Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes.
Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes.
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DOI：
10.1007/s00439-015-1585-y
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发表时间：
2015-10
期刊：
影响因子：
5.3
通讯作者：
Wijsman EM
中科院分区：
文献类型：
--
作者：
Chapman NH;Nato AQ Jr;Bernier R;Ankenman K;Sohi H;Munson J;Patowary A;Archer M;Blue EM;Webb SJ;Coon H;Raskind WH;Brkanac Z;Wijsman EM
自闭症谱系障碍(ASD)是一组神经发育障碍，以沟通和社会互动障碍为特征，并以重复行为为特征。自闭症是高度可遗传的，对风险基因座数量的估计从数百到1000不等。我们考虑了7个大家庭(大小12-47个人)，每个家庭都有3个受≥影响的自闭症患者。所有个体均用密集的SNP板进行基因分型。每个家系的一小部分用全外显子组序列(WES)进行分型。我们使用了三步法来鉴定变异体。首先，我们使用SNP数据的家庭特定参数连锁分析来识别感兴趣的区域。其次，我们根据频率和功能对这些区域的变体进行了筛选，得到了正好200个候选基因。第三，我们比较了进一步缩小这一列表的两种方法。我们使用来自SNP数据的信息将外显子不同剂量归因于那些没有WES的人。我们使用基于系谱的亲属关系矩阵来解释关系，回归了变异等位基因剂量的影响状态。对于变异等位基因剂量与表型无关的零假设检验的p值被用来表明支持该变异的证据的强度。以p=0.05为临界值，可以得到28个变异。作为替代的第三种过滤器，我们要求WES患者具有孟德尔遗传，结果产生了70个变体。基于归因和联想的方法是有效的。我们确定了四个ASD的候选基因(SEZ6L、HISPPD1、FEZF1、SAMD11)，所有这些基因都曾在其他研究中被涉及，或者有很强的生物学证据证明它们之间的相关性。
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders, characterized by impairment in communication and social interactions, and by repetitive behaviors. ASDs are highly heritable, and estimates of the number of risk loci range from hundreds to > 1000. We considered 7 extended families (size 12 – 47 individuals), each with ≥ 3 individuals affected by ASD. All individuals were genotyped with dense SNP panels. A small subset of each family was typed with whole exome sequence (WES). We used a 3-step approach for variant identification. First, we used family-specific parametric linkage analysis of the SNP data to identify regions of interest. Second, we filtered variants in these regions based on frequency and function, obtaining exactly 200 candidates. Third, we compared two approaches to narrowing this list further. We used information from the SNP data to impute exome variant dosages into those without WES. We regressed affected status on variant allele dosage, using pedigree-based kinship matrices to account for relationships. The p-value for the test of the null hypothesis that variant allele dosage is unrelated to phenotype was used to indicate strength of evidence supporting the variant. A cutoff of p=0.05 gave 28 variants. As an alternative third filter, we required Mendelian inheritance in those with WES, resulting in 70 variants. The imputation and association based approach was effective. We identified four strong candidate genes for ASD (SEZ6L, HISPPD1, FEZF1, SAMD11), all of which have been previously implicated in other studies, or have a strong biological argument for their relevance.