PMID- 33441150
OWN - NLM
STAT- MEDLINE
DCOM- 20220119
LR  - 20240331
IS  - 1756-994X (Electronic)
IS  - 1756-994X (Linking)
VI  - 13
IP  - 1
DP  - 2021 Jan 13
TI  - Clinical laboratory test-wide association scan of polygenic scores identifies 
      biomarkers of complex disease.
PG  - 6
LID - 10.1186/s13073-020-00820-8 [doi]
LID - 6
AB  - BACKGROUND: Clinical laboratory (lab) tests are used in clinical practice to 
      diagnose, treat, and monitor disease conditions. Test results are stored in 
      electronic health records (EHRs), and a growing number of EHRs are linked to 
      patient DNA, offering unprecedented opportunities to query relationships between 
      genetic risk for complex disease and quantitative physiological measurements 
      collected on large populations. METHODS: A total of 3075 quantitative lab tests 
      were extracted from Vanderbilt University Medical Center's (VUMC) EHR system and 
      cleaned for population-level analysis according to our QualityLab protocol. Lab 
      values extracted from BioVU were compared with previous population studies using 
      heritability and genetic correlation analyses. We then tested the hypothesis that 
      polygenic risk scores for biomarkers and complex disease are associated with 
      biomarkers of disease extracted from the EHR. In a proof of concept analyses, we 
      focused on lipids and coronary artery disease (CAD). We cleaned lab traits 
      extracted from the EHR performed lab-wide association scans (LabWAS) of the 
      lipids and CAD polygenic risk scores across 315 heritable lab tests then 
      replicated the pipeline and analyses in the Massachusetts General Brigham 
      Biobank. RESULTS: Heritability estimates of lipid values (after cleaning with 
      QualityLab) were comparable to previous reports and polygenic scores for lipids 
      were strongly associated with their referent lipid in a LabWAS. LabWAS of the 
      polygenic score for CAD recapitulated canonical heart disease biomarker profiles 
      including decreased HDL, increased pre-medication LDL, triglycerides, blood 
      glucose, and glycated hemoglobin (HgbA1C) in European and African descent 
      populations. Notably, many of these associations remained even after adjusting 
      for the presence of cardiovascular disease and were replicated in the MGBB. 
      CONCLUSIONS: Polygenic risk scores can be used to identify biomarkers of complex 
      disease in large-scale EHR-based genomic analyses, providing new avenues for 
      discovery of novel biomarkers and deeper understanding of disease trajectories in 
      pre-symptomatic individuals. We present two methods and associated software, 
      QualityLab and LabWAS, to clean and analyze EHR labs at scale and perform a 
      Lab-Wide Association Scan.
FAU - Dennis, Jessica K
AU  - Dennis JK
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
AD  - Department of Medical Genetics, University of British Columbia, Vancouver, BC, 
      V5Z 4H4, Canada.
FAU - Sealock, Julia M
AU  - Sealock JM
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
FAU - Straub, Peter
AU  - Straub P
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
FAU - Lee, Younga H
AU  - Lee YH
AD  - Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, 
      Massachusetts General Hospital, Boston, MA, 02114, USA.
AD  - Department of Psychiatry, Harvard Medical School, Boston, MA, 02115, USA.
AD  - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 
      Cambridge, MA, 02142, USA.
FAU - Hucks, Donald
AU  - Hucks D
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
FAU - Actkins, Ky'Era
AU  - Actkins K
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
AD  - Department of Microbiology, Immunology, and Physiology, Meharry Medical College, 
      Nashville, TN, 37232, USA.
FAU - Faucon, Annika
AU  - Faucon A
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
FAU - Feng, Yen-Chen Anne
AU  - Feng YA
AD  - Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, 
      Massachusetts General Hospital, Boston, MA, 02114, USA.
AD  - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 
      Cambridge, MA, 02142, USA.
AD  - Analytic and Translational Genetics Unit, Center for Genomic Medicine, 
      Massachusetts General Hospital, Boston, MA, 02114, USA.
FAU - Ge, Tian
AU  - Ge T
AD  - Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, 
      Massachusetts General Hospital, Boston, MA, 02114, USA.
AD  - Department of Psychiatry, Harvard Medical School, Boston, MA, 02115, USA.
AD  - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 
      Cambridge, MA, 02142, USA.
FAU - Goleva, Slavina B
AU  - Goleva SB
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University Medical 
      Center, Nashville, TN, 37232, USA.
FAU - Niarchou, Maria
AU  - Niarchou M
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
FAU - Singh, Kritika
AU  - Singh K
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
FAU - Morley, Theodore
AU  - Morley T
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
FAU - Smoller, Jordan W
AU  - Smoller JW
AD  - Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, 
      Massachusetts General Hospital, Boston, MA, 02114, USA.
AD  - Department of Psychiatry, Harvard Medical School, Boston, MA, 02115, USA.
AD  - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 
      Cambridge, MA, 02142, USA.
FAU - Ruderfer, Douglas M
AU  - Ruderfer DM
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA.
