Mendelian Randomization Studies of Myopia: Choosing the Right Summary Statistics.

PURPOSE

To examine whether the choice of genome-wide association study (GWAS) summary statistics can yield invalid or misleading conclusions in Mendelian randomization (MR) studies of myopia.

METHODS

The relationships between (1) years of full-time education and myopia, and (2) myopia and primary open-angle glaucoma (POAG), were used as exemplar test cases. 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 for myopia in either 66,773 unrelated participants or 93,036 participants that included relatives).

RESULTS

Using the two newly derived sets of summary statistics from GWAS for myopia in unrelated and related samples, MR analyses demonstrated a 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 a 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 inconsistent results, including MR estimates that suggested education protected against myopia and that myopia reduced the risk of POAG. Re-analysis of a selection of published MR studies of myopia confirmed that most published results were invalid.

CONCLUSIONS

Care is required when designing MR analyses. Many published MR studies of myopia have reported misleading results.