A biologically informed framework for instrument selection in dietary Mendelian randomization using chemosensory...

Area of Science:

• Nutritional Epidemiology
• Genetic Epidemiology
• Human Genetics

Background:

• Mendelian randomization (MR) is vital for causal inference in nutritional epidemiology.
• Traditional dietary MR studies face challenges like pleiotropy and reverse causation due to reliance on self-reported intake and statistical significance for instrument selection.
• A biologically informed framework using chemosensory receptor genes is proposed to enhance genetic instrument validity.

Purpose of the Study:

• To develop and evaluate a novel framework for selecting valid genetic instruments for dietary exposures.
• To leverage genes encoding taste and olfactory receptors to improve causal inference in nutritional epidemiology.
• To reduce susceptibility to pleiotropy and reverse causation in dietary MR studies.

Main Methods:

• Prioritized 1,214 variants in taste and olfactory receptor genes.
• Tested associations with 140 food-liking traits in UK Biobank and Avon Longitudinal Study of Parents and Children cohorts.
• Applied a multi-stage filtering pipeline including replication, concordance, socioeconomic status exclusion, specificity assessment, and directionality testing.

Main Results:

• Identified 268 variants in 101 olfactory and 16 taste receptor genes associated with 96 food-liking traits.
• Filtered down to 24 candidate instruments for 20 foods, with onion liking being high confidence.
• Genetically proxied onion liking showed associations with lower blood pressure and reduced type 2 diabetes risk.

Conclusions:

• Instrument selection guided by chemosensory genetics offers a scalable strategy to improve dietary MR validity.
• This approach enhances instrument credibility and reduces bias from pleiotropy and reverse causation.
• While prioritizing biological specificity may reduce instrument numbers, it strengthens causal evaluation of diet-disease relationships.