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.

中文翻译：

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自闭症谱系障碍和扩展谱系中广泛自闭症表型的全基因组连锁研究

尽管现在已经确定了自闭症谱系障碍（ASD）的几种遗传变异，但这些变异大多是零星发生的，或者是从头开始的。尽管大多数情况下疾病本身是家族性的，但在鉴定遗传变异方面却进展甚微。这项研究的目的是使用一种在扩展谱系的独特样本中检查ASD和广泛自闭症表型（BAP）的方法，鉴定具有遗传变异的染色体区域，这些变异会增加ASD的风险。在来自加拿大和美国的28个家谱中，使用标准化工具对ASD和BAP进行了评估，每个家谱中至少有3名来自两个核心家庭的ASD诊断者。全基因组连锁分析是使用连锁后验概率（PPL）统计数据进行的，一种准贝叶斯方法，以基本无模型的方式提供支持或反对链接的证据强度，其结果在概率范围内。结果证实了明显的家族间异质性和高水平的家族内异质性。ASD和组合的ASD / BAP特定基因座都是显而易见的。包括亚临床表型（如BAP）应在ASD的遗传学研究中更广泛地应用，作为鉴定该疾病遗传遗传变异的一种方法。此外，结果强调需要一种方法来鉴定扩展谱系中的遗传危险因素，这些遗传因素对高水平的间/颅内基因座和等位基因异质性具有鲁棒性。结果证实了明显的家族间异质性和高水平的家族内异质性。ASD和组合的ASD / BAP特定基因座都是显而易见的。包括亚临床表型（如BAP）应在ASD的遗传学研究中更广泛地应用，作为鉴定该疾病遗传遗传变异的一种方法。此外，结果强调需要一种方法来鉴定扩展谱系中的遗传危险因素，这些遗传因素对高水平的间/颅内基因座和等位基因异质性具有鲁棒性。结果证实了明显的家族间异质性和高水平的家族内异质性。ASD和组合的ASD / BAP特定基因座都是显而易见的。包括亚临床表型（如BAP）应在ASD的遗传学研究中更广泛地应用，作为鉴定该疾病遗传遗传变异的一种方法。此外，结果强调了对鉴定扩展谱系中遗传风险因素的方法的需求，这些谱系对高水平的间/颅内基因座和等位基因异质性具有鲁棒性。