Health effects of high serum calcium levels: Updated phenome-wide Mendelian randomisation investigation and review of Mendelian randomisation studies

Shuai Yuan; Lili Yu; Wanglong Gou; Lijuan Wang; Jing Sun; Doudou Li; Ying Lu; Xiaxia Cai; Huanling Yu; Changzheng Yuan; Ju-Sheng Zheng; Susanna C Larsson; Evropi Theodoratou; Xue Li

doi:10.1016/j.ebiom.2022.103865

Health effects of high serum calcium levels: Updated phenome-wide Mendelian randomisation investigation and review of Mendelian randomisation studies

EBioMedicine. 2022 Feb:76:103865. doi: 10.1016/j.ebiom.2022.103865. Epub 2022 Feb 6.

Authors

Shuai Yuan¹, Lili Yu², Wanglong Gou³, Lijuan Wang², Jing Sun², Doudou Li², Ying Lu², Xiaxia Cai⁴, Huanling Yu⁴, Changzheng Yuan⁵, Ju-Sheng Zheng³, Susanna C Larsson⁶, Evropi Theodoratou⁷, Xue Li⁸

Affiliations

¹ Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
² Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
⁴ Department of Nutrition and Food Hygiene, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China.
⁵ Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, USA.
⁶ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁷ Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK; Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁸ Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK. Electronic address: xueli157@zju.edu.cn.

Abstract

Background: Calcium plays a role in a wide range of biological functions. Here we conducted a phenome-wide Mendelian randomisation (MR-PheWAS) analysis and a systematic review for MR studies to comprehensively investigate the health effects of serum calcium.

Methods: One-hundred and thirty genetic variants strongly associated with serum calcium levels were used as instrumental variables. A phenome-wide association analysis (PheWAS) was conducted to examine the associations of genetically predicted serum calcium with 1473 distinct phenotypes in the UK Biobank including 339,197 individuals. Observed associations in PheWAS were further tested for replication in two-sample MR replication analysis. A systematic review for MR studies on serum calcium was performed to synthesize the published evidence and compare with the current MR-PheWAS findings.

Findings: Higher genetically predicted calcium levels were associated with decreased risk of 5 diseases in dermatologic and musculoskeletal systems and increased risk of 17 diseases in circulatory, digestive, endocrine, genitourinary and immune systems. Eight associations were replicated in two-sample MR analysis. These included decreased risk of osteoarthritis and increased risk of coronary artery disease, myocardial infarction, coronary atherosclerosis, hyperparathyroidism, disorder of parathyroid gland, gout, and calculus of kidney and ureter with increased serum calcium. Systematic review of 25 MR studies provided supporting evidence on five out of the eight disease outcomes, while the increased risk of gout, hyperparathyroidism and disorder of parathyroid gland were novel findings.

Interpretation: This study found wide-ranged health effects of high serum calcium, which suggests that the benefits and adversities of strategies promoting calcium intake should be assessed.

Funding: ET is supported by a CRUK Career Development Fellowship (C31250/A22804). XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province. SCL acknowledges research funding from the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019-00977), and the Swedish Cancer Society (Cancerfonden).

Keywords: Calcium; Health; Mendelian randomisation; PheWAS; Systematic review.

Publication types

Systematic Review

MeSH terms

Calcium*
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis*
Phenomics
Phenotype
Polymorphism, Single Nucleotide

Substances

Calcium

Grants and funding

22804/CRUK_/Cancer Research UK/United Kingdom