Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs

Abstract

Autism is a neurodevelopmental syndrome with early childhood onset and deficits in three behavioral and cognitive dimensions: language, social skills and repetitive or restrictive behaviors. We hypothesized that using these endophenotypes would provide more power to detect linkage than the diagnosis of autism. Previously, we reported results for a nonparametric quantitative trait locus (QTL) genome scan in 152 families with autism, which revealed a linkage peak related to spoken language on 7q35. Here, we present the results of a nonparametric QTL scan of autism endophenotypes in 291 multiplex families, including the original 152. The strongest evidence for an 'age at first word' QTL was on chromosomes 3q at 147 cM (Z ¼ 3.10, Po0.001), and 17q at 93 cM (Z ¼ 2.84, P ¼ 0.002), both represent novel susceptibility loci for autism endophenotypes. There was also support for a previously identified autism peak on chromosome 17 at 43 cM (Z ¼ 2.22, P ¼ 0.013) with 'age at first phrase'. The 7q35 language peak was attenuated (Z ¼ 2.05, P ¼ 0.02) compared with the original finding. To explore the possibility of increased heterogeneity resulting from the addition of 135 families to the sample, we conducted an Ordered-Subsets Analysis on chromosome 7; these results suggest that the 132 autism families with the earliest average age at first word are responsible for the QTL on 7q35. This locus on 7q35 may harbor a gene contributing variability in spoken language that is not uniquely related to language delay in autism. Molecular Psychiatry (2005) 10, 747-757.

Evidence for multiple loci from a genome scan of autism kindreds

“…53 We did not find significant supporting evidence for language-related signals on other chromosomes (2, 3, 7q (B103 cM) or 13) that were identified in previous linkage studies. 13,29,30 In comparing our results to other studies, we provide strong support for a chromosome 7 autism locus, and lesser but still compelling support for loci on chromosomes 3, 4 and 11. However, we were not able to reproduce a number of substantial signals reported by others.…”

“…Based on recent findings by others, we also conducted secondary stratified and quantitative trait analyses of: (1) families with only male affected children (male-only, MO) versus families where there was at least one affected female child (female-containing, FC); 17,20 (2) families with or without developmental regression; 27 and (3) age at first word and phrase as quantitative traits. 13,[28][29][30] Our results provide strong evidence for an autism locus on chromosome 7q with the evidence for linkage being strongest in the subset with the strictest diagnosis. This provides strong confirmation of previous results for chromosome 7q.…”

“…Our secondary analyses attempted to replicate specific regional linkage signals reported by others who stratified their sample using gender, 20 developmental regression, 27 and language acquisition. 29 Our tertiary analyses explored the possibility of additional regions with relevant loci by completing the scan for the rest of the genome using strata defined by the same gender, developmental regression and language acquisition phenotypes.…”

“…Also, because of pragmatic difficulties with accumulating large sample sizes of affected sib pairs (ASPs), no study to date has restricted enrollment to only sib pairs with the strictest diagnosis of autism in all affected individuals, although some studies have required that one sib meets the strict diagnosis. In addition, to attempt to reduce genetic heterogeneity, some groups have also defined phenotypic subsets of autism families using measures such as regression, 27 age at first word or phrase, 28,29 language delay, 13,30 repetitive and stereotypic behaviors [28][29][30] and obsessive-compulsive behaviors. 31 These studies provide additional evidence for autism loci at 1q24.2, 7q, 13q, 17q and 21q.…”

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…40,[119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137] Research groups, study design and main findings of linkage studies that reported positive results are summarized in Table 1 for genome-wide linkage and association studies with a qualitative AD phenotype, and in Table 2 for linkage studies with either a quantitative phenotype, a specific qualitative endophenotype, or other specific linkage models. 122,123,127,130,[138][139][140][141][142][143][144][145][146][147][148] From Table 1, it can be seen that linkage has been found in at least two independent studies in regions 2q, 3q25-27, 3p25, 6q14-21, 7q31-36 and 17q11-21.…”