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- DOI: 10.1371/journal.pone.0087645
- PMID: 24520335
- UKPMCID: 24520335
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Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene.
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
PloS one. 2014;9(2):e87645.
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Full-text held externally
- DOI: 10.1371/journal.pone.0087645
- PMID: 24520335
- UKPMCID: 24520335
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.
Bibliographic metadata
- 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