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

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 = 3.10, P<0.001), and 17q at 93 cM ( Z = 2.84, P = 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 = 2.22, P = 0.013) with 'age at first phrase'. The 7q35 language peak was attenuated ( Z = 2.05, P = 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.