Blood pressure change in pregnancy: using Mendelian Randomization to determine maternal and offspring causes and consequences.

PhD project (3/4 yr research project leading to independent research at the doctorate level)

Prof Deborah Lawlor, Prof Kate Tilling, Corrie Macdonald-Wallis


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Rationale

Hypertensive disorders of pregnancy (HDP), including pre-eclampsia (PE) and gestational hypertension, are associated with adverse maternal and offspring short- and long-term outcomes. They are defined as elevated blood pressure after 20 weeks of gestation and are heritable. HDP is a binary characteristic that potentially masks different subtypes (e.g. women could reach diagnostic criteria through having high blood pressure (BP) from the start of pregnancy, a smaller early pregnancy decrease in BP, or a more rapid later pregnancy increase).

Novel fetal and maternal genetic variants have recently been identified as related to PE in a large genome wide association studies (GWAS). Identifying genetic variants that are related to different patterns of change in BP in pregnancy could help identify different sub-types of HDP and determine the causal effect of changes in gestational BP with maternal and offspring adverse outcomes.

Aims & objectives


1. Determine the association of maternal and fetal genetic variants identified in the recent PE GWAS with patterns of change in gestational BP.
2. Complete a GWAS of change of gestational BP.
3. Use multivariable regression to determine the association of different patterns of change in gestational BP with adverse maternal and offspring outcomes.
4. Use genetic variants (identified in objectives 1 and 2) to determine the causal effects of change in gestational BP with mat

Methods

The project will use data from the Early Growth Genetics (EGG) consortia, InterPreg genetic consortia, other relevant large datasets (e.g. UK Biobank) and pooled (aggregate results) in MRBase, as relevant for different aspects of the project.
Statistical analyses will involve use of appropriate methods to model different patterns of gestational BP change (e.g. fractional polynomials and multilevel models and latent class analyses). Both one- and two-sample Mendelian Randomization will be used to explore causal effects. Triangulation of findings with other methods, as appropriate will also be explored.

References

Interpreg Consortia. First sequence variants associated with preeclampsia.

Macdonald-Wallis C, et al. Associations of blood pressure change in pregnancy with fetal growth and gestational age at delivery. Hypertension 2014; 64:36-44

Lawlor DA. Two-sample Mendelian Randomization. IJE 2016


Created on Aug. 23, 2016, 8:01 a.m.

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