Linkage and candidate gene studies of autism spectrum disorders in European populations
Linkage and candidate gene studies of autism spectrum disorders in European populations
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DOI：
10.1038/ejhg.2010.69
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发表时间：
2010-09-10
影响因子：
5.2
通讯作者：
Monaco, Anthony P.
中科院分区：
文献类型：
--
作者：
Holt, Richard;Barnby, Gabrielle;Monaco, Anthony P.
在过去的十年里，关于自闭症和自闭症谱系障碍(ASDS)易感性的遗传变异的研究一直集中在连锁和候选基因研究上。这项研究涉及到多个染色体位点和基因。候选基因研究已被证明是特别棘手的，许多研究未能复制之前报道的相关性。在这篇文章中，我们使用四个欧洲血统的队列，研究了先前涉及的基因组区域在ASD易感性中的作用。最初，使用384个SNP Illumina GoldenGate阵列来检查先前涉及的6个基因座上的连锁。我们在2号染色体上发现了接近全基因组建议水平的连锁(rs2885116，MLOD=1.89)。关联分析显示，在芬兰和荷兰北部人群中，MKL2与ASD显著相关(rs756472，P=4.31 x 10(-5))，SND1与严格自闭症(rs1881084，P=7.76 x 10(-5))显著相关。随后，我们使用第二个384SNP Illumina GoldenGate阵列来检查7个候选基因中的关联，并且在RELN中发现了关联的证据(rs362780，P=0.00165)。进一步增加样本量加强了与RELN的关联(rs362780，P=0.001)，并在GRIK2中产生了第二个显著结果(rs2518261，P=0.008)。我们的结果支持了更详细地研究RELN和GRIK2在自闭症易感性中的作用，以及确定两个新的潜在候选基因，MKL2和SND1。《欧洲人类遗传学杂志》(2010年)1810131019年；DOI：10.1038/ejhg.2010.69；2010年5月5日在线出版
Over the past decade, research on the genetic variants underlying susceptibility to autism and autism spectrum disorders (ASDs) has focused on linkage and candidate gene studies. This research has implicated various chromosomal loci and genes. Candidate gene studies have proven to be particularly intractable, with many studies failing to replicate previously reported associations. In this paper, we investigate previously implicated genomic regions for a role in ASD susceptibility, using four cohorts of European ancestry. Initially, a 384 SNP Illumina GoldenGate array was used to examine linkage at six previously implicated loci. We identify linkage approaching genome-wide suggestive levels on chromosome 2 (rs2885116, MLOD=1.89). Association analysis showed significant associations in MKL2 with ASD (rs756472, P=4.31 x 10(-5)) and between SND1 and strict autism (rs1881084, P=7.76 x 10(-5)) in the Finnish and Northern Dutch populations, respectively. Subsequently, we used a second 384 SNP Illumina GoldenGate array to examine the association in seven candidate genes, and evidence for association was found in RELN (rs362780, P=0.00165). Further increasing the sample size strengthened the association with RELN (rs362780, P=0.001) and produced a second significant result in GRIK2 (rs2518261, P=0.008). Our results strengthen the case for a more detailed study of the role of RELN and GRIK2 in autism susceptibility, as well as identifying two new potential candidate genes, MKL2 and SND1. European Journal of Human Genetics (2010) 18, 1013-1019; doi:10.1038/ejhg.2010.69; published online 5 May 2010