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
Authors
Keywords
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.

Year of Publication
2014
Journal
PLoS One
Volume
9
Issue
2
Pages
e87645
Date Published
2014
ISSN
1932-6203
URL
DOI
10.1371/journal.pone.0087645
PubMed ID
24520335
PubMed Central ID
PMC3919745
Links
Grant list
R01-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