Fetal genome predicted birth weight and polycystic ovary syndrome in later life: a Mendelian randomization study

Associations between lower birth weight and higher polycystic ovary syndrome (PCOS) risk have been reported in previous observational studies, however, the causal relationship is still unknown. Based on decomposed fetal and maternal genetic effects on birth weight (n  =  406,063), we conducted a two-sample Mendelian randomization (MR) analysis to assess potential causal relationships between fetal genome predicted birth weight and PCOS risk using a large-scale genome-wide association study (GWAS) including 4,138 PCOS cases and 20,129 controls. To further eliminate the maternally transmitted or non-transmitted effects on fetal growth, we performed a secondary MR analysis by utilizing genetic instruments after excluding maternally transmitted or non-transmitted variants, which were identified in another birth weight GWAS (n = 63,365 parent-offspring trios from Icelandic birth register). Linkage disequilibrium score regression (LDSR) analysis was conducted to estimate the genetic correlation. We found little evidence to support a causal effect of fetal genome determined birth weight on the risk of developing PCOS (primary MR analysis, OR: 0.86, 95% CI: 0.52 to 1.43; secondary MR analysis, OR: 0.86, 95% CI: 0.54 to 1.39). In addition, a marginally significant genetic correlation (rg = -0.14, se = 0.07) between birth weight and PCOS was revealed via LDSR analysis. Our findings indicated that observed associations between birth weight and future PCOS risk are more likely to be attributable to genetic pleiotropy driven by the fetal genome rather than a causal mechanism.