Risk homozygous haplotype regions for autism identifies population-specific ten genes for numerous pathways

Abstract

Abstract Background Recessive homozygous haplotype (rHH) mapping is a reliable tool for identifying recessive genes by detecting homozygous segments of identical haplotype structures. These are shared at a higher frequency amongst probands compared to parental controls. Finding out such rHH blocks in autism subjects can help in deciphering the disorder etiology. Objectives The study aims to detect rHH segments of identical haplotype structure shared at a higher frequency in autism subjects than controls to identify recessive genes responsible for autism manifestation. Methods In the present study, 426 unrelated autism genotyped probands with 232 parents (116 trios) were obtained from Gene Expression Omnibus (GEO) Database. Homozygosity mapping analyses have been performed on the samples using standardized algorithms using the Affymetrix GeneChip® 500K SNP Nsp and Sty mapping arrays datasets. Results A total of 38 homozygous haplotype blocks were revealed across sample datasets. Upon downstream analysis, 10 autism genes were identified based on selected autism candidate genes criteria. Further, expressive Quantitative Trait Loci (QTL) analysis of SNPs revealed various binding sites for regulatory proteins BX3, FOS, BACH1, MYC, JUND, MAFK, POU2F2, RBBP5, RUNX3, and SMARCA4 impairing essential autism genes CEP290, KITLG, CHD8, and INS2. Pathways and processes such as adherens junction, dipeptidase activity, and platelet-derived growth factor—vital to autism manifestation were identified with varied protein-protein clustered interactions. Conclusion These findings bring various population clusters with significant rHH genes. It is suggestive of the existence of common but population-specific risk alleles in related autism subjects.

Keywords

• Homozygosity
• Recessive genes
• Autism
• Mutations
• Haplotype blocks