Fine mapping of autism susceptibility loci on chromosome 1q23-q24 and chromosome 13q13-q14

Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders where genetic heterogeneity has complicated the identification of genes involved in the pathogenesis in these disorders. To address this issue, we fine mapped a 30cM linkage interval on chromosome 1q23-q24 through high density microsatellite genotyping of 46 phenotypically homogeneous families described by Bartlett et al. (2005) who re-analyzed the Autism Genetic Resource Exchange (AGRE) genome scan by the Posterior Probability of Linkage (PPL). We identified genotyping errors in the original AGRE genome scan that led to an inflation of the linkage signal (PPL of 0.55) due to a false assumption of identity-by-descent (IBD). Our Multipoint PPL analysis narrowed the 30cM linkage interval to 5cM (PPL of 0.27). Subsequently, the Posterior Probability of Linkage Disequilibrium (PPLD) analysis of the AGRE 550K SNP data generated by the Autism Genome Project Consortium (AGP) and 116 tag SNPs genotyped and analyzed in our lab for the pre-B-cell leukemia transcription factor 1 (PBX1), provided the highest PPLD score for rs2800785 (0.13 and 0.12 respectively) which indicates possible association for rs2800785 (located in intron 2 of PBX1) with the trait locus. In addition, PDTPHASE single and multilocus analysis for the 116 tagSNPs showed association for rs7529254 which remained statistically significant (nominal P-value=0.0006) after correction for multiple testing with the simple M method by Gao, (alphacorrected=0.05/58)=0.0009. Four-marker PDTPHASE haplotype analysis showed transmission disequilibrium for rs1780334, rs7529254, rs2792253 and rs2800785. Global Chi-squared tests for all haplotypes produced a nominal P-value of 0.0077.;The second locus investigated was identified by multipoint PPL genome scan analysis of the 10K SNP data generated by the AGP. Ninety nine phenotypically homogeneous families were used to identify a 1.5 Mb linkage peak on chromosome 13q13-q14 with a maximum multipoint PPL score of 0.38. PPLD analysis of 142 genotyped tagSNPs from a 620.5kb peak interval which included TSC22D1, NUFIP1 and KIAA1704 showed weak evidence of LD.;No other studies have proposed PBX1 as a candidate gene for ASD. However, our positive association results with the two-point PPLD and single and multimarker PDTPHASE analysis suggests PBX1 as a likely susceptibility gene for ASD that warrants further investigation.