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  • Almlöf, Jonas CarlssonUppsala University,Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden (författare)

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

  • Artikel/kapitelEngelska2019

Förlag, utgivningsår, omfång ...

  • 2019-02-01
  • SPRINGER,2019
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:liu-154844
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-154844URI
  • https://doi.org/10.1007/s00439-018-01966-7DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-378191URI
  • https://lup.lub.lu.se/record/d5fdf66f-7a3d-4321-8cc0-6de4c60d232cURI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:140289390URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Funding Agencies|Knut and Alice Wallenberg Foundation; Swedish Research Council for Medicine and Health [D0283001, 2017-02000]; Swedish Rheumatism Association; King Gustaf Vs 80-year Foundation; Swedish Society of Medicine; Swedish Research Council for Infrastructures (VR-RFI)
  • 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Nystedt, SaraUppsala University,Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden(Swepub:uu)sarny218 (författare)
  • Leonard, Dag,1975-Uppsala University,Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden(Swepub:uu)dagle338 (författare)
  • Eloranta, Maija-LeenaUppsala University,Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden(Swepub:uu)maelo020 (författare)
  • Grosso, GiorgiaKarolinska Institutet,Karolinska Institute,Karolinska University Hospital (författare)
  • Sjöwall, ChristopherLinköping 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(Swepub:liu)chrsj93 (författare)
  • Bengtsson, Anders A.Lund University,Lunds universitet,Lund SLE Research Group,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital(Swepub:lu)reum-abe (författare)
  • Jönsen, AndreasLund University,Lunds universitet,Lund SLE Research Group,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital(Swepub:lu)reum-ajo (författare)
  • Gunnarsson, IvaKarolinska Institutet,Karolinska Institute,Karolinska University Hospital (författare)
  • Svenungsson, ElisabetKarolinska Institutet,Karolinska Institute,Karolinska University Hospital (författare)
  • Rönnblom, LarsUppsala University,Uppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden(Swepub:uu)larsronn (författare)
  • Sandling, Johanna K.Uppsala University,Uppsala universitet,Science for Life Laboratory, SciLifeLab,Reumatologi,Uppsala Univ, Sweden(Swepub:uu)josan062 (författare)
  • Syvänen, Ann-Christine,1950-Uppsala University,Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Sweden(Swepub:uu)anncsyva (författare)
  • Uppsala universitetMolekylär medicin (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Human Genetics: SPRINGER138:2, s. 141-1500340-67171432-1203

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