PMID- 33462484
OWN - NLM
STAT- MEDLINE
DCOM- 20210304
LR  - 20230127
IS  - 1546-1718 (Electronic)
IS  - 1061-4036 (Print)
IS  - 1061-4036 (Linking)
VI  - 53
IP  - 2
DP  - 2021 Feb
TI  - Genetics of 35 blood and urine biomarkers in the UK Biobank.
PG  - 185-194
LID - 10.1038/s41588-020-00757-z [doi]
AB  - Clinical laboratory tests are a critical component of the continuum of care. We 
      evaluate the genetic basis of 35 blood and urine laboratory measurements in the 
      UK Biobank (n = 363,228 individuals). We identify 1,857 loci associated with at 
      least one trait, containing 3,374 fine-mapped associations and additional sets of 
      large-effect (>0.1 s.d.) protein-altering, human leukocyte antigen (HLA) and copy 
      number variant (CNV) associations. Through Mendelian randomization (MR) analysis, 
      we discover 51 causal relationships, including previously known agonistic effects 
      of urate on gout and cystatin C on stroke. Finally, we develop polygenic risk 
      scores (PRSs) for each biomarker and build 'multi-PRS' models for diseases using 
      35 PRSs simultaneously, which improved chronic kidney disease, type 2 diabetes, 
      gout and alcoholic cirrhosis genetic risk stratification in an independent 
      dataset (FinnGen; n = 135,500) relative to single-disease PRSs. Together, our 
      results delineate the genetic basis of biomarkers and their causal influences on 
      diseases and improve genetic risk stratification for common diseases.
FAU - Sinnott-Armstrong, Nasa
AU  - Sinnott-Armstrong N
AUID- ORCID: 0000-0003-4490-0601
AD  - Department of Genetics, School of Medicine, Stanford University, Stanford, CA, 
      USA. nasa@stanford.edu.
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland. nasa@stanford.edu.
AD  - VA Palo Alto Health Care System, Palo Alto, CA, USA. nasa@stanford.edu.
FAU - Tanigawa, Yosuke
AU  - Tanigawa Y
AUID- ORCID: 0000-0001-9759-157X
AD  - Department of Biomedical Data Science, School of Medicine, Stanford University, 
      Stanford, CA, USA. ytanigaw@stanford.edu.
FAU - Amar, David
AU  - Amar D
AUID- ORCID: 0000-0002-9719-0837
AD  - Department of Biomedical Data Science, School of Medicine, Stanford University, 
      Stanford, CA, USA.
AD  - Division of Cardiovascular Medicine and the Cardiovascular Institute, School of 
      Medicine, Stanford University, Stanford, CA, USA.
FAU - Mars, Nina
AU  - Mars N
AUID- ORCID: 0000-0002-7259-5993
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Benner, Christian
AU  - Benner C
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Aguirre, Matthew
AU  - Aguirre M
AD  - Department of Biomedical Data Science, School of Medicine, Stanford University, 
      Stanford, CA, USA.
FAU - Venkataraman, Guhan Ram
AU  - Venkataraman GR
AD  - Department of Biomedical Data Science, School of Medicine, Stanford University, 
      Stanford, CA, USA.
FAU - Wainberg, Michael
AU  - Wainberg M
AD  - Department of Computer Science, Stanford University, Stanford, CA, USA.
FAU - Ollila, Hanna M
AU  - Ollila HM
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
AD  - Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, 
      CA, USA.
AD  - Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical 
      School, Boston, MA, USA.
FAU - Kiiskinen, Tuomo
AU  - Kiiskinen T
AUID- ORCID: 0000-0002-6306-8227
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
AD  - Finnish Institute for Health and Welfare, Helsinki, Finland.
FAU - Havulinna, Aki S
AU  - Havulinna AS
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
AD  - Finnish Institute for Health and Welfare, Helsinki, Finland.
FAU - Pirruccello, James P
AU  - Pirruccello JP
AUID- ORCID: 0000-0001-6088-4037
AD  - Massachusetts General Hospital Division of Cardiology, Boston, MA, USA.
AD  - Program in Medical and Population Genetics and Stanley Center for Psychiatric 
      Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
FAU - Qian, Junyang
AU  - Qian J
AD  - Department of Statistics, Stanford University, Stanford, CA, USA.
FAU - Shcherbina, Anna
AU  - Shcherbina A
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
AD  - Division of Cardiovascular Medicine and the Cardiovascular Institute, School of 
      Medicine, Stanford University, Stanford, CA, USA.
CN  - FinnGen
FAU - Rodriguez, Fatima
AU  - Rodriguez F
AD  - Division of Cardiovascular Medicine and the Cardiovascular Institute, School of 
      Medicine, Stanford University, Stanford, CA, USA.
FAU - Assimes, Themistocles L
AU  - Assimes TL
AUID- ORCID: 0000-0003-2349-0009
AD  - VA Palo Alto Health Care System, Palo Alto, CA, USA.
AD  - Division of Cardiovascular Medicine and the Cardiovascular Institute, School of 
      Medicine, Stanford University, Stanford, CA, USA.
