期刊
SCIENCE
卷 359, 期 6381, 页码 1233-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aal4043
关键词
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资金
- National Library of Medicine [R01-LM010685, K22-LM011939, T15-LM007359]
- U01 grants [HG004603, HG006378, HG008672]
- National Human Genome Research Institute [T32-HG008341, U01-HG009086]
- National Center for Research Resources [UL1-RR024975]
- National Center for Advancing Translational Sciences [UL1-TR000445]
- National Institute for General Medical Sciences [R01-GM114128, P50-GM115305, R01-GM120523]
- National Heart, Lung, and Blood Institute [R01-HL133786]
- American Heart Association [16FTF30130005]
- University of Oklahoma Health Sciences Center
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR002243, UL1TR000445] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR024975] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL140074, R01HL133786, F32HL137385, R01HL136748] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U01HG006378, U01HG008672, U01HG009086, T32HG008341, U01HG004603, U01HG007674] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM114128, R01GM120523, P50GM115305] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH113362] Funding Source: NIH RePORTER
- NATIONAL LIBRARY OF MEDICINE [T15LM007359, R01LM010685, T15LM007450] Funding Source: NIH RePORTER
Genetic association studies often examine features independently, potentially missing subpopulations with multiple phenotypes that share a single cause. We describe an approach that aggregates phenotypes on the basis of patterns described by Mendelian diseases. We mapped the clinical features of 1204 Mendelian diseases into phenotypes captured from the electronic health record (EHR) and summarized this evidence as phenotype risk scores (PheRSs). In an initial validation, PheRS distinguished cases and controls of five Mendelian diseases. Applying PheRS to 21,701 genotyped individuals uncovered 18 associations between rare variants and phenotypes consistent with Mendelian diseases. In 16 patients, the rare genetic variants were associated with severe outcomes such as organ transplants. PheRS can augment rare-variant interpretation and may identify subsets of patients with distinct genetic causes for common diseases.
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