PMID- 28759005 OWN - NLM STAT- MEDLINE DCOM- 20171025 LR - 20220323 IS - 1546-1718 (Electronic) IS - 1061-4036 (Print) IS - 1061-4036 (Linking) VI - 49 IP - 9 DP - 2017 Sep TI - Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank. PG - 1311-1318 LID - 10.1038/ng.3926 [doi] AB - Genetic discovery from the multitude of phenotypes extractable from routine healthcare data can transform understanding of the human phenome and accelerate progress toward precision medicine. However, a critical question when analyzing high-dimensional and heterogeneous data is how best to interrogate increasingly specific subphenotypes while retaining statistical power to detect genetic associations. Here we develop and employ a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Our method displays a more than 20% increase in power to detect genetic effects over other approaches and identifies new associations between classical human leukocyte antigen (HLA) alleles and common immune-mediated diseases (IMDs). By applying the approach to genetic risk scores (GRSs), we show the extent of genetic sharing among IMDs and expose differences in disease perception or diagnosis with potential clinical implications. FAU - Cortes, Adrian AU - Cortes A AUID- ORCID: 0000-0002-3490-007X AD - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. AD - Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK. FAU - Dendrou, Calliope A AU - Dendrou CA AUID- ORCID: 0000-0003-1179-4021 AD - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. AD - Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK. AD - MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. FAU - Motyer, Allan AU - Motyer A AUID- ORCID: 0000-0002-5552-2469 AD - Centre for Systems Genomics, Schools of Mathematics and Statistics and of BioSciences, University of Melbourne, Parkville, Victoria, Australia. FAU - Jostins, Luke AU - Jostins L AD - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. FAU - Vukcevic, Damjan AU - Vukcevic D AUID- ORCID: 0000-0001-7780-9586 AD - Centre for Systems Genomics, Schools of Mathematics and Statistics and of BioSciences, University of Melbourne, Parkville, Victoria, Australia. AD - Murdoch Children's Research Institute, Parkville, Victoria, Australia. FAU - Dilthey, Alexander AU - Dilthey A AUID- ORCID: 0000-0002-6394-4581 AD - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. AD - Genome Informatics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA. FAU - Donnelly, Peter AU - Donnelly P AD - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. AD - Department of Statistics, University of Oxford, Oxford, UK. FAU - Leslie, Stephen AU - Leslie S AD - Centre for Systems Genomics, Schools of Mathematics and Statistics and of BioSciences, University of Melbourne, Parkville, Victoria, Australia. AD - Murdoch Children's Research Institute, Parkville, Victoria, Australia. FAU - Fugger, Lars AU - Fugger L AD - Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK. AD - MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. AD - Danish National Research Foundation Centre PERSIMUNE, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. FAU - McVean, Gil AU - McVean G AUID- ORCID: 0000-0002-5012-4162 AD - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. AD - Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. LA - eng GR - 204290/WT_/Wellcome Trust/United Kingdom GR - MC_UU_12010/3/MRC_/Medical Research Council/United Kingdom GR - 100956/WT_/Wellcome Trust/United Kingdom GR - MC_UU_00008/3/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - 100308/WT_/Wellcome Trust/United Kingdom GR - MC_QA137853/MRC_/Medical Research Council/United Kingdom PT - Journal Article DEP - 20170731 PL - United States TA - Nat Genet JT - Nature genetics JID - 9216904 RN - 0 (HLA Antigens) SB - IM MH - Adult MH - Aged MH - Alleles MH - *Bayes Theorem MH - Cluster Analysis MH - Delivery of Health Care/classification/*statistics & numerical data MH - Female MH - Genetic Association Studies/*statistics & numerical data MH - Genetic Predisposition to Disease/genetics MH - Genome-Wide Association Study/statistics & numerical data MH - HLA Antigens/genetics MH - Health Information Systems/*statistics & numerical data MH - Humans MH - International Classification of Diseases/classification/statistics & numerical data MH - Logistic Models MH - Male MH - Middle Aged MH - Polymorphism, Single Nucleotide MH - United Kingdom PMC - PMC5580804 MID - EMS73360 COIS- Competing Financial Interests G.M. and P.D. are cofounders of, holder of shares in, and consultants to Genomics PLC. G.M., P.D. and S.L. are partners in Peptide Groove LLP. Peptide Groove has licensed HLA typing technology to Affymetrix Ltd. The other authors declare no competing financial interests. EDAT- 2017/08/02 06:00 MHDA- 2017/10/27 06:00 PMCR- 2018/01/31 CRDT- 2017/08/01 06:00 PHST- 2017/02/03 00:00 [received] PHST- 2017/07/06 00:00 [accepted] PHST- 2017/08/02 06:00 [pubmed] PHST- 2017/10/27 06:00 [medline] PHST- 2017/08/01 06:00 [entrez] PHST- 2018/01/31 00:00 [pmc-release] AID - ng.3926 [pii] AID - 10.1038/ng.3926 [doi] PST - ppublish SO - Nat Genet. 2017 Sep;49(9):1311-1318. doi: 10.1038/ng.3926. Epub 2017 Jul 31.