A Mendelian Randomisation study uses a genetic variant (SNP) as an instrumental variable to assess the causal effect of LDL cholesterol on coronary artery disease. Which assumption of this method is violated if the SNP also independently influences triglyceride levels?

• A Relevance assumption — the instrument must be associated with the exposure
• B Independence assumption — the instrument must be independent of confounders
• C Positivity assumption — all exposure levels must occur in the population
• D Exclusion restriction — the instrument must affect the outcome only through the exposure ✓

Explanation

The exclusion restriction (third assumption of Mendelian Randomisation) requires that the genetic instrument (SNP) affects the outcome solely through the exposure of interest (LDL cholesterol), with no direct pathway. If the SNP also raises triglycerides, it can affect CAD independently of LDL — termed 'horizontal pleiotropy' — violating the exclusion restriction. This is the most problematic assumption as genetic variants often have multiple phenotypic effects.

Reference: Park's Textbook of Preventive and Social Medicine, 27th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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