Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study.

This is the final version. Available from Oxford University Press via the DOI in this record. Data Availability: The genotype and phenotype data are available on application from UK Biobank (http://www.ukbiobank.ac.uk/). Individual cohorts participating in the EGG consortium should be contacted directly as each cohort has different data-access policies. GWAS summary statistics of birthweight are available via the EGG website (https://egg-consortium.org/). Genome-wide summary statistics for urate used in this study are publicly available at the CKDGen Consortium via http://ckdgen.imbi.uni-freiburg.de. Summary statistics from EFSOCH are available on request. Researchers interested in accessing the data are expected to send a reasonable request by sending an e-mail to the Exeter Clinical Research Facility at [email protected]: Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight. METHODS: We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n = 872) and UK Biobank (UKB; n = 133 187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n = 288 649 European ancestry] on offspring birthweight (n = 406 063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n = 199 768). RESULTS: Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: -50, 6); P = 0.13] and UKB [-28 g (95% CI: -31, -25); P = 1.8 × 10-75]. The MR causal effect estimate was directionally consistent, but smaller [-11 g (95% CI: -25, 3); PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P = 7.8 × 10-22], consistent with that previously published in women and men. CONCLUSION: The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweight. Maternal urate levels are unlikely to be an important contributor to offspring birthweight.Wellcome TrustBritish Heart FoundationEuropean Research CouncilUS National Institute of HealthQUEX InstituteWellcome Trus