International Meeting for Autism Research (London, May 15-17, 2008): Replication and Association Analysis of a 1p13-q12 Locus for Nonverbal Communication Deficits in Autism Spectrum Disorder

Replication and Association Analysis of a 1p13-q12 Locus for Nonverbal Communication Deficits in Autism Spectrum Disorder

Thursday, May 15, 2008
Champagne Terrace/Bordeaux (Novotel London West)
10:30 AM
J. L. Yoon , Human Genetics, UCLA
M. Alarcon , Neurology, UCLA
D. Geschwind , Neurology, University of California, Los Angeles
R. M. Cantor , Human Genetics, UCLA, Los Angeles, CA
Background: The heritability of Autism Spectrum Disorder(ASD) is well established; however, inconsistent linkage and association results reveal its genetic complexity. Analysis of individual heritable quantitative features of ASD offers an opportunity to reduce complexity and increase consistency. Applying this strategy, the deficit in nonverbal communication (NVC) was quantified in children from 236 families in the Autism Genetics Resource Exchange(AGRE) using an Autism Diagnostic Instrument Revised sub-score. A nonparametric multipoint whole genome linkage analysis of the 299 sibpairs revealed an NVC quantitative trait locus(QTL) at 1p13-q12(p < .0001), among others(Chen et. al., Mol Psych, 2006).
Objectives: To replicate the NVC QTL in a whole genome scan analysis of an independent sample of AGRE families and to identify genes predisposing to deficits in NVC by conducting association analyses in the replicated QTL.
Methods: A nonparametric QTL analysis was conducted using the Genehunter software in an independent sample of 219 AGRE families with 274 sibpairs. To identify genes associated with NVC, empiric family based analysis was conducted with the FBAT software on the 12,019 Affymetrix 550K SNPs located in the 1p13-q12 QTL on 680 children from 286 AGRE families.
Results: The 1p13-q12 NVC QTL was replicated(p < .0001), providing strong evidence that genes in this region predispose to deficits in NVC. Setting .0001 as the level of significance, SNPs in or near 3 genes within the QTL were associated with NVC, with one SNP exceeding a Bonferroni correction(p<.000004). Associated haplotypes were detected (p < .0001), and a haplotype within one of the genes was also associated with ASD(p<.00007).
Conclusions: Gene(s) in 1p13-q12 contribute to deficits in NVC. Conducting QTL analyses of heritable quantitative features of ASD, filtering by replication, and following with targeted association studies is an effective strategy to identify genes predisposing to features of ASD as well as the disorder itself.