Genetics and pathophysiology of systemic lupus erythematosus in global populations

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

The LGGHDU is focused on understanding how rare genetic variants contribute to systemic lupus erythematosus (SLE) pathogenesis in a large cohort of early-onset SLE patients. We also aim to understand the genetic architecture of childhood-onset SLE (cSLE) in a cohort of patients worldwide. We have established collaborations with cSLE researchers in five countries. We were able to perform whole genome sequencing on more than 700 childhood and adult onset SLE patients worldwide, and in many cases also collect samples from unaffected relatives. Using this dataset, we are identifying rare variants which may be important to refine the heterogenous clinical phenotype of cSLE into precise molecular phenotypes. Additionally, with whole genome data, we can better understand the comprehensive genetic architecture of these patients. With these data, we will be able to define the burden of both rare and common variants in these patients and try to understand the balance in different pediatric age groups and ancestral backgrounds. Defining the genetic architecture of SLE will help us to further understand the role of genetics in disease onset and severity in the pathogenesis of this complex disease. Our study aims to include patients of diverse ages and ancestral backgrounds. Additionally, we are aiming to understand more about the clinical spectrum of cSLE. Rare Variant Analysis of childhood-onset SLE Whole genome sequencing data have a remarkable capacity for discovery of variations associated with diseases across the genome. However, the massive amounts of resulting variant data impose challenges in analysis and identifying causative variants. Trio analysis of unaffected parents and affected patients or multiplex families allows more effective variant prioritization. We have collected and sequenced 780 cSLE patients and 170 parents/unaffected relatives, of which 50 were parent/patient trios from diverse ancestral backgrounds. We have prioritized analyzing rare variants to first focus on those with a large effect on protein function. We have identified the first variants of interest. We are in the process of sequencing 70 additional SLE patients and we are continuing analysis of these samples over the coming year. We are maintaining our collaborative network to be inclusive of cSLE patients nationally and internationally. Our sequencing efforts to date will allow us to investigate a large sample of genomic data, which increases potential for discovery but also for validation of important variants. Sequencing patients across a wider age range will help us understand more about the genetic contribution of SLE along the continuum of age at disease onset. Importantly, the foundation for analysis of whole genome data in a diverse cSLE cohort has been established with this initial data analysis. Subsequent studies will be accelerated as a result of the robust methodology we have developed. Pathway Analysis of Rare Variants Enriched in cSLE We have developed and conducted pathway analysis at the cohort level to understand not only individual variants, but important biologic processes that contribute to SLE pathogenesis. Previous studies have analyzed unrelated individuals who share variants in individual genes and did not consider possible gene clustering of rare variants in SLE in genes participating in related biological processes. We performed genome sequencing in a diverse cohort of cSLE patients and parental controls and described a network-of-pathways approach to identify biological pathways enriched in genes with rare variants that may contribute to cSLE pathogenesis. Network analysis is a useful approach to identify biological pathways and specific genes that could contribute to cSLE risk. Ongoing detailed analysis of the specific variants identified in each pathway will allow us to prioritize key genes and pathways for further study. In total, this analysis may contribute to advancing the understanding of cSLE beyond a broad clinical phenotype and towards a more precise molecular diagnosis. To date, we have investigated promising variants in the RNA processing pathway. Genetic Architecture of SLE The pathogenesis of SLE is not fully understood but could be triggered by environmental events in a genetically susceptible individual. Whole exome sequencing (WES) and WGS are powerful tools for researchers elucidating genetic variants linked to human diseases. Many genome-wide association studies (GWAS) have been done in SLE, however only a few WES/WGS studies reported rare, highly penetrant genetic variants with a large impact on protein function. Whole genome data can also be mined for common variants described to confer risk for SLE by studying common variants. To understand the genetic architecture of cSLE, we first used transmission disequilibrium testing (TDT) for the families for whom we had complete trios (n=42). TDT is a family-based genetic association analysis that employs robust methodology. Our group was the first to use TDT to analyze whole genome sequencing data in SLE. We used both single nucleotide variant (SNV) based analysis to assess common variation and a gene-based analysis to detect rare variants. Our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein and DNAH11, a ciliary movement protein. Our approach identified several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort, adding to the evidence that the cSLE population is enriched in rare variants contributing to disease. In order to understand genetic architecture, we will assess the burden of known rare and common SLE risk variants in our cSLE population. Previous studies have determined that earlier onset of disease is associated with higher burden of common variants and could be quantified by utilizing polygenic risk score (PRS). A cSLE study showed that a higher score is associated with severe manifestations such as nephritis. This will be the first study to investigate the burden of both rare and common variants in a diverse, global cSLE patient cohort compared to unaffected relatives, and pair it with Type I IFN gene expression levels. The current paradigm for genetic risk in cSLE is that younger and more severe patients have a higher burden of rare damaging variants but a low burden of common milder variants. However, the actual distribution and balance between rare and common variants in cSLE patients has not been reported. We have completed an assessment of the burden of common risk variants for SLE in our diverse cohort of 83 cSLE patients using a weighted PRS and described the balance of known common and rare SLE risk variants in our cSLE cohort using whole genome data and paired it with gene expression of Type I IFN for a comprehensive analysis of genetic architecture. We have performed WGS on 780 SLE patients and 170 unaffected relatives to date. Sequencing patients across a wider age range will help us understand more about the genetic contribution of SLE along the continuum of age at disease onset. Importantly, the foundation for analysis of whole genome data in a diverse cSLE cohort has been established with this initial data analysis.