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PLoS One. 2014 Feb 10;9(2):e87645. doi: 10.1371/journal.pone.0087645. eCollection 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.

Author information

1
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America ; Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan ; Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
2
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
3
New York University Hospital for Joint Diseases, New York, New York, United States of America.
4
Molecular Biology and Biotechnology Department, Human Genetics Division, Damascus, Syria.
5
The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
6
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
7
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
8
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
9
Department of Medicine, Albany Medical Center and The Center for Rheumatology, Albany, New York, United States of America.
10
Division of Rheumatology, Department of Medicine, New York, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
11
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
12
The Department of Psychiatry at Mount Sinai School of Medicine, New York, New York, United States of America.
13
Center for Human Genetics Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
14
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
15
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
16
Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
17
Service de Rhumatologie et INSERM U699 Hôpital Bichat Claude Bernard, Assistance Publique des Hôpitaux de Paris, Paris, France ; Université Paris 7-Diderot, Paris, France.
18
Institut National de la Santé et de la Recherche Médicale (INSERM) U1012, Université Paris-Sud, Rhumatologie, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.
19
Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
20
Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal ; Rheumatology Department, Santa Maria Hospital-CHLN, Lisbon, Portugal.
21
Department of Clinical Immunology and Rheumatology & Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
22
Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands ; GlaxoSmithKline, Stevenage, United Kingdom.
23
Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
24
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
25
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts, United States of America ; Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts, United States of America.
26
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan ; Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.
27
Université Paris 13 Sorbonne Paris Cité, UREN (Nutritional Epidemiology Research Unit), Inserm (U557), Inra (U1125), Cnam, Bobigny, France.
28
McGill University and Génome Québec Innovation Centre, Montréal, Canada.
29
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America ; Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
30
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America ; NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
31
Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom ; National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
32
Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
33
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada ; Toronto General Research Institute, Toronto, Canada ; Department of Medicine, University of Toronto, Toronto, Canada.
34
The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, United States of America.
35
Weill Cornell Medical College-Qatar, Education City, Doha, Qatar.
36
Tishreen Hospital, Damascus, Syria ; Syrian Association for Rheumatology, Damascus, Syria.

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.

PMID:
24520335
PMCID:
PMC3919745
DOI:
10.1371/journal.pone.0087645
[Indexed for MEDLINE]
Free PMC Article

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