Mendelian Randomization Studies of Myopia: Choosing the right Summary Statistics

PurposeTo examine if the choice of genome-wide association study (GWAS) summary statistics can yield invalid or misleading conclusions in Mendelian randomization (MR) studies of myopia. MethodsThe relationships between (1) years of full-time education and myopia, and (2) myopia and primary open-angle glaucoma (POAG), were used as exemplar testcases. MR analyses were performed with nine different sets of summary statistics for myopia: seven from sources widely used in published MR studies, plus two newly derived sets (a GWAS in either 66,773 unrelated participants or 93,036 participants that included relatives). ResultsUsing the two newly derived sets of summary statistics from GWAS for myopia in unrelated and related samples, MR analyses demonstrated the expected positive causal relationship between education and myopia: odds ratio (OR) for myopia = 1.18, 95% confidence interval (CI) = 1.10 to 1.26 and OR = 1.16, 95% CI = 1.09 to 1.23 per additional year of education, respectively, and the expected positive relationship between myopia and POAG: OR = 1.11, 95% CI = 1.03 to 1.19 and OR = 1.12, 95% CI = 1.03 to 1.21, respectively. MR analyses performed using existing published GWAS summary statistics yielded highly inconsistent results, including MR estimates that suggested education protected against myopia and that myopia reduced the risk of POAG. ConclusionsCare is required when designing MR analyses. Our findings imply that the results of some past MR studies of myopia were invalid.