Buhm Han^1-4,25, Jennie G Pouget^1,5-7,25, Kamil Slowikowski^1,3,4,8, Eli Stahl⁹, Cue Hyunkyu Lee¹⁰, Dorothee Diogo^1,3,4, Xinli Hu^1,3,4,11, Yu Rang Park^10,12, Eunji Kim^10,13, Peter K Gregersen¹⁴, Solbritt Rantapaa Dahlqvist¹⁵, Jane Worthington^16,17, Javier Martin¹⁸, Steve Eyre^16,17, Lars Klareskog¹⁹, Tom Huizinga²⁰, Wei-Min Chen²¹, Suna Onengut-Gumuscu²¹, Stephen S Rich²¹, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium²², Naomi R Wray²³ & Soumya Raychaudhuri<sup>1,3,4,19,24

1</sup>Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA. ²Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea. ³Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. ⁴Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA. ⁵Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. ⁶Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. ⁷Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. ⁸Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts, USA. ⁹Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. ¹⁰Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. ¹¹Harvard.MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA. ¹²Department of Biomedical Informatics, Asan Medical Center, Seoul, Republic of Korea. ¹³Department of Chemistry, Seoul National University, Seoul, Republic of Korea. ¹⁴Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA. ¹⁵Department of Public Health and Clinical Medicine, Rheumatology, Umea University, Umea, Sweden. ¹⁶Arthritis 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. ¹⁷National 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. ¹⁸Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, Granada, Spain. ¹⁹Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden. ²⁰Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands. ²¹Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. ²²A full list of members and affiliations appears in the Supplementary Note. ²³Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. ²⁴Institute of Inflammation and Repair, University of Manchester, Manchester, UK. ²⁵These authors contributed equally to this work.

Correspondence to : Buhm Han or Soumya Raychaudhuri

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 (P_BUHMBOX = 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).