A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation.
A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation.
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DOI：
10.1038/tp.2013.75
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发表时间：
2013-09-03
影响因子：
6.8
通讯作者：
Cheyette BN
中科院分区：
文献类型：
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作者：
Martin PM;Yang X;Robin N;Lam E;Rabinowitz JS;Erdman CA;Quinn J;Weiss LA;Hamilton SP;Kwok PY;Moon RT;Cheyette BN
Wnt信号传导，其包括调节细胞外Wnt糖蛋白配体下游的神经发育的多种生化途径，已被认为有助于主要精神障碍，包括自闭症谱系障碍（ASD）。我们使用新一代测序和Sequenom基因分型技术对198名ASD患者和240名匹配对照的10个Wnt信号通路基因进行了重新测序。单核苷酸多态性（SNP）的结果在第二组91个ASD和144个对照样本中得到证实。我们发现，PolyPhen-2预测为有害的极其罕见的错义变体的负担显著增加，分布在ASD样本中的7个基因中（ASD中为3.5%，对照中为0.8%; Fisher精确检验，比值比（OR）=4.37，P=0.04）。我们还发现WNT 1中的一个错义变体（S88 R）在ASD样本中过度代表（267名ASD中的8 A/T（次要等位基因频率（MAF）=1.69%）与377名对照中的1 A/T（MAF=0.13%），OR=13.0，Fisher精确检验，P=0.0048;人群分层校正后OR=8.2和P=0.053）。功能分析显示，WNT 1-S88 R在Wnt/β-catenin信号通路的测定中比野生型WNT 1更有活性。我们的研究结果表明，ASD中分布在10个Wnt信号通路基因中的7个中的罕见错义变体的负担更高，并且WNT 1位点的功能变体与ASD相关，支持该通路的功能障碍有助于ASD易感性。鉴于最近在ASD、精神分裂症和情感障碍中的常见分子机制的发现，这些位点在其他精神疾病中也值得仔细研究。
Wnt signaling, which encompasses multiple biochemical pathways that regulate neural development downstream of extracellular Wnt glycoprotein ligands, has been suggested to contribute to major psychiatric disorders including autism spectrum disorders (ASD). We used next-generation sequencing and Sequenom genotyping technologies to resequence 10 Wnt signaling pathway genes in 198 ASD patients and 240 matched controls. Results for single-nucleotide polymorphisms (SNPs) of interest were confirmed in a second set of 91 ASD and 144 control samples. We found a significantly increased burden of extremely rare missense variants predicted to be deleterious by PolyPhen-2, distributed across seven genes in the ASD sample (3.5% in ASD vs 0.8% in controls; Fisher's exact test, odds ratio (OR)=4.37, P=0.04). We also found a missense variant in WNT1 (S88R) that was overrepresented in the ASD sample (8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048; OR=8.2 and P=0.053 after correction for population stratification). Functional analysis revealed that WNT1-S88R is more active than wild-type WNT1 in assays for the Wnt/β-catenin signaling pathway. Our findings of a higher burden in ASD of rare missense variants distributed across 7 of 10 Wnt signaling pathway genes tested, and of a functional variant at the WNT1 locus associated with ASD, support that dysfunction of this pathway contributes to ASD susceptibility. Given recent findings of common molecular mechanisms in ASD, schizophrenia and affective disorders, these loci merit scrutiny in other psychiatric conditions as well.
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影响因子：
16.2
作者：
Ataman, Bulent;Ashley, James;Budnik, Vivian
通讯作者：
Budnik, Vivian
影响因子：
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通讯作者：
Bhat, Krishna Moorthi
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作者：
Long, JM;LaPorte, P;Wynshaw-Boris, A
通讯作者：
Wynshaw-Boris, A
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作者：
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通讯作者：
Rowitch, DH
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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