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Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-8454-1351
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2019 (English)In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 138, no 2, p. 141-150Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 138, no 2, p. 141-150
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:uu:diva-378191DOI: 10.1007/s00439-018-01966-7ISI: 000458432800003PubMedID: 30707351OAI: oai:DiVA.org:uu-378191DiVA, id: diva2:1293182
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, D0283001Swedish Research Council, 2017-02000Swedish Research CouncilThe King Gustaf V's Jubilee FoundationSwedish Rheumatism AssociationAvailable from: 2019-03-04 Created: 2019-03-04 Last updated: 2019-03-04Bibliographically approved

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Almlöf, Jonas CarlssonNystedt, SaraLeonard, DagEloranta, Maija-LeenaRönnblom, LarsSandling, Johanna K.Syvänen, Ann-Christine

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Almlöf, Jonas CarlssonNystedt, SaraLeonard, DagEloranta, Maija-LeenaSjowall, ChristopherRönnblom, LarsSandling, Johanna K.Syvänen, Ann-Christine
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