Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Abstract

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF ≤ 0.01) variant BP associations ( P < 5 × 10 -8 ), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci ( e.g. GATA5 , PLCB3 ). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Loss of Function Glucose-Dependent Insulinotropic Polypeptide Receptor Variants Are Associated With Alterations in BMI, Bone Strength and Cardiovascular Outcomes

“…Next, we examined the association with several traits of importance for cardio-metabolic health and disease. First, we evaluated the impact of R190Q and E288G on blood pressure in summary data from a newly published paper of rare genetic variations associating with blood pressure measures, which comprised > 800,000 individuals ( Surendran et al, 2020 ). Both GIPR variants were associated with higher systolic blood pressure (R190Q: 0.045 SD; E288G: 0.049 SD), although the diastolic blood pressure was not significantly different between carriers and non-carriers ( Figure 2 ).…”

“…The lipid levels association results were derived from summary data of an exome-wide meta-analysis ( N = ∼350,000) contributed by Lu et al (2017) , and we downloaded the data from http://csg.sph.umich.edu/willer/public/lipids2017EastAsian/ . Blood pressure and hypertension were investigated based on summary data derived from a meta-analysis of rare variants associated with blood pressure measures in European individuals ( N = 1,164,961) performed by Surendran et al (2020) . These summary data were downloaded from https://app.box.com/s/1ev9iakptips70k8t4cm8j347if0ef2u .…”

G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials

“…Given this scenario, it is then possible that additional association signals could derived from rare genetic variants located in this locus. However, these association signals could only be detected in studies with large sample sizes, as illustrated by the UK10k consortium (Walter et al, 2015) and the study of genetic variants related to blood pressure (Surendran et al, 2020). It is worth noting that the telomeric location of the G6PD gene on the X chromosome imposes serious limitations in terms of the assay costs and scalability to a large number of samples and SNP under analysis, as illustrated in the most comprehensive genetic study of G6PD variation conducted so far (Clarke et al, 2017).…”

The total and direct effects of systolic and diastolic blood pressure on cardiovascular disease and longevity using Mendelian randomisation

“…Mendelian randomisation (MR) using genetic variants as instrumental variables 10 , which are randomly allocated at conception, is much less open to confounding 11 . Previous MR studies suggested diastolic BP was not associated with CVD overall or by subtype independent of systolic BP 12 , and was inversely associated with risk of large artery stroke 13 , suggesting some cerebrovascular-protective effects of diastolic BP. Another MR study suggested diastolic BP was more strongly associated with shorter lifespan than systolic BP 14 , but did not consider the relative contribution of systolic and diastolic BP together, i.e.…”