Associations of Circulating Biomarkers with Disease Risks: A Two-Sample Mendelian Randomization Study

Area of Science:

• Genetics and personalized medicine
• Biomarker discovery
• Causal inference in disease etiology

Background:

• Circulating biomarkers are crucial for personalized medicine but establishing causal links to diseases is difficult.
• Mendelian Randomization (MR) is a powerful genetic approach to infer causal relationships.
• Utilizing multiple MR methods increases the reliability of identified causal associations.

Purpose of the Study:

• To investigate causal relationships between a wide range of circulating biomarkers and complex diseases using multiple MR methods.
• To identify novel causal biomarkers for diseases, particularly bipolar disorder.
• To validate known biomarker-disease associations and explore potential causal links for cardiovascular conditions.

Main Methods:

• Employed multiple Mendelian Randomization (MR) methods: inverse variance weighted, simple mode, weighted mode, weighted median, and MR-Egger.
• Utilized the MR-base resource (v0.5.6) for genetic instrument data.
• Analyzed 212 circulating biomarkers against 99 complex diseases from diverse data sources (UK Biobank, Shin et al., Roederer et al., Kettunen et al., MRC IEU, Biobank Japan).

Main Results:

• Identified novel causal relationships between glucose and bipolar disorder (Mean Effect Size: 0.39) and cystatin C and bipolar disorder (Mean Effect Size: -0.31), supported by four or more MR methods.
• Confirmed known associations: urate with gout and creatine with chronic kidney disease.
• Found potential causal links for cardiovascular diseases: apolipoprotein B, cholesterol, LDL, lipoprotein A, and triglycerides in coronary heart disease; and lipoprotein A, LDL, cholesterol, and apolipoprotein B in myocardial infarction.

Conclusions:

• The study successfully corroborated known biomarker-disease links and uncovered two novel potential causal biomarkers for bipolar disorder.
• Findings contribute to understanding the etiological role of circulating biomarkers in disease development.
• The results support the advancement of precision diagnostics and interventions through improved understanding of biomarker-disease pathways.