| Schizophrenia is a major mental disorder characterized by a deep disruption of emotional response and thinking process, and it affects approximately 1% of the population worldwide. Genetic factors play a major role in the development of schizophrenia, which has an estimated heritability between 60-85%. The etiology of schizophrenia is thought to be multifactorial, with many small-effect and fewer large-effect susceptibility genes interacting with several environmental factors. Our understanding of the causes of schizophrenia is still limited, and a large proportion of genetic risk factors remain to explore. Here, we performed a series of studies to identify genetic risk variants for schizophrenia.Study I: To identify new common genetic risk factors, we conducted a genome-wide association study(GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 patients and 6,468 healthy controls(1,578 cases and 1,592 controls from the Northern Han; 1,238 cases and 2,856 controls from the Central Han; 934 cases and 2,020 controls from the Southern Han); and we followed up the top association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese. Meta-analysis identified genome-wide significant(GWS) association(P < 5×10-8) of common SNPs with schizophrenia on chromosome 8p12(rs16887244, PBIOX-meta = 1.27×10-10, G allele odds ratio(OR)=0.84, 95% confidence interval(CI)=0.79-0.88; rs1488935, PBIOX-meta = 5.06×10-9, T allele OR = 0.85, 95% CI = 0.81-0.90) and 1q24.2(rs10489202, PBIOX-meta = 9.50×10-9, A allele OR = 1.23, 95% CI = 1.15-1.32). Several promising candidate genes are implicated in these two regions. It’s difficult to decide precisely which genes contain the causative variants in these two chromosomal regions. Nevertheless identification of these novel common genetic risk variants that predispose to schizophrenia is an encouraging first step in a process that has the potential to be translated into improved methods for the prediction/treatment of the disease.Study II: Meta-analysis and mega-analysis of very large number of samples would provide greater power to detect the associations with small effect. A large schizophrenia GWAS of 17,836 cases and 33,859 controls of European ancestry reported by Psychiatric GWAS Consortium(PGC), and extensive replication of PGC(CLOZUK) identified several GWS loci. We try to validate the newly identified loci in Han Chinese population using 3,585 cases and 5,496 controls, considering a previously reported GWAS dataset(BIOX) in the Han Chinese population. For the combined analysis, 2 loci(ITIH3/4: rs2239547, G allele OR = 0.86, 95% CI = 0.82-0.91, P = 5.96×10-9 and CALN1: rs2944829, A allele OR = 0.85, 95% CI = 0.81-0.90 P = 9.59×10-9) showed GWS. We independently confirm association to ITIH3/4 previously reported to be GWS, and identify GWS of CALN1 that had not previously attained GWS. Replication across different ethnic groups provide stronger evidence for association between schizophrenia and these two loci, and their biological mechanisms will become increasingly important to understand the etiology of schizophrenia.Study III: GWASs have identified over 100 schizophrenia-associated genetic loci. However, the majority of the published GWASs have been on individuals of European ancestry. Here, we conducted a meta-analysis of schizophrenia GWASs using a common set of 4,323,463 variants across 39,651 cases and 57,309 controls in multi-ancestral cohorts. Ninety-four loci were identified as having a GWS, of which 78 have been previously reported. The remaining 16 GWS loci, along with 45 additional loci with an association at P < 5×10-7, which had not previously been identified as schizophrenia loci, were then tested in an independent set of 4,194 cases and 4,747 controls of Chinese ancestry for validation. Polygenic scoring analysis suggested that cross-ethnic meta-analyses are valuable and powerful approaches for genetic research. The final combined analysis revealed 13 new schizophrenia susceptibility loci(2p23.2, 2q21.2, 3q26.1, 5q11.1, 5q14.3, 6q21, 7q21.11, 8p22, 8p21.2, 8q13.3, 9p24.1, 15q25.2 and Xp21.3) with GWS, and the independent analysis of Chinese samples identified an additional two loci(8p23.1 and 14q24.2). The schizophrenia risk genes and their direct protein-protein interaction(PPI) network show a significant overlap with anti-schizophrenia drug targets(P < 1×10-5). The pathway analysis implicated energy metabolism, axon guidance and glycosphingolipid biosynthesis pathways in schizophrenia pathogenesis. Together, our findings provide new insight into the genetic architecture and biological etiology of schizophrenia.Study IV: Compelling evidences suggested the role of copy number variants(CNVs) in schizophrenia susceptibility. We performed a whole-genome copy number variation study on 6,588 schizophrenia cases and 11,904 controls from Chinese populations. Our data confirm increased genome-wide CNVs(< 1% and > 100kb) burden in schizophrenia, and the effect predominantly came from rare duplications in our sample. We also replicate several associated CNVs which were previously identified in the Caucasian populations, including duplications at 16p11.2, 15q11.2-13.1, 7q11.23 and VIPR2 and deletions at 22q11.2, 1q21.1-q21.2, 16p13.11 and NRXN1. In addition, we report additional three new loci(OR > 6, P < 0.05): duplications at 1p36.32, 10p12.1 and 13q13.3, involving many neurodevelopmental and synaptic related genes. However, these novel findings need independent confirmation in further large samples. Taken together, our findings provide further support for the role of rare CNVs in the etiology of schizophrenia.In summary, the results from the series of genetic susceptibility studies for schizophrenia confirm that the use of large samples and stringent statistical cut-offs results in reproducible findings. The identifying of so many robustly supported findings offers good opportunities for investigating and advancing our understanding of etiology, and may lead to possible further development of effective diagnosis and therapies in future. |
