S79Rare Variant Analyses from Whole Genome Sequencing of 20 Chinese Schizophrenia Families

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European Neuropsychopharmacology





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Background: Schizophrenia (SCZ) is a severe psychiatric disorder with high heritability. However, the largest GWAS has only identified approximately 100 common variants, suggesting that many risk variants, especially rare variants, remain to be discovered. Methods: In this study, we selected 20 Han Chinese SCZ families with at least 2 affected siblings and 1 unaffected sibling and conducted whole genome sequencing (WGS). We used the GATK protocols to align sequence reads and annotate variants. In the first pass of analyses, we generated a list of genetic variants that were found in two affected individuals but not in the unaffected siblings within each family. We then matched the list across the families and generated a new list of variants that were shared for at least 2 families. In the end, we excluded variants on the X chromosome and focused on rare variants with minor allele frequencies (MAF) of less than 0.01, based on the GnomAD database (https://gnomad.broadinstitute.org/). Fisher's test was used to measure the P value as compared to the data from the above database. Furthermore, we did the Gene Set Enrichment Analysis (GSEA) (http://software.broadinstitute.org/gsea/) for enrichment in biological pathways. Results: 990 rare variants across 562 genes were identified to be significant after the Bonferroni correction. 3.43% of the rare variants were located in exonic regions, of which multiple variants were from HLA-C, HLA-DQA2 and HLA-DQB2 genes located on chromosome 6. These results were consistent with previous GWAS data. The variant (rs199925757 C/T at chromosome 1: 117802127) in the VTCN1 gene was the most significant (P value = 2.66E-18). Three other variants were also found to be significant in the same gene. All these variants were visually inspected and confirmed by Integrated Genome Viewer (IGV). Using GESA and KEGG database, we found that 21 pathways were significantly (FDR< 0.05) enriched in SCZ, of which include pathways involved in immune/autoimmune regulation, neuroactive ligand-receptor interaction, and cell adhesion molecules. Discussion: Rare variant analyses from the WGS of 20 Chinese SCZ families identified VTCN1(V-Set Domain Containing T-Cell Activation Inhibitor 1), a gene involved in cancer and immune regulation, strongly associated with SCZ. GSEA analysis also indicated that rare variants from SCZ families were enriched in neurological, immunological processes, and cell-cell communication. Further investigation of these variants, genes, and pathways could provide new insights to better understand the genetic risk of this disease.


Chinese Studies | Mental Disorders | Neuroscience and Neurobiology



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