Maternal and fetal origins of offspring blood pressure: statistical analysis using genetic correlation and genetic risk score-based Mendelian randomization.

Abstract

Epidemiological studies demonstrated that adverse in utero environment was associated with increased risk of offspring high blood pressure, by using birthweight as the proxy of maternal intrauterine exposure; however, the nature of such association remains less understood. With maternal/fetal-specific summary statistics of birthweight (n = 297 356 for own birthweight and n = 210 248 for offspring birthweight) and summary statistics of blood pressure [i.e. systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP)] (n = 757 601), we evaluated the genetic correlation between fetal-specific birthweight and blood pressure using cross-trait linkage disequilibrium score regression, and next detected pleiotropic genes for them with a pleiotropy mapping method called mixture-adjusted intersect-union pleiotropy test. Furthermore, we conducted a genetic risk score (GRS)-based Mendelian randomization analysis in parent-offspring pairs (n = 6031) of the UK Biobank cohort, to assess the causal relation between maternal-specific GRS and blood pressure conditioning on fetal genotypes. We found fetal-specific birthweight had a negative genetic correlation with DBP (ρ^g = -0.174, P = 1.68 × 10-10), SBP (ρ^g = -0.198, P = 8.09 × 10-12), and PP (ρ^g = -0.152, P = 6.04 × 10-8), and detected 143, 137 and 135 pleiotropic genes shared between fetal-specific birthweight and PP, SBP and DBP, respectively. These genes often exhibited opposite genetic effects, and were more likely to be differentially expressed in pancreas, liver, heart, brain, whole blood and muscle skeletal tissues. A causal negative association of maternal-specific birthweight was identified with SBP (P = 2.20 × 10-2) and PP (P = 7.67 × 10-3) but not DBP (P = 0.396) in mother-offspring pairs, after accounting for the influence of fetal-specific GRS; and the two significant relations were robust against the horizontal pleiotropy of instruments and the confounding influence of gestational duration and preterm birth. However, these causal associations could not be detected in father-offspring pairs. This study revealed common genetic components underlying birthweight and blood pressure, and provided important insight into aetiology and early prevention of high blood pressure.