Comprehensive Integrative Analyses Identify TIGD5 rs75547282 as a Risk Variant for Autism Spectrum Disorder

Although recent genome-wide association studies have identified risk loci that strongly associates with autism spectrum disorder (ASD), how to pinpoint the causal genes remains a challenge. We aimed to pinpoint the potential causal genes and explore the possible susceptibility and mechanism. A convergent functional genomics (CFG) method was used to prioritize the candidate genes by combining lines of evidence, including Sherlock analysis, spatio-temporal expression patterns, expression analysis, protein-protein interactions, co-expression and association with brain structure. A higher score in the CFG approach suggested that more evidence supported this gene as an ASD risk gene. We screened genes with higher CFG scores for candidate functional single nucleotide polymorphisms (SNPs). A genotyping experiment (602 ASD children and 604 healthy sex-matched children) and the dual-luciferase reporter gene assay were followed to validate the effects of SNPs. We identified three genes (MAPT, ZNF285, and TIGD5) as candidate causal genes using the CFG approach. The genotyping experiment showed that TIGD5 rs75547282 was associated with an increased risk of ASD under the dominant model (OR = 1.37, 95% CI = 1.09-1.72, P = 0.006) though the statistical power was limited (5.2%). The T allele of rs75547282 activated the expression of TIGD5 compared with the C allele in the dual-luciferase reporter assay. Our study indicates that such comprehensive integrative analyses may be an effective way to explore promising ASD susceptibility variants and needs to be further investigated in future research. Genotyping experiments should, however, be based on a larger population sample to increase statistical power. LAY SUMMARY: We set out to pinpoint the potential causal genes of ASD and explore the possible susceptibility and mechanism by combining lines of evidence from different analyses. Our results show that TIGD5 rs75547282 is associated with the risk of ASD in the Han Chinese population. In addition, a similar framework to seek promising ASD risk variants could be further investigated in future research Autism Res 2021, 14: 631-644. © 2021 International Society for Autism Research and Wiley Periodicals LLC.