Institute of Neuroscience, Newcastle University, Sir James Spence Institute, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.
Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
J Neurodev Disord. 2018 Jun 11;10(1):20. doi: 10.1186/s11689-018-9238-9.
Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees.
ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale.
The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent.
Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity.
尽管现在已经确定了几个自闭症谱系障碍（ASD）的遗传变异，但这些变异大多是偶然发生的或属于新生变异。即使这种疾病在大多数情况下是家族性的，但在识别遗传变异方面的进展要小得多。本研究的目的是使用一种方法来识别增加 ASD 风险的染色体区域，该方法检查了加拿大和美国的 28 个扩展家系中的 ASD 和广泛自闭症表型（BAP）。
使用来自加拿大和美国的 28 个家系中的标准化工具评估 ASD 和 BAP，每个家系都有来自两个核心家庭的至少三个 ASD 诊断个体。使用后验连锁概率（PPL）统计量进行全基因组连锁分析，这是一种准贝叶斯方法，以基本无模型的方式提供了对连锁的证据强度，其结果在概率尺度上。
结果证实了相当大的家族间异质性以及高水平的家族内异质性。都有明显的 ASD 和联合 ASD/BAP 特定的基因座。
应该更广泛地将亚临床表型（如 BAP）纳入 ASD 的遗传研究中，以识别该疾病的遗传变异。此外，结果强调了需要采用识别扩展家系遗传风险因素的方法，这些方法对于家族间和等位基因异质性具有稳健性。
