|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Okada, Y, Diogo, D, Greenberg, JD, Mouassess, F, Achkar, WA, Fulton, RS, Denny, JC, Gupta, N, Mirel, D, Gabriel, S, Li, G, Kremer, JM, Pappas, DA, Carroll, RJ, Eyler, AE, Trynka, G, Stahl, EA, Cui, J, Saxena, R, Coenen, MJ, Guchelaar, HJ, Huizinga, TW, Dieudé, P, Mariette, X, Barton, A, Canhão, H, Fonseca, JE, de Vries, N, Tak, PP, Moreland, LW, Bridges SL, J, Miceli-Richard, C, Choi, HK, Kamatani, Y, Galan, P, Lathrop, M, Raj, T, De Jager, PL, Raychaudhuri, S, Worthington, J, Padyukov, L, Klareskog, L, Siminovitch, KA, Gregersen, PK, Mardis, ER, Arayssi, T, Kazkaz, LA, Plenge, RM|
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.