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Nat Genet. 2016 Jul;48(7):803-10. doi: 10.1038/ng.3572. Epub 2016 May 16.

A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases.

Author information

1
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
4
Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.
5
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
6
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
7
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
8
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts, USA.
9
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
10
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
11
Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA.
12
Department of Biomedical Informatics, Asan Medical Center, Seoul, Republic of Korea.
13
Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
14
Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
15
Department of Public Health and Clinical Medicine, Rheumatology, Umeå University, Umeå, Sweden.
16
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.
17
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.
18
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
19
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
20
Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.
21
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
22
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
23
Institute of Inflammation and Repair, University of Manchester, Manchester, UK.

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).

PMID:
27182969
PMCID:
PMC4925284
DOI:
10.1038/ng.3572
[Indexed for MEDLINE]
Free PMC Article

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