Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (original) (raw)
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Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Nature Genetics, 2017
Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. Combined with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure raising genetic variants on future cardiovascular disease risk.
European Journal of Preventive Cardiology, 2021
Aims Observational studies suggest elevated blood pressure (BP) as the leading risk factor for incident atrial fibrillation (AF), but whether this relationship is causal remains unknown. In this study, we used Mendelian randomization (MR) to investigate the potential causal association of BP levels with the risk of developing AF. Methods and results Genetic variants associated with the BP traits were retrieved from the International Consortium of Blood Pressure-Genome Wide Association Studies (N = 299 024). From 901 reported variants, 894 were assessed in a dedicated Genome-Wide Association Study of AF genetics, including >1 000 000 subjects of European ancestry. We used two-sample MR analyses to examine the potential causal association of systolic BP (SBP) and diastolic BP (DBP) as well as of pulse pressure (PP) with AF. MR analysis identified a potentially causal association between AF and SBP [odds ratio (OR): 1.018 per 1 mmHg increase, 95% confidence interval (CI): 1.012–1.02...
ARMC5 Variants and Risk of Hypertension in Blacks: MH‐GRID Study
Journal of the American Heart Association, 2019
Background We recently found that ARMC 5 variants may be associated with primary aldosteronism in blacks. We investigated a cohort from the MH ‐ GRID (Minority Health Genomics and Translational Research Bio‐Repository Database) and tested the association between ARMC 5 variants and blood pressure in black s. Methods and Results Whole exome sequencing data of 1377 black s were analyzed. Target single‐variant and gene‐based association analyses of hypertension were performed for ARMC 5 , and replicated in a subset of 3015 individuals of African descent from the UK Biobank cohort. Sixteen rare variants were significantly associated with hypertension ( P =0.0402) in the gene‐based (optimized sequenced kernel association test) analysis; the 16 and one other, rs116201073 , together, showed a strong association ( P =0.0003) with blood pressure in this data set. The presence of the rs116201073 variant was associated with lower blood pressure. We then used human embryonic kidney 293 and adre...
Identification of 20 novel loci associated to ischemic stroke. Epigenome-Wide Association Study
2019
ABSTRACTRationaleDNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1–2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism.ObjectiveTo detect epigenetic variants associated to stroke occurrence and stroke subtypes.Methods and ResultsA two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N=226 and N=166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus ZFHX3, which i...
Nature Genetics, 2018
High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic, pulse pressure) to date in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
Nature genetics, 2018
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on t...
Nature genetics, 2018
High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
Genomic basis of insularity and ecological divergence in barn owls (Tyto alba) of the Canary Islands
Heredity
Islands, and the particular organisms that populate them, have long fascinated biologists. Due to their isolation, islands offer unique opportunities to study the effect of neutral and adaptive mechanisms in determining genomic and phenotypical divergence. In the Canary Islands, an archipelago rich in endemics, the barn owl (Tyto alba), present in all the islands, is thought to have diverged into a subspecies (T. a. gracilirostris) on the eastern ones, Fuerteventura and Lanzarote. Taking advantage of 40 whole-genomes and modern population genomics tools, we provide the first look at the origin and genetic makeup of barn owls of this archipelago. We show that the Canaries hold diverse, long-standing and monophyletic populations with a neat distinction of gene pools from the different islands. Using a new method, less sensitive to structure than classical FST, to detect regions involved in local adaptation to insular environments, we identified a haplotype-like region likely under sel...
Genetic analysis of over one million people identifies 535 novel loci for blood pressure
High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.