Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants
Autor: | Marta E. Alarcón-Riquelme, David López Herráez, Helga Kristjansdottir, Manuel Martínez-Bueno, Nina Oparina, Kristjan Steinsson, Sergey V. Kozyrev, Angelica M. Delgado-Vega |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male Genotype Iceland lcsh:Medicine Locus (genetics) Biology 03 medical and health sciences Exome Sequencing medicine Humans Lupus Erythematosus Systemic Exome Gene Regulatory Networks Genetic Predisposition to Disease Allele lcsh:Science Genotyping Gene Exome sequencing Medicinsk genetik Genetics Multidisciplinary Lupus erythematosus lcsh:R Genetic Variation Molecular Sequence Annotation medicine.disease Pedigree 030104 developmental biology lcsh:Q Female Medical Genetics |
Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-17 (2018) Digibug. Repositorio Institucional de la Universidad de Granada instname |
Popis: | In an effort to identify rare alleles associated with SLE, we have performed whole exome sequencing of the most distantly related affected individuals from two large Icelandic multicase SLE families followed by Ta targeted genotyping of additional relatives. We identified multiple rare likely pathogenic variants in nineteen genes co-segregating with the disease through multiple generations. Gene co-expression and protein-protein interaction analysis identified a network of highly connected genes comprising several loci previously implicated in autoimmune diseases. These genes were significantly enriched for immune system development, lymphocyte activation, DNA repair, and V(D)J gene recombination GO-categories. Furthermore, we found evidence of aggregate association and enrichment of rare variants at the FAM71E1/EMC10 locus in an independent set of 4,254 European SLE-cases and 4,349 controls. Our study presents evidence supporting that multiple rare likely pathogenic variants, in newly identified genes involved in known disease pathogenic pathways, segregate with SLE at the familial and population level. Supported in part by the Proyecto de Excelencia de la Junta de Andalucía (http://www.juntadeandalucia.es/, CTS-2548, MEAR), the Fundación Ramón Areces (http://www.fundacionareces.es/, MEAR), the King Gustaf Vth −80th Jubilee Fund (http://www.kungahuset.se/ monarkinhovstaterna/kungligastiftelser/forskning/konunggustafvs80arsfond/, FAI-2015-0098, SVK and MEAR), Clas Groschinskys Minnesfond (http://www.groschinsky.org/, M9 25, SVK), Olle Engkvist Byggmästare Fund (http://engkviststiftelserna.se/, SOEB 210/226, SVK), Marcus Borgströms Foundation (SVK) and the Swedish Rheumatism association (https://www.reumatikerforbundet.org/, R-548551, R-145981, R-230461, R-309971, SVK and MEAR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
Databáze: | OpenAIRE |
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