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De novo mutations i...
De novo mutations implicate novel genes in systemic lupus erythematosus
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- Pullabhatla, Venu (författare)
- Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, GSTFT, NIHR,KCL, London SE1 9RT, England.
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- Roberts, Amy L. (författare)
- Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.
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- Lewis, Myles J. (författare)
- Queen Mary Univ London, William Harvey Res Inst, Ctr Expt Med & Rheumatol, London EC1M 6BQ, England.
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- Mauro, Daniele (författare)
- Queen Mary Univ London, William Harvey Res Inst, Ctr Expt Med & Rheumatol, London EC1M 6BQ, England.
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- Morris, David L. (författare)
- Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.
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- Odhams, Christopher A. (författare)
- Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.
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- Tombleson, Philip (författare)
- Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.
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- Liljedahl, Ulrika (författare)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- Vyse, Simon (författare)
- 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.
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- Simpson, Michael A. (författare)
- Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.
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- Sauer, Sascha (författare)
- 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.
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- de Rinaldis, Emanuele (författare)
- Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, GSTFT, NIHR,KCL, London SE1 9RT, England.
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- Syvänen, Ann-Christine, 1950- (författare)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- Vyse, Timothy J. (författare)
- Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.
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Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, GSTFT, NIHR,KCL, London SE1 9RT, England Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England. (creator_code:org_t)
- 2017-11-21
- 2018
- Engelska.
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 27:3, s. 421-429
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https://uu.diva-port... (primary) (Raw object)
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https://academic.oup...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
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- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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- Av författaren/redakt...
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Pullabhatla, Ven ...
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Roberts, Amy L.
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Lewis, Myles J.
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Mauro, Daniele
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Morris, David L.
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Odhams, Christop ...
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visa fler...
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Tombleson, Phili ...
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Liljedahl, Ulrik ...
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Vyse, Simon
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Simpson, Michael ...
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Sauer, Sascha
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de Rinaldis, Ema ...
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Syvänen, Ann-Chr ...
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Vyse, Timothy J.
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Uppsala universitet