AD  - Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical 
      Center, Nashville, TN, 37232, USA.
AD  - Departments of Medicine and Biomedical Informatics, Vanderbilt University Medical 
      Center, Nashville, TN, 37232, USA.
FAU - Mosley, Jonathan D
AU  - Mosley JD
AD  - Departments of Medicine and Biomedical Informatics, Vanderbilt University Medical 
      Center, Nashville, TN, 37232, USA.
FAU - Chen, Guanhua
AU  - Chen G
AD  - Department of Biostatistics and Medical Informatics, University of 
      Wisconsin-Madison, Madison, WI, 53706, USA.
FAU - Davis, Lea K
AU  - Davis LK
AUID- ORCID: 0000-0001-5143-2282
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, TN, 37232, USA. lea.k.davis@gmail.com.
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      TN, 37232, USA. lea.k.davis@gmail.com.
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University Medical 
      Center, Nashville, TN, 37232, USA. lea.k.davis@gmail.com.
AD  - Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical 
      Center, Nashville, TN, 37232, USA. lea.k.davis@gmail.com.
AD  - Departments of Medicine and Biomedical Informatics, Vanderbilt University Medical 
      Center, Nashville, TN, 37232, USA. lea.k.davis@gmail.com.
AD  - Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics 
      Institute, Vanderbilt University, 511-A Light Hall, 2215 Garland Ave, Nashville, 
      TN, 37232, USA. lea.k.davis@gmail.com.
LA  - eng
GR  - R00 AG054573/AG/NIA NIH HHS/United States
GR  - UL1 RR024975/RR/NCRR NIH HHS/United States
GR  - T32 GM080178/GM/NIGMS NIH HHS/United States
GR  - R01 MH118233/MH/NIMH NIH HHS/United States
GR  - K99 AG054573/AG/NIA NIH HHS/United States
GR  - U54 MD010722/MD/NIMHD NIH HHS/United States
GR  - R01 MH113362/MH/NIMH NIH HHS/United States
GR  - 16FTF30130005/AHA/American Heart Association-American Stroke Association/United 
      States
GR  - U01 HG008685/HG/NHGRI NIH HHS/United States
GR  - S10 RR025141/RR/NCRR NIH HHS/United States
GR  - UL1 TR000445/TR/NCATS NIH HHS/United States
GR  - U24 CA242637/CA/NCI NIH HHS/United States
GR  - R01 GM120736/GM/NIGMS NIH HHS/United States
GR  - UL1 TR002373/TR/NCATS NIH HHS/United States
GR  - P50 HD103537/HD/NICHD NIH HHS/United States
GR  - R56 MH120736/MH/NIMH NIH HHS/United States
GR  - R01 GM130791/GM/NIGMS NIH HHS/United States
GR  - UL1 TR002243/TR/NCATS NIH HHS/United States
GR  - UL1 TR000427/TR/NCATS NIH HHS/United States
PT  - Journal Article
DEP - 20210113
PL  - England
TA  - Genome Med
JT  - Genome medicine
JID - 101475844
RN  - 0 (Biomarkers)
RN  - 0 (Lipids)
SB  - IM
MH  - Biological Specimen Banks
MH  - Biomarkers/*metabolism
MH  - *Clinical Laboratory Techniques
MH  - Coronary Artery Disease/blood/genetics
MH  - Disease/*genetics
MH  - Female
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Lipids/blood
MH  - Male
MH  - Middle Aged
MH  - Multifactorial Inheritance/*genetics
MH  - Reproducibility of Results
PMC - PMC7807864
OTO - NOTNLM
OT  - Biomarkers
OT  - Electronic health records
OT  - Genetic epidemiology
OT  - Population genetics
COIS- JWS is an unpaid member of the Bipolar/Depression Research Community Advisory 
      Panel of 23andMe, is a member of the Leon Levy Foundation Neuroscience Advisory 
      Board, and received an honorarium for an internal seminar at Biogen, Inc. He is 
      PI of a collaborative study of the genetics of depression and bipolar disorder 
      sponsored by 23andMe for which 23andMe provides analysis time as in-kind support 
      but no payments. The remaining authors declare that they have no competing 
      interests.
EDAT- 2021/01/15 06:00
MHDA- 2022/01/20 06:00
PMCR- 2021/01/13
CRDT- 2021/01/14 05:32
PHST- 2020/02/25 00:00 [received]
PHST- 2020/12/08 00:00 [accepted]
PHST- 2021/01/14 05:32 [entrez]
PHST- 2021/01/15 06:00 [pubmed]
PHST- 2022/01/20 06:00 [medline]
PHST- 2021/01/13 00:00 [pmc-release]
AID - 10.1186/s13073-020-00820-8 [pii]
AID - 820 [pii]
AID - 10.1186/s13073-020-00820-8 [doi]
PST - epublish
SO  - Genome Med. 2021 Jan 13;13(1):6. doi: 10.1186/s13073-020-00820-8.