Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants
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AuthorDelgado-Vega, Angélica M.; Martínez Bueno, Manuel; Oparina, Nina Y.; López Herráez, David; Kristjansdottir, Helga; Steinsson, Kristján; Kozyrev, Sergey V.; Alarcón-Riquelme, Marta E.
Springer Nature Publishing AG
Delgado-Vega, Angélica M.; Martínez Bueno, Manuel; Oparina, Nina Y.; López Herráez, David; Kristjansdottir, Helga; Steinsson, Kristján; Kozyrev, Sergey V.; Alarcón-Riquelme, Marta E. Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants. Scientific reports (2018) 8:8775. [http://hdl.handle.net/10481/54819]
SponsorshipSupported 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.
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.