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.
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.
authors: 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.
authors: Yukinori
authors: Y
authors: Okada
authors: 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.
authors: Dorothee
authors: D
authors: Diogo
authors: New York University Hospital for Joint Diseases, New York, New York, United States of America.
authors: Jeffrey D
authors: JD
authors: Greenberg
authors: Molecular Biology and Biotechnology Department, Human Genetics Division, Damascus, Syria.
authors: Faten
authors: F
authors: Mouassess
authors: Molecular Biology and Biotechnology Department, Human Genetics Division, Damascus, Syria.
authors: Walid A L
authors: WA
authors: Achkar
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Robert S
authors: RS
authors: Fulton
authors: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Joshua C
authors: JC
authors: Denny
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Namrata
authors: N
authors: Gupta
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Daniel
authors: D
authors: Mirel
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Stacy
authors: S
authors: Gabriel
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Gang
authors: G
authors: Li
authors: Department of Medicine, Albany Medical Center and The Center for Rheumatology, Albany, New York, United States of America.
authors: Joel M
authors: JM
authors: Kremer
authors: 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.
authors: Dimitrios A
authors: DA
authors: Pappas
authors: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Robert J
authors: RJ
authors: Carroll
authors: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Anne E
authors: AE
authors: Eyler
authors: 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.
authors: Gosia
authors: G
authors: Trynka
authors: The Department of Psychiatry at Mount Sinai School of Medicine, New York, New York, United States of America.
authors: Eli A
authors: EA
authors: Stahl
authors: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Jing
authors: J
authors: Cui
authors: Center for Human Genetics Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Richa
authors: R
authors: Saxena
authors: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Marieke J H
authors: MJ
authors: Coenen
authors: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Henk-Jan
authors: HJ
authors: Guchelaar
authors: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Tom W J
authors: TW
authors: Huizinga
authors: Service de Rhumatologie et INSERM U699 Hôpital Bichat Claude Bernard, Assistance Publique des Hôpitaux de Paris, Paris, France ; Université Paris 7-Diderot, Paris, France.
authors: Philippe
authors: P
authors: Dieudé
authors: 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.
authors: Xavier
authors: X
authors: Mariette
authors: Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors: Anne
authors: A
authors: Barton
authors: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal ; Rheumatology Department, Santa Maria Hospital-CHLN, Lisbon, Portugal.
authors: Helena
authors: H
authors: Canhão
authors: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal ; Rheumatology Department, Santa Maria Hospital-CHLN, Lisbon, Portugal.
authors: João E
authors: JE
authors: Fonseca
authors: Department of Clinical Immunology and Rheumatology & Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
authors: Niek
authors: N
authors: de Vries
authors: Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands ; GlaxoSmithKline, Stevenage, United Kingdom.
authors: Paul P
authors: PP
authors: Tak
authors: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Larry W
authors: LW
authors: Moreland
authors: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: S Louis
authors: SL
authors: Bridges
authors: 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.
authors: Corinne
authors: C
authors: Miceli-Richard
authors: 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.
authors: Hyon K
authors: HK
authors: Choi
authors: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan ; Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.
authors: Yoichiro
authors: Y
authors: Kamatani
authors: Université Paris 13 Sorbonne Paris Cité, UREN (Nutritional Epidemiology Research Unit), Inserm (U557), Inra (U1125), Cnam, Bobigny, France.
authors: Pilar
authors: P
authors: Galan
authors: McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors: Mark
authors: M
authors: Lathrop
authors: 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.
authors: Towfique
authors: T
authors: Raj
authors: 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.
authors: Philip L
authors: PL
authors: De Jager
authors: 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.
authors: Soumya
authors: S
authors: Raychaudhuri
authors: 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.
authors: Jane
authors: J
authors: Worthington
authors: Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
authors: Leonid
authors: L
authors: Padyukov
authors: Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
authors: Lars
authors: L
authors: Klareskog
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada ; Toronto General Research Institute, Toronto, Canada ; Department of Medicine, University of Toronto, Toronto, Canada.
authors: Katherine A
authors: KA
authors: Siminovitch
authors: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, United States of America.
authors: Peter K
authors: PK
authors: Gregersen
authors: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Elaine R
authors: ER
authors: Mardis
authors: Weill Cornell Medical College-Qatar, Education City, Doha, Qatar.
authors: Thurayya
authors: T
authors: Arayssi
authors: Tishreen Hospital, Damascus, Syria ; Syrian Association for Rheumatology, Damascus, Syria.
authors: Layla A
authors: LA
authors: Kazkaz
authors: 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.
authors: Robert M
authors: RM
authors: Plenge
mesh_terms: D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics*; D001483:Base Sequence; D015331:Cohort Studies; D003241:Consanguinity; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008245:Lysophospholipase / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D008245:Lysophospholipase