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Whole-genome sequen...
Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus
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- Almlöf, Jonas Carlsson (author)
- Uppsala University,Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden
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- Nystedt, Sara (author)
- Uppsala University,Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden
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- Leonard, Dag, 1975- (author)
- Uppsala University,Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden
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- Eloranta, Maija-Leena (author)
- Uppsala University,Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden
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- Grosso, Giorgia (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital
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- Sjöwall, Christopher (author)
- Linköping University,Linköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten,Region Östergötland, Reumatologiska kliniken i Östergötland,Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Rheumatol, S-58183 Linkoping, Sweden
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- Bengtsson, Anders A. (author)
- Lund University,Lunds universitet,Lund SLE Research Group,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital
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- Jönsen, Andreas (author)
- Lund University,Lunds universitet,Lund SLE Research Group,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital
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- Gunnarsson, Iva (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital
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- Svenungsson, Elisabet (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital
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- Rönnblom, Lars (author)
- Uppsala University,Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden
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- Sandling, Johanna K. (author)
- Uppsala University,Uppsala universitet,Science for Life Laboratory, SciLifeLab,Reumatologi,Uppsala Univ, Sweden
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- Syvänen, Ann-Christine, 1950- (author)
- Uppsala University,Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden
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(creator_code:org_t)
- 2019-02-01
- 2019
- English.
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In: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 138:2, s. 141-150
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https://urn.kb.se/re...
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https://urn.kb.se/re...
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https://lup.lub.lu.s...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
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Almlöf, Jonas Ca ...
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Nystedt, Sara
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Leonard, Dag, 19 ...
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Eloranta, Maija- ...
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Grosso, Giorgia
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Sjöwall, Christo ...
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Bengtsson, Ander ...
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Jönsen, Andreas
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Gunnarsson, Iva
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Svenungsson, Eli ...
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Rönnblom, Lars
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Sandling, Johann ...
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Syvänen, Ann-Chr ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Rheumatology and ...
- Articles in the publication
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Human Genetics
- By the university
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Linköping University
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Uppsala University
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Lund University
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Karolinska Institutet