SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data

Background: Despite thousands of variants identified by genome-wide association studies (GWAS) to be associated with autism spectrum disorder (ASD), it is unclear which mutations are causal because most are noncoding. Consequently, reliable diagnostic biomarkers are lacking. RNA-seq analysis captures biomolecular complexity that GWAS cannot by considering transcriptomic patterns. Therefore, integrating DNA and RNA testing may reveal causal genes and useful biomarkers for ASD. Methods We performed gene-based association studies using an adaptive test method with GWAS summary statistics from two large Psychiatric Genomics Consortium (PGC) datasets (ASD2019: 18,382 cases and 27,969 controls; ASD2017: 6,197 cases and 7,377 controls). We also investigated differential expression for genes identified with the adaptive test using an RNA-seq dataset (GSE30573: 3 cases and 3 controls) and DESeq2. Results We identified 5 genes significantly associated with ASD in ASD2019 (KIZ-AS1, p = 8.67×10 − 10 ; KIZ, p = 1.16×10 − 9 ; XRN2, p = 7.73×10 − 9 ; SOX7, p = 2.22×10 − 7 ; LOC101929229 (also known as PINX1-DT), p = 2.14×10 − 6 ). Two of the five genes were replicated in ASD2017: SOX7 (p = 0.00087) and LOC101929229 (p = 0.009), and KIZ was close to the replication boundary of replication (p = 0.06). We identified significant expression differences for SOX7 (p = 0.0017, adjusted p = 0.0085), LOC101929229 (p = 5.83×10 − 7 , adjusted p = 1.18×10 − 5 ), and KIZ (p = 0.00099, adjusted p = 0.0055). SOX7 encodes a transcription factor that regulates developmental pathways, alterations in which may contribute to ASD. Limitations: The limitation of the gene-based analysis is the reliance on a reference population for estimating linkage disequilibrium between variants. The similarity of this reference population to the population of study is crucial to the accuracy of many gene-based analyses, including those performed in this study. As a result, the extent of our findings is limited to European populations, as this was our reference of choice. Future work includes a tighter integration of DNA and RNA information as well as extensions to non-European populations that have been under-researched. Conclusions These findings suggest that SOX7 and its related SOX family genes encode transcription factors that are critical to the downregulation of the canonical Wnt/\(\beta\)-catenin signaling pathway, an important developmental signaling pathway, providing credence to the biologic plausibility of the association between gene SOX7 and autism spectrum disorder.