Genetics of 35 blood and urine biomarkers in the UK Biobank
Open accessAbstract
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 5,794 independent loci associated with at least one trait (p < 5 × 10−9), 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. Genetic analysis of 35 blood and urine laboratory measurements from 363,228 individuals identifies 1,857 loci associated with at least one laboratory value.
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Mendelian randomization analysis assessing the causal effect of statin-adjusted apoB on AD risk was inconclusive due to confounding by the APOE region and significant evidence of heterogeneity and horizontal pleiotropy.
“mendelian randomization (MR) analysis assessing the causal effect of statin-adjusted apoB [13] on AD risk [14] were inconclusive due to confounding by the APOE region, and significant evidence of heterogeneity and horizontal pleiotropy”
From Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants (2023) · cites this paper as [13]
The Results (Genetics of biomarkers) discuss apolipoprotein B, and the Results (Causal inference) describe Mendelian-randomization analyses of biomarkers. But the Online Methods specify statin-related adjustment for LDL, not apoB; the passages do not report an apoB–Alzheimer’s disease analysis or attribute an inconclusive result to APOE confounding, heterogeneity, and horizontal pleiotropy. In the citing sentence, [13] follows 'statin-adjusted apoB,' while [14] follows 'AD risk.' (LLM, conf=0.82)
Experimental — accuracy not yet measuredPOR variant rs17853284 (P228L) has been linked to lower testosterone levels.
“Recent genome-wide association studies have indicated a link to lower testosterone levels with the presence of POR variant rs17853284 [22,23].”
From Loss of Protein Stability and Function Caused by P228L Variation in NADPH-Cytochrome P450 Reductase Linked to Lower Testosterone Levels (2022) · cites this paper as [23]
The Results section discusses genetic associations with testosterone, but the passage names PLA2G12A variants, not POR rs17853284. Searches of our copy for rs17853284 and POR P228L found no passage linking that variant to lower testosterone levels; no page numbers were available. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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References 101 · Cited by 744
- Authors
- Sinnott-Armstrong, N., Tanigawa, Y., Amar, D., Mars, N., Benner, C., Aguirre, M., Venkataraman, G. R., Wainberg, M., Ollila, H. M., Kiiskinen, T., Havulinna, A. S., Pirruccello, J. P., Qian, J., Shcherbina, A., FinnGen, Rodriguez, F., Assimes, T. L., Agarwala, V., Tibshirani, R., Hastie, T., Ripatti, S., Pritchard, J. K., Daly, M. J., & Rivas, M. A.
- Affiliations
- University of Helsinki (FI)
- Stanford Medicine (US)
- Stanford University (US)
- Broad Institute (US)
- Stanford Cardiovascular Institute (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Sinnott-Armstrong, Nasa
- Tanigawa, Yosuke
- Rivas, Manuel A.
- ORCID
- Sinnott-Armstrong, Nasa
- Tanigawa, Yosuke
- Amar, David
- Mars, Nina
- Benner, Christian
- Aguirre, Matthew
- Venkataraman, Guhan Ram
- Wainberg, Michael
- Ollila, Hanna M.
- Kiiskinen, Tuomo
- Havulinna, Aki S.
- Pirruccello, James P.
- Shcherbina, Anna
- Assimes, Themistocles L.
- Tibshirani, Robert
- Hastie, Trevor
- Ripatti, Samuli
- Pritchard, Jonathan K.
- Daly, Mark J.
- Rivas, Manuel A.
- Venue
- Nature Genetics
- Published
- 2021-01-18
- Volume
- 53
- Issue
- 2
- Pages
- 185-194
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC7867639
- OpenAlex
- W3121239749
- Semantic Scholar
- a41b6bd88ad795b8c4bffba4e5d6b972cd2681e1
- Cited by
- 744
- References
- 101
- Citations by year
- 2026: 92 · 2025: 151 · 2024: 160 · 2023: 145 · 2022: 139 · 2021: 50 · 2020: 5 · 2019: 1 · 2018: 1
- FWCI
- 70.82
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-10-04)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (1K01HL144607, R01EB001988-21, R01HG008140, R01HG010140, 5U01 HG009080)
- The Department of Defense through a National Defense Science and Engineering Grant and by a Stanford Graduate Fellowship
- Funai Overseas Scholarship from the Funai Foundation for Information Technology and the Stanford University School of Medicine
- Academy of Finland (#331671, #309643)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- blood and urine biomarkers, genetic loci, fine mapping, Mendelian randomization, polygenic risk score, uric acid, gout, cystatin C, stroke, chronic kidney disease, type 2 diabetes, alcoholic cirrhosis, HLA association, copy number variation, protein-altering variants, genetic risk stratification
- MeSH terms
- Cardiovascular Diseases, Diabetes Mellitus, Type 2, United Kingdom, HLA Antigens, Humans, Proteins, Serine Endopeptidases, Biomarkers, Linkage Disequilibrium, Biological Specimen Banks, Polymorphism, Single Nucleotide, Liver-Specific Organic Anion Transporter 1, Renal Insufficiency, Chronic, DNA Copy Number Variations, Mendelian Randomization Analysis, Genetic Pleiotropy
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