2.3 Mendelian randomization design and instrumental variable
(IV) selection
Figure 1 showed a brief description of the overall design of the study
for UVMR and MVMR. The potential causal relationships between factors
and abortion were deduced from UVMR and the main risk factors for MA
were identified through different models of MVMR. In MR, genetic
variants are used as IVs to assess the causal effect of an exposure on
an outcome. Genetic variants used as IV need to meet the following three
pivotal assumptions: First, the SNPs are closely associated with
exposure. Second, the SNPs are independent from any confounders of
exposure-outcome causality. Third, the SNPs do not directly affect
outcome, but only have an impact on outcomes via the exposure. We
selected the significant genetic variants that match with the
genome-wide statistical significance threshold
(Pā<ā5āĆ10-8). Using PLINK clustering, the
linkage disequilibrium between these SNPs for each exposure was
estimated on the basis of the 1000 Genomes reference panel confined to
the European population, and SNPs were thresholded at linkage
disequilibrium r2 < 0.001 at a 0-10,000 kb
window to guarantee the independence of the selected genetic variants.
Removing the SNPs for being palindromic with intermediate allele
frequencies. For UVMR, we calculated the F-statistic for each exposure
to assess the strength of each tool in the abortion GWAS, and SNPs with
F statistics <10 were identified as weak
instruments(Supplementary table 3-12). In addition, we calculated the
conditional F-statistic for assessing instrument strength in two sample
summary MVMR
Statistical analyses