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, Y and Diogo, D and Greenberg, JD and Mouassess, F and Achkar, WAL and Fulton, RS and Denny, JC and Gupta, N and Mirel, D and Gabriel, S and Li, G and Kremer, JM and Pappas, DA and Carroll, RJ and Eyler, AE and Trynka, G and Stahl, EA and Cui, J and Saxena, R and Coenen, MJH and Guchelaar, HJ and Huizinga, TWJ and Dieudé, P and Mariette, X and Barton, A and Canhão, H and Fonseca, JE and De Vries, N and Tak, PP and Moreland, LW and Bridges, SL and Miceli-Richard, C and Choi, HK and Kamatani, Y and Galan, P and Lathrop, M and Raj, T and De Jager, PL and Raychaudhuri, S and Worthington, J and Padyukov, L and Klareskog, L and Siminovitch, KA and Gregersen, PK and Mardis, ER and Arayssi, T and Kazkaz, LA and Plenge, RM
(2014)
Integration of sequence data from a consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.
PLoS ONE, 9 (2).
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. © 2014 Plenge et al.
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Article
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Published |
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Creators | Email | Pitt Username | ORCID |
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Okada, 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, HJ | | | | Huizinga, TWJ | | | | Dieudé, P | | | | Mariette, X | | | | Barton, A | | | | Canhão, H | | | | Fonseca, JE | | | | De Vries, N | | | | Tak, PP | | | | Moreland, LW | lwm5@pitt.edu | LWM5 | | Bridges, SL | | | | 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 | | | |
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Contributors: |
Contribution | Contributors Name | Email | Pitt Username | ORCID |
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Editor | Sawalha, Amr H. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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Date: |
10 February 2014 |
Date Type: |
Publication |
Journal or Publication Title: |
PLoS ONE |
Volume: |
9 |
Number: |
2 |
DOI or Unique Handle: |
10.1371/journal.pone.0087645 |
Schools and Programs: |
School of Medicine > Medicine |
Refereed: |
Yes |
Date Deposited: |
18 Jun 2014 20:04 |
Last Modified: |
22 Jun 2021 15:55 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/21907 |
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