Genetic instrumental variable selection
Three fundamental conditions of MR analysis should be satisfied to
ensure the validity of genetic variants as IVs. The MR assumptions were
depicted in Figure 1 and listed as follows: (1) The genetic variations
considered as IVs should be closely associated with the exposure, (2)
the genetic variations designated as IVs should not be associated with
any confounding factors, and (3) the genetic variations used as IVs
should only influence the risk of the outcome through the exposure(9).
We performed rigorous filtering steps to control for SNP quality in the
merging of two distinct GWAS datasets. Firstly, SNPs associated with the
telomere length were selected using a genome-wide significance threshold
(P < 5×10-8). Secondly, SNPs with
high overall linkage disequilibrium (LD, R2 > 0.001 and
10000kb) were excluded. Thirdly, SNPs with an F-statistic less than 10
were omitted to ensure the strength of the genetic instruments.
Additionally, after data harmonization, palindromic SNPs were excluded
as they have intermediate allele frequencies(10, 14).