Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus

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. Electronic supplementary material The online version of this article (10.1007/s00439-018-01966-7) contains supplementary material, which is available to authorized users.

Interferon pathway in SLE: one key to unlocking the mystery of the disease

“…Some of the patients have a clear SLE phenotype, and it is possible that genes responsible for the interferonopathies also contribute to the development of the disease in a subset of patients with SLE normally encountered at the rheumatology department. In fact, a recent study of whole-genome sequencing of patients with SLE shows that ultra-rare, coding heterozygous variant connected to the diverse spectrum of interferonopathies are over-represented among patients with SLE 74…”

“…Genetic profiling will also help to determine the underlying mechanism of disease in single patients. Individuals with rare monogenic SLE, including patients with rare variants of genes linked to interferonopathies,74 or genetic complement deficiency may benefit from individualised treatment. As discussed above, patients with risk gene variants linked to IFN-γ signalling including STAT4 and IL12 might benefit from inhibition of this pathway.…”

Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing

“…Due to the high cost, whole genome sequencing studies (WGS) in SLE have so far mainly focused on families or smaller samples, as have exome sequencing studies (WES). [6][7][8][9] Today it is feasible to perform targeted sequencing in larger cohorts; however, the number of such studies focusing on SLE is still limited. 10 Additionally, association analysis for rare variants discovered through sequencing is hampered by low statistical power.…”

Next Generation Sequencing and Bioinformatics Analysis of Family Genetic Inheritance

“…There are benefits to using family based GWAS (Wijsman, 2012). This approach combines both association and linkage analysis unlike population based GWAS which only provide association analysis (Almlöf et al, 2019). This approach is thus, able to perform genetic analyses that otherwise cannot be conducted on a sample of unrelated individuals.…”