Two-sample MR analyses were performed using GWAS summary data. These two GWAS datasets were required to have a similar genetic ancestry. Three plasma lipid fractions— LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG)—were included in this study as the exposure variables. For the exposure dataset, a publicly available summary statistics data, based on 188,577 European-ancestry individuals, were identified through a meta-analysis of GWAS from the Global Lipids Genetics Consortium (GLGC) (Sample 1) [
21,
22]. For the outcome dataset, we extracted the summary statistic datasets from a recent GWAS of POAG conducted among the United Kingdom (UK) Biobank study participants with a total of 463,010 European-ancestry individuals (Sample 2) and accessed through the MR-Base database (
http://www.mrbase.org/). The MR-Base is home to a huge collection of summary data from many GWASs [
23]. For the two-sample MR, it was important to certify that the IVs for the exposure were robustly independent. Therefore, we examined the clumping test to assess the linkage disequilibrium (LD) (
r2 threshold of 0.001). In addition, if a particular SNP is not obtained in the outcome dataset, then we will use SNPs that are LD ‘proxies’ instead; these lookups are automatically provided by MR-Base.
In the GWASs of GLGC, a total of 185 independent SNPs robustly associated with plasma lipid concentrations reached a threshold of genome-wide significance (
P < 5.0 × 10
− 8) and were selected as IVs for MR analysis (Supplementary Table
1). These 185 SNPs accounted for 6.9% of the variance in LDL-C, 6.4% of the variance in HDL-C, and 5.2% of variance in TG. Of these selected SNPs, 82 were associated with LDL-C, 96 were associated with HDL-C, and 60 were associated with TG. From amongst these 82 SNPs associated with LDL-C, 26 (rs1998013, rs1010167, rs903319, rs646776, rs515135, rs3817588, rs4148218, rs2030746, rs2247056, rs2297374, rs4722551, rs217386, rs10102164, rs2980885, rs8176720, rs174532, rs11220462, rs6489818, rs1186380, rs2288002, rs4791641, rs688, rs10401969, rs6859, rs7264396, rs6016381) were excluded as potential instrumental variables for having a pairwise LD coefficient of determination (
r2) > 0.001 with another variant in the set. From amongst these 96 SNPs associated with HDL-C, 24 (rs6680658, rs355838, rs13326165, rs442177, rs6450176, rs17286602, rs4332136, rs894210, rs4871137, rs2980885, rs2472509, rs17788930, rs11246602, rs12226802, rs12801636, rs653178, rs10773105, rs2412710, rs261342, rs2652834, rs5880, rs11660468, rs1800961) were excluded as potential instrumental variables for having a pairwise LD
r2 > 0.001 with another variant in the set. From amongst these 60 SNPs associated with TG, 14 (rs10493326, rs3817588, rs10029254, rs799160, rs4921914, rs894210, rs2980885, rs603446, rs2412710, rs261342, rs2652834, rs9930333, rs5880, rs1688030) were excluded as potential instrumental variables for having a pairwise LD
r2 > 0.001 with another variant in the set.