Genetics and pathophysiology of systemic lupus erythematosus in global populations

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications & trials

Abstract

This unit is focused on understanding how rare genetic variants contribute to systemic lupus erythematosus (SLE) pathogenesis in a diverse cohort of early-onset SLE patients. We also aim to understand the genetic architecture of childhood-onset SLE (cSLE) in a large cohort of patients worldwide. We have established collaborations with cSLE researchers in four countries. In doing so, we were able to perform whole genome sequencing on more than 500 childhood and adult onset SLE patients worldwide, and in many cases also collect samples from unaffected relatives. Using this collection, we are beginning to identify 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, as previous studies have focused on mostly patients of European ancestry and of very early onset of disease. In addition, through collaboration, we are aiming to understand more about the clinical spectrum of cSLE. Rare Variant Analysis of childhood-onset SLE Whole genome data have remarkable capacity for discovery of variation causing disease across the genome. Yet whole genome sequencing (WGS) studies yield massive amounts of variant data, and it can be difficult to identify causative variants. Trio analysis of unaffected parents and affected patients or multiplex families allows more effective variant prioritization. We have collected and sequenced 443 cSLE patients and 170 parents, of which 50 were parent/patient trios from diverse ancestral backgrounds. We have prioritized rare variants through bioinformatic pipelines 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 270 additional SLE patients and we are continuing analysis of these samples over the coming year. We are currently growing our collaborative network to include more cSLE patients nationally and internationally. Additional sequencing efforts will allow us to increase sample size, 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. Therefore, subsequent studies will be accelerated by benefitting from the robust methodology we have developed. Pathway Analysis of Rare Variants Enriched in cSLE In addition, we will conduct pathway analysis at the cohort level to understand not only individual variants, but important biologic processes that contribute to SLE pathogenesis. Historically, studies have focused on unrelated individuals who share variants in individual genes. However, this approach doesnt consider that rare variants in SLE could cluster in genes participating in related biological processes. We performed genome sequencing in a diverse cohort of cSLE patients and parental controls, and describe 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. Genetic Architecture of SLE The pathogenesis of SLE is not fully understood but thought to 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. In addition to rare variant analysis, whole genome data can 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, and our group was the first to use it 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, among others. 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 which contribute to disease. Another approach to understand genetic architecture is to assess the burden of known rare and common SLE risk variants in our cSLE population. A cumulative genetic risk score can describe the burden of common risk variants carried within a cohort of patients. Previous studies have determined that earlier onset of disease is associated with higher polygenic risk score (PRS). A study in cSLE showed that a higher score is associated with severe manifestations such as nephritis. No studies compiling a PRS from whole genome data in cSLE patients have been completed to date. This will be the first study to investigate the burden of both rare and common variants in a cSLE patient cohort compared to unaffected relatives. The current paradigm for genetic risk in cSLE is that the burden of rare and common SLE risk variants is inversely related in patients, with younger and more severe patients having a higher burden of rare, damaging variants but a low burden of common milder variants. Inversely, adolescent patients and those with milder phenotypes are expected to have a higher burden of common SLE risk variants and few rare variants. However, the actual distribution and balance between rare and common variants in cSLE patients have 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 polygenic risk score. We will map the balance of known common and rare SLE risk variants in our cSLE cohort using whole genome data. We will compare the burden of common variants of the patients to those of their unaffected parents. We have performed WGS on 545 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.