title: A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases.
abstract: There is growing evidence of shared risk alleles for complex traits (pleiotropy), including autoimmune and neuropsychiatric diseases. This might be due to sharing among all individuals (whole-group pleiotropy) or a subset of individuals in a genetically heterogeneous cohort (subgroup heterogeneity). Here we describe the use of a well-powered statistic, BUHMBOX, to distinguish between those two situations using genotype data. We observed a shared genetic basis for 11 autoimmune diseases and type 1 diabetes (T1D; P < 1 × 10(-4)) and for 11 autoimmune diseases and rheumatoid arthritis (RA; P < 1 × 10(-3)). This sharing was not explained by subgroup heterogeneity (corrected PBUHMBOX > 0.2; 6,670 T1D cases and 7,279 RA cases). Genetic sharing between seronegative and seropostive RA (P < 1 × 10(-9)) had significant evidence of subgroup heterogeneity, suggesting a subgroup of seropositive-like cases within seronegative cases (PBUHMBOX = 0.008; 2,406 seronegative RA cases). We also observed a shared genetic basis for major depressive disorder (MDD) and schizophrenia (P < 1 × 10(-4)) that was not explained by subgroup heterogeneity (PBUHMBOX = 0.28; 9,238 MDD cases).
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.
authors.forename: Buhm
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jennie G
authors.initials: JG
authors.lastname: Pouget
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Kamil
authors.initials: K
authors.lastname: Slowikowski
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Stahl
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Cue Hyunkyu
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Diogo
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.|Department of Biomedical Informatics, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Yu Rang
authors.initials: YR
authors.lastname: Park
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.|Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Kim
authors.affiliation: Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Department of Public Health and Clinical Medicine, Rheumatology, Umeå University, Umeå, Sweden.
authors.forename: Solbritt Rantapää
authors.initials: SR
authors.lastname: Dahlqvist
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Musculoskeletal Research Centre, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.|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, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Musculoskeletal Research Centre, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.|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, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Huizinga
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.|Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D019295:Computational Biology; D030541:Databases, Genetic; D003865:Major Depressive Disorder / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000235:genetics*; D058685:Genetic Pleiotropy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D005819:Genetic Markers