Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease
Assumptions of a Mendelian Randomization Analysis
Genetic variants, which are assigned at birth and largely randomly assorted in a population, can be used as instrumental variables to estimate the causal association of an exposure (eg, waist-to-hip ratio [WHR] adjusted for body mass index [BMI]) with an outcome of interest (eg, coronary heart disease). This approach rests on 3 assumptions. First, the genetic variants must be associated with the exposure (assumption 1). Second, the genetic variants must not be associated with confounders (assumption 2). Third, the genetic variants must influence risk of the outcome through the exposure and not through other pathways (assumption 3). Mendelian randomization can be extended to estimate the association of exposure with outcome that is mediated by a given a mediator (eg, triglycerides).
A polygenic score of 48 single-nucleotide polymorphisms was used as an instrument to estimate the causal association of waist-to-hip ratio (WHR) adjusted for body mass index (BMI) with cardiometabolic quantitative traits, type 2 diabetes, and coronary heart disease; sources of data for analysis included the UK Biobank and publicly available genome-wide association studies. CARDIOGRAMplusC4D indicates Coronary Artery DIsease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium 11 ; CKDGen, Chronic Kidney Disease Genetics Consortium 12 ; DIAGRAM, Diabetes Genetics Replication and Meta-analysis 13 ; GIANT, Genetic Investigation of Anthropometric Traits 14 , 15 ; GLGC, Global Lipids Genetics Consortium 16 Continue reading