Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, School of Medicine, CB# 3367, Chapel Hill, NC 27599, USA.
Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital, 575 Children's Crossroad, Columbus, OH 43215, USA.
J Neurodev Disord. 2013 Oct 5;5(1):30. doi: 10.1186/1866-1955-5-30.
Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD.
We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior.
Results reveal substantial between-family locus heterogeneity and support the importance of previously reported ASD loci in inherited, familial, forms of ASD. Additional loci, not seen in the ASD analyses, show evidence for linkage to the broad autism phenotype (BAP). BAP peaks are well supported by multiple subphenotypes (including anxiety, pragmatic language, and social behavior) showing linkage to regions overlapping with the compound BAP phenotype. Whereas 'repetitive behavior', showing the strongest evidence for linkage (Posterior Probability of Linkage = 62% at 6p25.2-24.3, and 69% at 19p13.3), appears to be linked to novel regions not detected with other compound or narrow phenotypes examined in this study.
These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears to correspond to sets of subclinical features segregating with ASD within pedigrees, and that different features of the ASD phenotype segregate independently of one another. These findings support the additional study of larger, even more individually informative pedigrees, together with measurement of multiple, behavioral- and biomarker-based phenotypes, in both affected and non-affected individuals, to elucidate the complex genetics of familial ASD.
揭示与自闭症谱系障碍（ASD）家族性质相关的风险基因型的努力取得的成果有限。通过将额外的 ASD 相关表型纳入连锁分析来研究扩展的家系，为寻找遗传 ASD 易感性变异提供了一种替代方法，这种方法补充了用于研究 ASD 遗传学的传统方法。
我们检查了通过至少两个（大多数情况下为三个）核家庭中传播的 ASD 病例确定的 19 个扩展家系中的连锁证据。既检查了复合表型（即 ASD 以及非 ASD 个体中的广泛自闭症表型），也检查了这些表型的更狭义的成分，例如社交和重复行为、语用语言和焦虑。总体目标是最大限度地增加可用于最大数量个体的综合信息，并对综合征表型进行细分，以检查 ASD 行为的更狭义方面的遗传基础。
结果显示出明显的家系间基因座异质性，并支持先前报道的 ASD 基因座在遗传性、家族性 ASD 中的重要性。在 ASD 分析中未看到的其他基因座显示出与广泛自闭症表型（BAP）连锁的证据。BAP 峰由多个亚表型（包括焦虑、语用语言和社交行为）提供了很好的支持，这些亚表型与重叠的复合 BAP 表型的区域显示出连锁。而“重复行为”显示出最强的连锁证据（连锁后验概率为 62%，位于 6p25.2-24.3 处，19p13.3 处为 69%），似乎与本研究中检查的其他复合或狭义表型未检测到的新区域有关。
这些结果为 ASD 遗传结构复杂性的关键特征的存在提供了支持：明显的家系间基因座异质性，BAP 似乎对应于与家系内 ASD 一起分离的亚临床特征集，以及 ASD 表型的不同特征彼此独立分离。这些发现支持对更大的、甚至更具个体信息量的家系进行额外研究，以及对受影响和未受影响个体的多个行为和基于生物标志物的表型进行测量，以阐明家族性 ASD 的复杂遗传学。
