title: A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity.
abstract: Rare-variant association studies in common, complex diseases are customarily conducted under an additive risk model in both single-variant and burden testing. Here, we describe a method to improve detection of rare recessive variants in complex diseases termed RAFT (recessive-allele-frequency-based test). We found that RAFT outperforms existing approaches when the variant influences disease risk in a recessive manner on simulated data. We then applied our method to 1,791 Finnish individuals with type 2 diabetes (T2D) and 2,657 matched control subjects. In BBS10, we discovered a rare variant (c.1189A>G [p.Ile397Val]; rs202042386) that confers risk of T2D in a recessive state (p = 1.38 × 10(-6)) and would be missed by conventional methods. Testing of this variant in an established in vivo zebrafish model confirmed the variant to be pathogenic. Taken together, these data suggest that RAFT can effectively reveal rare recessive contributions to complex diseases overlooked by conventional association tests.
authors.affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA. Electronic address: tengting.lim@childrens.harvard.edu.
authors.forename: Elaine T
authors.initials: ET
authors.lastname: Lim
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Duke University, Durham, NC 27710, USA.
authors.forename: Yangfan P
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Yingleong
authors.initials: Y
authors.lastname: Chan
authors.affiliation: Department of Internal Medicine/Diabetology, Helsinki University Central Hospital, Helsinki 00029, Finland; The Institute for Diabetes Genetics, Folkhalsan Research Center, University of Helsinki, Helsinki 00014, Finland; Research Program for Diabetes and Obesity, University of Helsinki, Haartmaninkatu 8, Helsinki 00014, Finland.
authors.forename: Tuomi
authors.initials: T
authors.lastname: Tiinamaija
authors.affiliation: Department of Primary Health Care, Vaasa Central Hospital, Hietalahdenkatu 2-4, 65 130 Vaasa, Finland; Diabetes Center, Vaasa Health Care Center, Sepänkyläntie 14-16, 65 100 Vaasa, Finland.
authors.forename: AnnMari
authors.initials: A
authors.lastname: Käräjämäki
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Duke University, Durham, NC 27710, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Madsen
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Altshuler
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester M13 9PT, UK.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland; Lund University Diabetes Center, Department of Clinical Sciences, Diabetes & Endocrinology, Skåne University Hospital, Lund University, Malmö 205 02, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Duke University, Durham, NC 27710, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: mjdaly@atgu.mgh.harvard.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
mesh_terms: D000818:Animals; D018833:Chaperonins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005387:Finland; D005787:Gene Frequency; D005808:Genes, Recessive / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D056385:Group II Chaperonins / Q000235:genetics*; D006801:Humans; D016013:Likelihood Functions; D008957:Models, Genetic; D009765:Obesity / Q000235:genetics*; D016017:Odds Ratio; D015027:Zebrafish
chemical_list: C512111:BBS10 protein, human; D018833:Chaperonins; D056385:Group II Chaperonins