Identification of Susceptibility Loci for Systemic Lupus Erythematosus (Sle) in Asians and Functional Characterization of the Related Genes

This dissertation, "Identification of Susceptibility Loci for Systemic Lupus Erythematosus (SLE) in Asians and Functional Characterization of the Related Genes" by Jing, Zhang, 张婧, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: SLE is a complicated autoimmune disease with a strong genetic basis. Owing to the successful application of genome-wide association study (GWAS) on complex traits, significant progresses have been made in identifying susceptible loci for SLE. So far, more than 30 loci have been shown to have robust association with the disease, significantly improving our understanding of this disease. On the other hand, these loci only confer relatively small increments in disease risk, leaving a large amount of disease heritability unexplained. Several limitations may lead to the issue of "missing heritability," such as the insufficient statistical power of standard GWAS, the failure to explore independent signals with marginal effects, and other forms of genetic variations or interactions that can hardly be detected by the current GWAS approach. In the current study, efforts have been made on solving the issue of missing heritability. Firstly, in order to increase the statistical power of GWAS, we performed meta-analysis of two existing SLE GWASs on Chinese populations, and replicated the findings in additional samples from Hong Kong, Anhui, and Thailand. We identified ARID5B and CDKN1B as novel SLE susceptibility genes through this approach. Secondly, considering the limitation of previous GWASs that only focus on the most significant signal in an individual region, we revisited the established loci by in-depth analysis on the basis of meta-analysis and followed up the findings with large-scale replication efforts. We found three additional independent signals in 11q23.3 as being associated with SLE. Thirdly, given the importance of independent effects in predisposing disease susceptibility, we performed gene-based analysis to combine the marginal independent signals within a gene to identify novel susceptibility genes. Our results demonstrated the widespread existence of independent effects within known SLE susceptibility genes, and we also identified ANXA6 as a novel SLE susceptibility gene. Lastly, we also made some efforts in the characterization of the related genes, and we identified several regulatory SNPs (rSNPs) predisposing individuals to SLE via affecting expression of the corresponding genes. In addition, we also found that epistatic interaction of variants in a previously established susceptibility gene, ETS1, correlates with cytokine (e.g.IL-17) abnormality in SLE cases. The current work represents several practical approaches to improve the power of GWAS. The findings might enrich the list of SLE susceptibility genes as well as advance our knowledge on the etiology of this complicated disease. Importantly, the current study highlights the importance of independent effects and rSNPs in conferring disease susceptibility, which may shed light on further exploration on the genetic architecture of SLE. DOI: 10.5353/th_b5066204 Subjects: Systemic lupus erythematosus - Genetic aspects