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(B) Manhattan plots showing the SNP-exposure estimates for each of the three SNPs are derived from a genome-wide association studies (GWAS) of the exposure variable. (C) The estimates of association between these three same SNPs and the outcome variable are then obtained from the outcome GWAS (results that are also depicted in a Manhattan plot). (D) Effects are harmonized to ensure that the ‘effect’ estimates in both the exposure and outcome GWASs correspond to the same allele (i. e., one that consistently either increases or decreases the exposure variable) for each SNP.

Therefore, any differences observed in the outcome of interest between these randomly allocated groups should be due to the exposure with which the genetic variant(s) are associated. (C) In the most simple of scenarios, the causal estimate of the association between the exposure (X) and outcome (Y) can be derived using the instrumental variable ratio method (otherwise known as the Wald ratio), where 𝛽𝐼𝑉 is the causal estimate derived from instrumental variable (i.


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