Bibliographic Details
| Title: |
Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene |
| Authors: |
Diogo, Dorothee, Mouassess, Faten, Achkar, Walid A. L., Denny, Joshua C., Mirel, Daniel, Gupta, Namrata, Gabriel, Stacy, Li, Gang, Eyler, Anne E., Carroll, Robert J., Trynka, Gosia, Saxena, Richa, Guchelaar, Henk-Jan, Huizinga, Tom W. J., Dieudé, Philippe, Moreland, Larry W., Bridges Jr., S. Louis, Miceli-Richard, Corinne, Choi, Hyon K., Kamatani, Yoichiro, Galan, Pilar, Lathrop, Mark, Raj, Towfique, De Jager, Philip L., Siminovitch, Katherine A., Mardis, Elaine R., Arayssi, Thurayya, Kazkaz, Layla A. |
| Publication Year: |
2014 |
| Collection: |
Columbia University: Academic Commons |
| Subject Terms: |
Consanguinity, Rheumatoid arthritis--Etiology, Nucleotide sequence--Data processing, Genetics |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://doi.org/10.7916/D8KS6RW8 |
| DOI: |
10.7916/D8KS6RW8 |
| Availability: |
https://doi.org/10.7916/D8KS6RW8 |
| Accession Number: |
edsbas.14001781 |
| Database: |
BASE |