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

Academic Article

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.
  • Published In

  • PLoS ONE  Journal
  • Keywords

  • Arthritis, 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
  • Digital Object Identifier (doi)

    Pubmed Id

  • 22495295
  • Author List

  • Okada Y; Diogo D; Greenberg JD; Mouassess F; Achkar WAL; Fulton RS; Denny JC; Gupta N; Mirel D; Gabriel S
  • Start Page

  • e87645
  • Volume

  • 9
  • Issue

  • 2