Abstract
BackgroundIt has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD) would benefit from the analysis of more narrowly defined ASD phenotypes. Previous research indicates that 'insistence on sameness' (IS) and 'repetitive sensory-motor actions' (RSMA) are two factors within the ASD 'repetitive and stereotyped behavior' domain. The primary aim of this study was to identify genetic risk markers of both factors to allow comparison of those markers with one another and with markers found in the same set of pedigrees using ASD diagnosis as the phenotype. Thus, we empirically addresses the possibilities that more narrowly defined phenotypes improve linkage analysis signals and that different narrowly defined phenotypes are associated with different loci. Secondary aims were to examine the correlates of IS and RSMA and to assess the heritability of both scales.MethodsA genome-wide linkage analysis was conducted with a sample of 70 multiplex ASD pedigrees using IS and RSMA as phenotypes. Genotyping services were provided by the Center for Inherited Disease Research using the 6 K single nucleotide polymorphism linkage panel. Analysis was done using the multipoint linkage software program MCLINK, a Markov chain Monte Carlo (MCMC) method that allows for multilocus linkage analysis on large extended pedigrees.ResultsGenome-wide significance was observed for IS at 2q37.1-q37.3 (dominant model heterogeneity lod score (hlod) 3.42) and for RSMA at 15q13.1-q14 (recessive model hlod 3.93). We found some linkage signals that overlapped and others that were not observed in our previous linkage analysis of the ASD phenotype in the same pedigrees, and regions varied in the range of phenotypes with which they were linked. A new finding with respect to IS was that it is positively associated with IQ if the IS-RSMA correlation is statistically controlled.ConclusionsThe finding that IS and RSMA are linked to different regions that only partially overlap regions previously identified with ASD as the phenotype supports the value of including multiple, narrowly defined phenotypes in ASD genetic research. Further, we replicated previous reports indicating that RSMA is more strongly associated than IS with measures of ASD severity.
Highlights
It has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD) would benefit from the analysis of more narrowly defined autism spectrum disorders (ASDs) phenotypes
Background it is generally accepted that genetic factors play a major role in the etiology of autism spectrum disorders (ASDs)[1], identification of specific genetic risk markers is complicated by the phenotypic complexity of clinical diagnoses
It has been argued that the ability to identify susceptibility loci for ASD would be increased if specific ASD/autistic disorder (AD) traits were used as phenotypes [3,6]
Summary
It has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD) would benefit from the analysis of more narrowly defined ASD phenotypes. (DSM-IV)[2] diagnostic criteria for autistic disorder (AD) require impairments in three domains: social interaction, communication and repetitive and stereotyped behavior Each of these three domains has been shown to be heritable, but their covariation in the general population is modest, and genetic modeling suggests distinct genetic influences for each [35]. We used the Social Reciprocity Responsiveness Scale (SRS) [17] score as the phenotype in linkage analyses of multiplex ASD pedigrees (Coon et al, Genome-wide linkage using the Social Responsiveness Scale (SRS) in Utah autism pedigrees, submitted) Each of these methods has merit, it should be noted that the first method attempts to reduce heterogeneity of the diagnostic phenotype by stratification on a specific trait, whereas the second and third approaches seek to identify risk markers for the trait itself
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