Applying Mendelian randomization to define the causal relationship between phenotype and disease.

<p>An example based upon the report of Lintel-Nietschke et al. (2008) <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000356#pmed.1000356-LinselNitschke1" target="_blank">[74]</a> reporting the association between a gene variant in the <i>LDLR</i> gene with decreased low density lipoprotein-cholesterol (LDL-C) levels and with a reduced risk of coronary artery disease (CAD). The variant can be used in a Mendelian randomization approach to test the causal relationship between LDL-C and CAD. If LDL-C has a causal role in CAD, an association between the <i>LDLR</i> gene variant and disease risk would be seen (red dashed arrow). If LDL-C levels are correlated with CAD risk but not causal, then the gene variant will not show an association with CAD risk. This will establish whether reverse causation is at play and remove the potential confounding influence of factors such as smoking and nutritional status.