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PLoS One DOI:10.1371/journal.pone.0087645

Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.

Publication TypeJournal Article
Year of Publication2014
AuthorsOkada, Y, Diogo, D, Greenberg, JD, Mouassess, F, Achkar, WAL, 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, MJH, Guchelaar, H-J, Huizinga, TWJ, Dieude, P, Mariette, X, Barton, A, Canhao, H, Fonseca, JE, de Vries, N, Tak, PP, Moreland, LW, S Bridges, L, 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
JournalPLoS One
Date Published2014
KeywordsArthritis, Rheumatoid, Base Sequence, Cohort Studies, Consanguinity, European Continental Ancestry Group, Exome, Exons, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Lysophospholipase, Male, Meta-Analysis as Topic, Mutation, Pedigree, Polymorphism, Single Nucleotide, Reproducibility of Results, Risk Factors

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.


Alternate JournalPLoS ONE
PubMed ID24520335
PubMed Central IDPMC3919745
Grant ListR01-AR057108 / AR / NIAMS NIH HHS / United States
K08-KAR055688A / / PHS HHS / United States
P60 AR047785 / AR / NIAMS NIH HHS / United States
MOP79321 / / Canadian Institutes of Health Research / Canada
U01 GM092691 / GM / NIGMS NIH HHS / United States
R01-AR065944 / AR / NIAMS NIH HHS / United States
R01-AR059648 / AR / NIAMS NIH HHS / United States
R01-AR056768 / AR / NIAMS NIH HHS / United States
R01AR063759-01A1 / AR / NIAMS NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
MANMKBRU-2012-1 / / Department of Health / United Kingdom
R21 AR056042 / AR / NIAMS NIH HHS / United States
R01-AR056291 / AR / NIAMS NIH HHS / United States
U01-GM092691 / GM / NIGMS NIH HHS / United States
20385 / / Arthritis Research UK / United Kingdom
U01 GM097119 / GM / NIGMS NIH HHS / United States