Early-onset schizophrenia is associated with immune-related rare variants in a Chinese sample

BackgroundRare variants are likely to contribute to schizophrenia (SCZ), given the large discrepancy between the heritability estimated from twin and GWAS studies. Furthermore, the nature of the rare-variant contribution to SCZ may vary with the "age-at-onset" (AAO), since early-onset has been suggested as being indicative of neurodevelopment deviance. ObjectiveTo examine the association of rare deleterious coding variants in early- and adult-onset SCZ in a Chinese sample. MethodExome sequencing was performed on DNA from 197 patients with SCZ spectrum disorder and 82 healthy controls (HC) of Chinese ancestry recruited in Hong Kong. We also gathered AAO information in the majority of SCZ samples. Patients were classified into early-onset (EOS, AAO<18) and adult-onset (AOS, AAO>18). We collapsed the rare variants to improve statistical power and examined the overall association of rare variants in SCZ versus HC, EOS versus HC, and AOS versus HC at the gene and gene-set levels by Sequence Kernel Association Test. The quantitative rare-variant association test of AAO was also conducted. We focused on variants which were predicted to have a medium or high impact on the protein-encoding process as defined by Ensembl. We applied a 100000-time permutation test to obtain empirical p-values, with significance threshold set at p < 1e-3 to control family-wise error rates. Moreover, we compared the burden of targeted rare variants in significant risk genes and gene sets in cases and controls. ResultsBased on several binary-trait association tests (i.e., SCZ vs HC, EOS vs HC and AOS vs HC), we identified 7 candidate risk genes and 20 gene ontology biological processes (GOBP) terms, which exhibited higher burdens in SCZ than in controls. Based on quantitative rare-variant association tests, we found that alterations in 5 candidate risk genes and 7 GOBP pathways were significantly correlated with AAO. Based on biological and functional profiles of the candidate risk genes and gene sets, our findings suggested that, in addition to the involvement of perturbations in neural systems in SCZ in general, altered immune responses may be specifically implicated in EOS. ConclusionDisrupted immune responses may exacerbate abnormal perturbations during neurodevelopment and trigger the early onset of SCZ. We provided evidence of rare variants increasing SCZ risk in the Chinese population.