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Sökning: onr:"swepub:oai:DiVA.org:uu-346884" > De novo mutations i...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00005319naa a2200469 4500
001oai:DiVA.org:uu-346884
003SwePub
008180327s2018 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3468842 URI
0247 a https://doi.org/10.1093/hmg/ddx4072 DOI
040 a (SwePub)uu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Pullabhatla, Venuu Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, GSTFT, NIHR,KCL, London SE1 9RT, England.4 aut
2451 0a De novo mutations implicate novel genes in systemic lupus erythematosus
264 c 2017-11-21
264 1b Oxford University Press,c 2018
338 a electronic2 rdacarrier
520 a The omnigenic model of complex disease stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing, high-density imputation, and in vitro cellular assays, we identify candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies. In a follow-up cohort of 10, 995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. Gene-level analyses indicate three functional candidates: DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD associated with SLE risk (P = 0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on NF-kappa B activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results identify three novel genes in SLE susceptibility and support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Medicinsk genetik0 (SwePub)301072 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medical Genetics0 (SwePub)301072 hsv//eng
7001 a Roberts, Amy L.u Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.4 aut
7001 a Lewis, Myles J.u Queen Mary Univ London, William Harvey Res Inst, Ctr Expt Med & Rheumatol, London EC1M 6BQ, England.4 aut
7001 a Mauro, Danieleu Queen Mary Univ London, William Harvey Res Inst, Ctr Expt Med & Rheumatol, London EC1M 6BQ, England.4 aut
7001 a Morris, David L.u Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.4 aut
7001 a Odhams, Christopher A.u Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.4 aut
7001 a Tombleson, Philipu Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.4 aut
7001 a Liljedahl, Ulrikau Uppsala universitet,Institutionen för medicinska vetenskaper4 aut0 (Swepub:uu)ullil257
7001 a Vyse, Simonu Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.;Inst Canc Res, Dept Canc Biol, London SW3 6JB, England.4 aut
7001 a Simpson, Michael A.u Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.4 aut
7001 a Sauer, Saschau Max Planck Inst Mol Genet, Nutrigen & Gene Regulat Res Grp, Otto Warburg Labs, D-14195 Berlin, Germany.;Max Delbruck Ctr Mol Med, BIMSB, Lab Funct Gen Nutrigen & Syst Biol, Sci Genom Platforms,BIH, D-13092 Berlin, Germany.4 aut
7001 a de Rinaldis, Emanueleu Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, GSTFT, NIHR,KCL, London SE1 9RT, England.4 aut
7001 a Syvänen, Ann-Christine,d 1950-u Uppsala universitet,Institutionen för medicinska vetenskaper4 aut0 (Swepub:uu)anncsyva
7001 a Vyse, Timothy J.u Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.4 aut
7102 a Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, GSTFT, NIHR,KCL, London SE1 9RT, England.b Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.4 org
7730 t Human Molecular Geneticsd : Oxford University Pressg 27:3, s. 421-429q 27:3<421-429x 0964-6906x 1460-2083
8564 u https://uu.diva-portal.org/smash/get/diva2:1193642/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
8564 u https://academic.oup.com/hmg/article-pdf/27/3/421/24325756/ddx407.pdf
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-346884
8564 8u https://doi.org/10.1093/hmg/ddx407

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