Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14
Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14
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DOI：
10.1038/sj.mp.4001927
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发表时间：
2007-04-01
影响因子：
11
通讯作者：
Pericak-Vance, M. A.
中科院分区：
文献类型：
--
作者：
Ma, D. Q.;Cuccaro, M. L.;Pericak-Vance, M. A.
自闭症基因座异质性。迄今为止，已经使用同胞对家庭（父母和受影响的儿童）的各种数据集进行了12个微卫星基因组筛选，从而在整个基因组中产生了许多潜在的连锁区域。然而，没有通用的区域或一致的候选基因从这些地区已经出现。使用大的，扩展的家系是一个公认的强大的方法来确定显着的连锁结果，因为这些家庭可能包含更多的潜在的连锁信息比同胞对家庭。对26个自闭症大家庭（65个受影响，184个个体）进行了全基因组连锁分析。每个家庭有两到四个受影响的个人组成的叔叔或堂兄弟对。为了进行分析，我们使用了高密度单核苷酸多态性基因分型检测，Affyssin基因芯片人类图谱10K阵列。两点分析得出在染色体14 q上的rs2877739处的峰值异质性检测限（HLOD）为2.82。在1q、2q、5q、6p、11q和12q染色体上也发现了两点连锁证据（HLOD > 2）。染色体12q是唯一的区域显示显着的连锁证据，多点分析与峰值HLOD = 3.02在rs1445442。此外，这种联系的证据得到了加强显着的家庭只有男性受影响（多点HLOD = 4.51），这表明一个显着的性别特异性的影响自闭症的病因。对12号染色体的全染色体单倍型分析将潜在的自闭症基因定位在一个4 cM的区域，该区域在连锁家族中受影响的个体中共享。染色体12q上的这一新的连锁峰进一步支持了自闭症基因座异质性的假说。
Autism locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD > 2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p, 11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD = 3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD = 4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.