 0.02) and three separate two-SNP haplotypes across the gene (p = 0.007, 0.012, and 0.012). NRCAM, LRRN3, KIAA0716 are unlikely to be involved in autism. There is some evidence that variation in or near the LAMB1 gene may be involved in autism.