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Title: Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene
Authors: Okada, Yukinori;Diogo, Dorothee;Greenberg, Jeffrey D.;Mouassess, Faten;Achkar, Walid A. L.;Fulton, Robert S.;Denny, Joshua C.;Gupta, Namrata;Mirel, Daniel;Gabriel, Stacy;Li, Gang;Kremer, Joel M.;Pappas, Dimitrios A.;Carroll, Robert J.;Eyler, Anne E.;Trynka, Gosia;Stahl, Eli A.;Cui, Jing;Saxena, Richa;Coenen, Marieke J. H.;Guchelaar, Henk-Jan;Huizinga, Tom W. J.;Dieudé, Philippe;Mariette, Xavier;Barton, Anne;Canhão, Helena;Fonseca, João E.;de Vries, Niek;Tak, Paul P.;Moreland, Larry W.;Bridges, S. Louis;Miceli-Richard, Corinne;Choi, Hyon K.;Kamatani, Yoichiro;Galan, Pilar;Lathrop, Mark;Raj, Towfique;De Jager, Philip L.;Raychaudhuri, Soumya;Worthington, Jane;Padyukov, Leonid;Klareskog, Lars;Siminovitch, Katherine A.;Gregersen, Peter K.;Mardis, Elaine R.;Arayssi, Thurayya;Kazkaz, Layla A.;Plenge, Robert M.
subject: Biology;Computational Biology;Genomics;Genome Analysis Tools;Genome Scans;Genome Sequencing;Molecular Genetics;Gene Identification and Analysis;Genetics;Population Genetics;Genetic Polymorphism;Genetic Screens;Genetics of Disease;Human Genetics;Population Biology;Medicine;Clinical Immunology;Autoimmune Diseases;Rheumatoid Arthritis;Epidemiology;Disease Mapping
Year: 2014
Publisher: Public Library of Science
Description: Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10−6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
Standard no: Okada, Y., D. Diogo, J. D. Greenberg, F. Mouassess, W. A. L. Achkar, R. S. Fulton, J. C. Denny, et al. 2014. “Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene.” PLoS ONE 9 (2): e87645. doi:10.1371/journal.pone.0087645.
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