FAU - Agarwala, Vineeta
AU  - Agarwala V
AD  - Division of Cardiovascular Medicine and the Cardiovascular Institute, School of 
      Medicine, Stanford University, Stanford, CA, USA.
FAU - Tibshirani, Robert
AU  - Tibshirani R
AD  - Department of Biomedical Data Science, School of Medicine, Stanford University, 
      Stanford, CA, USA.
AD  - Department of Statistics, Stanford University, Stanford, CA, USA.
FAU - Hastie, Trevor
AU  - Hastie T
AD  - Department of Biomedical Data Science, School of Medicine, Stanford University, 
      Stanford, CA, USA.
AD  - Department of Statistics, Stanford University, Stanford, CA, USA.
FAU - Ripatti, Samuli
AU  - Ripatti S
AUID- ORCID: 0000-0002-0504-1202
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
AD  - Program in Medical and Population Genetics and Stanley Center for Psychiatric 
      Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
AD  - Department of Public Health, Clinicum, University of Helsinki, Helsinki, Finland.
FAU - Pritchard, Jonathan K
AU  - Pritchard JK
AUID- ORCID: 0000-0002-8828-5236
AD  - Department of Genetics, School of Medicine, Stanford University, Stanford, CA, 
      USA.
AD  - Department of Biology, Stanford University, Stanford, CA, USA.
FAU - Daly, Mark J
AU  - Daly MJ
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
AD  - Program in Medical and Population Genetics and Stanley Center for Psychiatric 
      Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
AD  - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 
      MA, USA.
FAU - Rivas, Manuel A
AU  - Rivas MA
AUID- ORCID: 0000-0003-1457-9925
AD  - Department of Biomedical Data Science, School of Medicine, Stanford University, 
      Stanford, CA, USA. mrivas@stanford.edu.
LA  - eng
GR  - R01 HG008140/HG/NHGRI NIH HHS/United States
GR  - U01 HG009080/HG/NHGRI NIH HHS/United States
GR  - R01 GM134483/GM/NIGMS NIH HHS/United States
GR  - R01 EB001988/EB/NIBIB NIH HHS/United States
GR  - T15 LM007033/LM/NLM NIH HHS/United States
GR  - R01 HG010140/HG/NHGRI NIH HHS/United States
GR  - K01 HL144607/HL/NHLBI 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 - 20210118
PL  - United States
TA  - Nat Genet
JT  - Nature genetics
JID - 9216904
RN  - 0 (Biomarkers)
RN  - 0 (HLA Antigens)
RN  - 0 (Liver-Specific Organic Anion Transporter 1)
RN  - 0 (Proteins)
RN  - 0 (SLCO1B1 protein, human)
RN  - EC 3.4.21.- (HGF activator)
RN  - EC 3.4.21.- (Serine Endopeptidases)
SB  - IM
CIN - Nat Rev Nephrol. 2021 Apr;17(4):222. PMID: 33514940
EIN - Nat Genet. 2021 Nov;53(11):1622. PMID: 34608296
MH  - Biological Specimen Banks
MH  - Biomarkers/*blood/*urine
MH  - Cardiovascular Diseases/genetics/metabolism
MH  - DNA Copy Number Variations
MH  - Diabetes Mellitus, Type 2/genetics/metabolism
MH  - Genetic Pleiotropy
MH  - HLA Antigens/*genetics
MH  - Humans
MH  - Linkage Disequilibrium
MH  - Liver-Specific Organic Anion Transporter 1/genetics
MH  - Mendelian Randomization Analysis
MH  - Polymorphism, Single Nucleotide
MH  - Proteins/*genetics
MH  - Renal Insufficiency, Chronic
MH  - Serine Endopeptidases/genetics
MH  - United Kingdom
PMC - PMC7867639
MID - NIHMS1651539
COIS- Competing financial interests The Board of Trustees of the Leland Stanford Junior 
      University filed U.S. Provisional Application "Methods for diagnosis of polygenic 
      diseases and phenotypes from genetic variation" (Serial No. 62/852,738) 
      describing this work. J.K.P., M.A.R., N.S.-A., and Y.T. are designated as 
      inventors of the patent. M.A.R is on the SAB of 54Gene and Computational Advisory 
      Board for Goldfinch Bio and has advised BioMarin, Third Rock Ventures, MazeTx and 
      Related Sciences. The funders had no role in study design, data collection and 
      analysis, decision to publish, or preparation of the manuscript.
EDAT- 2021/01/20 06:00
MHDA- 2021/03/05 06:00
PMCR- 2021/07/18
CRDT- 2021/01/19 05:57
PHST- 2020/07/15 00:00 [received]
PHST- 2020/12/01 00:00 [accepted]
PHST- 2021/01/20 06:00 [pubmed]
PHST- 2021/03/05 06:00 [medline]
PHST- 2021/01/19 05:57 [entrez]
PHST- 2021/07/18 00:00 [pmc-release]
AID - 10.1038/s41588-020-00757-z [pii]
AID - 10.1038/s41588-020-00757-z [doi]
PST - ppublish
SO  - Nat Genet. 2021 Feb;53(2):185-194. doi: 10.1038/s41588-020-00757-z. Epub 2021 Jan 
      18.