Genetics of 35 blood and urine biomarkers in the UK Biobank

Nasa Sinnott-Armstrong; Yosuke Tanigawa; David Amar; Nina Mars; Christian Benner; Matthew Aguirre; Guhan Ram Venkataraman; Michael Wainberg; Hanna M Ollila; Tuomo Kiiskinen; Aki S Havulinna; James P Pirruccello; Junyang Qian; Anna Shcherbina; FinnGen; Fatima Rodriguez; Themistocles L Assimes; Vineeta Agarwala; Robert Tibshirani; Trevor Hastie; Samuli Ripatti; Jonathan K Pritchard; Mark J Daly; Manuel A Rivas

doi:10.1038/s41588-020-00757-z

Genetics of 35 blood and urine biomarkers in the UK Biobank

Nat Genet. 2021 Feb;53(2):185-194. doi: 10.1038/s41588-020-00757-z. Epub 2021 Jan 18.

Authors

Nasa Sinnott-Armstrong^#^{1

2

3}, Yosuke Tanigawa^#⁴, David Amar^{5

6}, Nina Mars⁷, Christian Benner⁷, Matthew Aguirre⁵, Guhan Ram Venkataraman⁵, Michael Wainberg⁸, Hanna M Ollila^{7

9

10}, Tuomo Kiiskinen^{7

11}, Aki S Havulinna^{7

11}, James P Pirruccello^{12

13}, Junyang Qian¹⁴, Anna Shcherbina^{7

6}; FinnGen; Fatima Rodriguez⁶, Themistocles L Assimes^{15

6}, Vineeta Agarwala⁶, Robert Tibshirani^{5

14}, Trevor Hastie^{5

14}, Samuli Ripatti^{7

13

16}, Jonathan K Pritchard^{17

18}, Mark J Daly^{7

13

19}, Manuel A Rivas^#²⁰

Affiliations

¹ Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA. nasa@stanford.edu.
² Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland. nasa@stanford.edu.
³ VA Palo Alto Health Care System, Palo Alto, CA, USA. nasa@stanford.edu.
⁴ Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA. ytanigaw@stanford.edu.
⁵ Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA.
⁶ Division of Cardiovascular Medicine and the Cardiovascular Institute, School of Medicine, Stanford University, Stanford, CA, USA.
⁷ Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
⁸ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁹ Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
¹⁰ Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Finnish Institute for Health and Welfare, Helsinki, Finland.
¹² Massachusetts General Hospital Division of Cardiology, Boston, MA, USA.
¹³ Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁴ Department of Statistics, Stanford University, Stanford, CA, USA.
¹⁵ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁶ Department of Public Health, Clinicum, University of Helsinki, Helsinki, Finland.
¹⁷ Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
¹⁸ Department of Biology, Stanford University, Stanford, CA, USA.
¹⁹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
²⁰ Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA. mrivas@stanford.edu.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Biological Specimen Banks
Biomarkers / blood*
Biomarkers / urine*
Cardiovascular Diseases / genetics
Cardiovascular Diseases / metabolism
DNA Copy Number Variations
Diabetes Mellitus, Type 2 / genetics
Diabetes Mellitus, Type 2 / metabolism
Genetic Pleiotropy
HLA Antigens / genetics*
Humans
Linkage Disequilibrium
Liver-Specific Organic Anion Transporter 1 / genetics
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Proteins / genetics*
Renal Insufficiency, Chronic
Serine Endopeptidases / genetics
United Kingdom

Substances

Biomarkers
HLA Antigens
Liver-Specific Organic Anion Transporter 1
Proteins
SLCO1B1 protein, human
HGF activator
Serine Endopeptidases

Abstract

Publication types

MeSH terms

Substances

Grants and funding