PMID- 32296164 OWN - NLM STAT- MEDLINE DCOM- 20210427 LR - 20220531 IS - 1530-0366 (Electronic) IS - 1098-3600 (Print) IS - 1098-3600 (Linking) VI - 22 IP - 7 DP - 2020 Jul TI - Electronic health record phenotypes associated with genetically regulated expression of CFTR and application to cystic fibrosis. PG - 1191-1200 LID - 10.1038/s41436-020-0786-5 [doi] AB - PURPOSE: The increasing use of electronic health records (EHRs) and biobanks offers unique opportunities to study Mendelian diseases. We described a novel approach to summarize clinical manifestations from patient EHRs into phenotypic evidence for cystic fibrosis (CF) with potential to alert unrecognized patients of the disease. METHODS: We estimated genetically predicted expression (GReX) of cystic fibrosis transmembrane conductance regulator (CFTR) and tested for association with clinical diagnoses in the Vanderbilt University biobank (N = 9142 persons of European descent with 71 cases of CF). The top associated EHR phenotypes were assessed in combination as a phenotype risk score (PheRS) for discriminating CF case status in an additional 2.8 million patients from Vanderbilt University Medical Center (VUMC) and 125,305 adult patients including 25,314 CF cases from MarketScan, an independent external cohort. RESULTS: GReX of CFTR was associated with EHR phenotypes consistent with CF. PheRS constructed using the EHR phenotypes and weights discovered by the genetic associations improved discriminative power for CF over the initially proposed PheRS in both VUMC and MarketScan. CONCLUSION: Our study demonstrates the power of EHRs for clinical description of CF and the benefits of using a genetics-informed weighing scheme in construction of a phenotype risk score. This research may find broad applications for phenomic studies of Mendelian disease genes. FAU - Zhong, Xue AU - Zhong X AUID- ORCID: 0000-0002-7482-8471 AD - Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. xue.zhong@vanderbilt.edu. AD - Vanderbilt Genetics Institute, Nashville, TN, USA. xue.zhong@vanderbilt.edu. FAU - Yin, Zhijun AU - Yin Z AD - Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN, USA. FAU - Jia, Gengjie AU - Jia G AD - Department of Medicine, Institute of Genomics and Systems Biology, University of Chicago, Chicago, IL, USA. FAU - Zhou, Dan AU - Zhou D AD - Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Vanderbilt Genetics Institute, Nashville, TN, USA. FAU - Wei, Qiang AU - Wei Q AD - Vanderbilt Genetics Institute, Nashville, TN, USA. AD - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. FAU - Faucon, Annika AU - Faucon A AD - Human Genetics Graduate Program, Vanderbilt University, Nashville, TN, USA. FAU - Evans, Patrick AU - Evans P AD - Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Vanderbilt Genetics Institute, Nashville, TN, USA. FAU - Gamazon, Eric R AU - Gamazon ER AD - Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Vanderbilt Genetics Institute, Nashville, TN, USA. AD - 'Life Member' of Clare Hall, University of Cambridge, Cambridge, United Kingdom. AD - MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom. FAU - Li, Bingshan AU - Li B AD - Vanderbilt Genetics Institute, Nashville, TN, USA. AD - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. FAU - Tao, Ran AU - Tao R AD - Vanderbilt Genetics Institute, Nashville, TN, USA. AD - Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Rzhetsky, Andrey AU - Rzhetsky A AD - Department of Medicine, Institute of Genomics and Systems Biology, University of Chicago, Chicago, IL, USA. AD - Committee on Genomics, Genetics and Systems Biology, University of Chicago, Chicago, IL, USA. AD - Department of Human Genetics, University of Chicago, Chicago, IL, USA. FAU - Bastarache, Lisa AU - Bastarache L AD - Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Cox, Nancy J AU - Cox NJ AD - Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. nancy.j.cox@vanderbilt.edu. AD - Vanderbilt Genetics Institute, Nashville, TN, USA. nancy.j.cox@vanderbilt.edu. LA - eng GR - R01 HL122712/HL/NHLBI NIH HHS/United States GR - UL1 TR000445/TR/NCATS NIH HHS/United States GR - P50 MH094267/MH/NIMH NIH HHS/United States GR - U01 HG004603/HG/NHGRI NIH HHS/United States GR - U01 HL108634/HL/NHLBI NIH HHS/United States GR - RC2 GM092618/GM/NIGMS NIH HHS/United States GR - U01 HG009086/HG/NHGRI NIH HHS/United States GR - U01HG009086/NH/NIH HHS/United States GR - R01 MH113362/MH/NIMH NIH HHS/United States GR - R35 HG010718/HG/NHGRI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20200416 PL - United States TA - Genet Med JT - Genetics in medicine : official journal of the American College of Medical Genetics JID - 9815831 RN - 0 (CFTR protein, human) RN - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) SB - IM MH - Adult MH - *Cystic Fibrosis/genetics MH - Cystic Fibrosis Transmembrane Conductance Regulator/genetics MH - Electronic Health Records MH - Humans MH - Mutation MH - Phenotype PMC - PMC7781195 MID - NIHMS1650776 OTO - NOTNLM OT - CFTR OT - Mendelian OT - cis-regulated expression OT - cystic fibrosis OT - phenotype risk score EDAT- 2020/04/17 06:00 MHDA- 2021/04/28 06:00 PMCR- 2021/01/04 CRDT- 2020/04/17 06:00 PHST- 2019/09/17 00:00 [received] PHST- 2020/03/17 00:00 [accepted] PHST- 2020/04/17 06:00 [pubmed] PHST- 2021/04/28 06:00 [medline] PHST- 2020/04/17 06:00 [entrez] PHST- 2021/01/04 00:00 [pmc-release] AID - S1098-3600(21)01182-5 [pii] AID - 10.1038/s41436-020-0786-5 [doi] PST - ppublish SO - Genet Med. 2020 Jul;22(7):1191-1200. doi: 10.1038/s41436-020-0786-5. Epub 2020 Apr 16.