Abstract
BackgroundEfforts 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.MethodsWe 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.ResultsResults 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.ConclusionsThese 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.
Highlights
Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success
The results are presented in four sections: i) we consider the comparison between pooled and sequentially updated results for both ASD and broad autism phenotype (BAP), in order to gauge the extent of between-family heterogeneity, and present primary ii) ASD and iii) BAP results, followed by iv) results for the secondary phenotypes
The proportion of the genome showing evidence against linkage (PPL
Summary
Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. Twin studies demonstrate that concordance for a phenotype that includes both autism and milder cognitive and social-communication deficits and rigidity (termed the broader autism phenotype or BAP), was >80% among monozygotic twins, compared with ~10% in dizygotic twin pairs [7], the dizygotic rate is substantially higher in the most recent twin study [8] This BAP appears more common in relatives ( parents) of ASD probands than controls (20% vs
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