Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

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).

[img]
Preview
PDF
Published Version
Available under License : See the attached license file.

Download (974kB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)

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.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
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, LWlwm5@pitt.eduLWM5
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
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSawalha, Amr H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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: 19 Aug 2019 14:55
URI: http://d-scholarship.pitt.edu/id/eprint/21907

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com


Actions (login required)

View Item View Item