Objectives: The aim of the present study was to conduct a linkage analysis using language onset for chromosome 7 in our sample of multiplex and extended pedigree families with ASD.
Methods: Participants were members of 70 pedigrees having at least 2 family members with ASD. A total of 653 family members were genotyped using the Center for Inherited Disease Research 6k Illumina Linkage Panel 12. 178 genotyped family members had language onset data (age at first words and age at first phrases) from the ADI-R. Of these affected subjects, 92 had delayed onset of words and 102 had delayed onset of phrases. Although there was substantial overlap (78 subjects showed delay for both words and phrases), 24 subjects showed only phrase delay, and 13 showed only delay of words. Linkage analyses were done using MCLINK multipoint linkage software. We performed nonparametric multipoint linkage analyses considering the traits as both qualitative and quantitative variables.
Results: Language traits showed some evidence for linkage on chromosome 7 at 121 – 135 cM. This is the location of a linkage peak found in our families for clinical affection status, and also using the Social Responsiveness Scale (SRS). However, linkage using the language variables at this location was diminished (HLOD=0.60 at 129 cM for word delay; HLOD=1.46 at 129 cM for phrase delay) in comparison to the clinical variables (HLOD=1.97 at 129cM for diagnosis; HLOD=2.55 at 133 cM for SRS). In contrast, linkage signals were stronger for the language variables in a more centromeric region at 55 cM – 68 cM (HLOD=1.96 at 57 cM for word delay; HLOD=1.54 at 63 cM). This region was not of great interest for clinical diagnosis in our families (HLOD=0.51 at 62 cM for diagnosis; HLOD=1.12 at 57 cM for SRS). Analyses using the language variables as quantitative traits are in progress.
Conclusions: Our peak at 121-135 cM using clinical diagnosis and SRS is consistent with multiple previous findings on chromosome 7 for autism diagnosis and language onset in autism. However, in our families the use of language delay variables did not strengthen this signal. Interestingly, the language variables suggest a peak on 7p at 55 cM – 68 cM. This peak overlaps with our previous study of a single 6-generation extended autism pedigree (Allen-Brady, et al., 2009), and also with several genetic studies of ADHD (Bakker, et al., 2003; Neale, et al., 2008; Zhou, et al., 2008). Our results suggest that language onset may provide a useful tool to identify chromosomal regions that may contain autism susceptibility loci.