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, Robert M. Plenge

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.