There is another important distinction that must be made in association analyses, that of direct versus indirect association. This distinction is critical and, in the authors’ experience, often lost or ignored in studies incorporating genetic components in fields outside genetics. Direct association arises because the genetic variant that is associated with the disease/outcome has a functional consequence and is directly involved in susceptibility or outcome. Indirect association arises when a genetic variant is associated with disease/outcome because it is very close to the causal variant, but the associated variant is not itself causal in any way. Indirect association results from a phenomenon called linkage disequilibrium (LD). This refers to the fact that an individual's genotype at any one location is not independent of what their genotype will be at nearby locations in the genome. In other words, genetic variants that are nearby are often correlated. To the degree that two variants are correlated, knowing one's genotype at one location also tells you something, albeit probabilistic, about what their genotype will be at the other location. This is because any time
