CONTEXT: The metabolic syndrome (MetS) is associated with type 2 diabetes (T2D). However, whether each of the 5 components of the MetS individually is causally associated with T2D is unknown.

OBJECTIVE: We tested the hypothesis that each component is causally associated with T2D.

DESIGN: Mendelian randomization using genetic variations that alter levels of the MetS components are randomly assorted at gamete formation and free of confounding and reverse causation, which allows us to infer causality.

SETTING: General community.

STUDY PARTICIPANTS: A total of 95 756 individuals from the prospective Copenhagen General Population Study.

MAIN OUTCOME MEASURE: Type 2 diabetes.

RESULTS: A 1-cm larger waist circumference was associated with an observational 5% (95% confidence interval, 4%-5%) and a causal genetic 5% (1%-10%) higher risk of T2D. In contrast, although a 1-unit higher level of triglycerides and blood pressure and a 1-unit lower level of high-density lipoprotein cholesterol were associated with higher observational T2D risk, the corresponding causal genetic risks were not. As expected, a 1 mmol/L higher glucose level was associated with an observational 32% (30%-34%) and a causal genetic 82% (21%-173%) higher T2D risk.

CONCLUSIONS: In conclusion, larger waist circumference and higher glucose levels were each causally associated with higher risk of T2D. Findings like these may change clinical thinking so that waist circumference control will be prioritized to the same extend as control of blood pressure, lipids, and glucose levels in T2D prevention.