Abstract
Runs of homozygosity (ROH) may play a role in complex diseases. In the current study, we aimed to test if ROHs are linked to the risk of autism and related language impairment. We analyzed 546,080 SNPs in 315 Han Chinese affected with autism and 1,115 controls. ROH was defined as an extended homozygous haplotype spanning at least 500 kb. Relative extended haplotype homozygosity (REHH) for the trait-associated ROH region was calculated to search for the signature of selection sweeps. Totally, we identified 676 ROH regions. An ROH region on 11q22.3 was significantly associated with speech delay (corrected p = 1.73×10−8). This region contains the NPAT and ATM genes associated with ataxia telangiectasia characterized by language impairment; the CUL5 (culin 5) gene in the same region may modulate the neuronal migration process related to language functions. These three genes are highly expressed in the cerebellum. No evidence for recent positive selection was detected on the core haplotypes in this region. The same ROH region was also nominally significantly associated with speech delay in another independent sample (p = 0.037; combinatorial analysis Stouffer’s z trend = 0.0005). Taken together, our findings suggest that extended recessive loci on 11q22.3 may play a role in language impairment in autism. More research is warranted to investigate if these genes influence speech pathology by perturbing cerebellar functions.
Highlights
Autistic disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, and behavioral patterns
The results suggest that the distributions of Runs of homozygosity (ROH) of early-age of first phrase (AFP) versus late-AFP groups appeared to be similar to each other (Figure 2)
A recent study identified several novel candidate genes in ROH regions associated with the risk of autism in a European-descent population [15]
Summary
Autistic disorder ( denoted as autism) is a neurodevelopmental disorder characterized by deficits in communication, social interaction, and behavioral patterns. Most genome-wide association studies (GWAS) have investigated the impact of genetic variants on the risk of autism one at a time [2,3,4]. Many of these GWAS-derived findings could not be successfully replicated across different populations [5]. Some of prior studies have focused on genes with relevant biological functions to investigate multi-locus effects on the risk of autism [7,8,9]. Wholegenome scans suggest that a cluster of rare variants across different genes may collectively predict the risk of autism [10,11]. Systemic approaches to investigating the effect of clusters of multiple loci from the whole genome may lead to discoveries that complement the GWAS-derived findings
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