Abstract
Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare ( ≤ 0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.
Highlights
Systemic lupus erythematosus (SLE, OMIM 152700) is a clinically heterogeneous autoimmune disease with an estimated heritability of 0.66 similar to other autoimmune diseases (Selmi et al 2012)
In an earlier study (Almlof et al 2017), we developed a random forest (RF) model to determine a score that indicates the risk to develop SLE based on the genotype data from a Swedish SLE case–control association study using the ImmunoChip with approximately 120 k SNPs across 186 loci known to be associated with immune-mediated diseases (Illumina) (Cortes and Brown 2011)
We here used the single nucleotide variant (SNV) calls from whole-genome sequencing (WGS) of 71 trio families with the offspring affected by SLE that overlap with the single nucleotide variants (SNVs) included on the ImmunoChip (97.4% overlap) to determine the RF derived risk scores for SLE for the trio family members
Summary
Systemic lupus erythematosus (SLE, OMIM 152700) is a clinically heterogeneous autoimmune disease with an estimated heritability of 0.66 similar to other autoimmune diseases (Selmi et al 2012). There exist several monogenic disorders with an SLE-like phenotype that are inherited in a Mendelian fashion and are caused by mutations in one out of 32 so far known genes (Tsokos et al 2016). These genes have been identified by familial manifestation of SLE that is mainly shared between mother and daughter or between female sibling pairs in a family. In ten of these genes there are mutations that cause classical SLE where a patient fulfills the classification criteria for SLE (Tan et al 1982). Another set of 12 genes carry mutations that cause dysregulation of genes in the type I interferon (IFN) system, which is a prominent feature shared by the majority of patients with SLE (Hagberg and Ronnblom 2015)
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