Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene

Yukinori Okada, Dorothee Diogo, Jeffrey D Greenberg, Faten Mouassess, Walid A L Achkar, Robert S Fulton, Joshua C Denny, Namrata Gupta, Daniel Mirel, Stacy Gabriel, Gang Li, Joel M Kremer, Dimitrios A Pappas, Robert J Carroll, Anne E Eyler, Gosia Trynka, Eli A Stahl, Jing Cui, Richa Saxena, Marieke J H Coenen, Henk-Jan Guchelaar, Tom W J Huizinga, Philippe Dieudé, Xavier Mariette, Anne Barton, Helena Canhão, João E Fonseca, Niek de Vries, Paul P Tak, Larry W Moreland, S Louis Bridges, Corinne Miceli-Richard, Hyon K Choi, Yoichiro Kamatani, Pilar Galan, Mark Lathrop, Towfique Raj, Philip L De Jager, Soumya Raychaudhuri, Jane Worthington, Leonid Padyukov, Lars Klareskog, Katherine A Siminovitch, Peter K Gregersen, Elaine R Mardis, Thurayya Arayssi, Layla A Kazkaz and Robert M Plenge

PLOS ONE, 2014, vol. 9, issue 2, 1-12

Abstract: 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.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0087645

DOI: 10.1371/journal.pone.0087645

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