Over 1000 genetic loci influencing blood pressure with multiple systems and tissues implicated

Cabrera, Claudia; Ng, Fu Liang; Nicholls, Hannah; Gupta, Ajay; Barnes, Michael R.; Munroe, Patricia B.; Caulfield, Mark J.

doi:10.1093/hmg/ddz197

Cited by 50 publications

(37 citation statements)

References 85 publications

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“…In humans, recent progress in large-scale genome-wide association studies (GWASs) has succeeded in the identification of over 1000 genetic loci influencing BP ( Cabrera et al, 2019 ). Despite the large number of loci, the genetic variance explained by all loci in aggregate remains low (at most 5.7% of BP variation), indicating that individual common variants mostly exert weak effects on BP.…”

Section: Introductionmentioning

confidence: 99%

Integrative genomic analysis of blood pressure and related phenotypes in rats

Takeuchi

Liang

Isono

et al. 2021

Disease Models &Amp; Mechanisms

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Despite remarkable progress made in human genome-wide association studies, there remains a substantial gap between statistical evidence for genetic associations and functional comprehension of the underlying mechanisms governing these associations. As a means of bridging this gap, we performed genomic analysis of blood pressure (BP) and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP), both of which are unique genetic models of severe hypertension and cardiovascular complications. By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n=1415), fine congenic mapping (maximum n=8704), pharmacological intervention and comparative analysis with transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY); e.g. inter-strain BP differences between SHRSP and WKY could be largely explained by an aggregate of BP changes in seven SHRSP-derived consomic strains. We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this study, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein–kinin/renin–angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs. In combination with a pharmacological intervention, we provide in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, in a rat polygenic hypertension model.

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Section: Introductionmentioning

confidence: 99%

Integrative genomic analysis of blood pressure and related phenotypes in rats

Takeuchi

Liang

Isono

et al. 2021

Disease Models &Amp; Mechanisms

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“…A study of the association between rs13107325 and putamen volume found it to be accompanied by decreased SLC39A8 expression in the putamen and with the SNP-trait association decreased in those with schizophrenia 33 . The rs13107325 SNP has also been associated with schizophrenia itself 23 , neurodevelopmental outcomes and intelligence test performance 34,35 , blood pressure 36 and numerous other factors 13,37,38 , including over 70 anthropometric traits (http://www.nealelab.is/uk-biobank/). The rs1800562 HFE SNP is also known as Cys282Tyr and has been associated with reduced putamen volume and T2star signal in the striatum 13 , as well as being involved in iron regulation and transport, being a major risk variant for hemochromatosis where it accounts for approximately 85% of cases 39 , mineral metabolism and haematological disorders 40 13 with VCAN, which encodes the extracellular matrix protein Versican and which plays a number of crucial roles in maintaining the extracellular matrix, including in nervous system development 43,44 .…”

Section: Discussionmentioning

confidence: 99%

Identifying genetic variants associated with cerebellar volume in 33,265 individuals from the UK-Biobank

Chambers

Escott‐Price

Legge

et al. 2020

Preprint

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There is expanding interest in researching the cerebellum given accumulating evidence of its important contributions to cognitive and emotional functions, in addition to more established sensorimotor roles. While large genome-wide association studies (GWAS) have shed light on the common allele architecture of cortical and subcortical brain structures, the cerebellum remains under investigated. We conducted a meta-GWAS of cerebellar volume in 33,265 UK-Biobank European participants. Results show cerebellar volume to be moderately heritable (h2SNP=50.6%). We identified 33 independent genome-wide associated SNPs with total cerebellar volume, with 6 of these SNPs mapped to protein-coding genes and 5 more shown to alter cerebellar gene expression. We highlight 21 unique candidate genes for follow-up analysis. Cerebellar volume showed significant genetic correlation with brainstem, pallidum and thalamus volumes, but no significant correlations with neuropsychiatric phenotypes. Our results provide important new knowledge of the genetic architecture of cerebellar volume and its relationship with other brain phenotypes.

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“…Genome-wide association studies (GWASs) have identified over 1000 genetic loci influencing blood pressure with multiple systems and tissues implicated [9]. Common variants are widely accepted to have effect on complex disease.…”

Section: Taking Into Account the Impact Of Rare Variants On Complex Dmentioning

confidence: 99%

Genetic-Based Hypertension Subtype Identification Using Informative SNPs

Jiang

Shah

et al. 2020

Genes

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In this work, we proposed a process to select informative genetic variants for identifying clinically meaningful subtypes of hypertensive patients. We studied 575 African American (AA) and 612 Caucasian hypertensive participants enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) study and analyzed each race-based group separately. All study participants underwent GWAS (Genome-Wide Association Studies) and echocardiography. We applied a variety of statistical methods and filtering criteria, including generalized linear models, F statistics, burden tests, deleterious variant filtering, and others to select the most informative hypertension-related genetic variants. We performed an unsupervised learning algorithm non-negative matrix factorization (NMF) to identify hypertension subtypes with similar genetic characteristics. Kruskal–Wallis tests were used to demonstrate the clinical meaningfulness of genetic-based hypertension subtypes. Two subgroups were identified for both African American and Caucasian HyperGEN participants. In both AAs and Caucasians, indices of cardiac mechanics differed significantly by hypertension subtypes. African Americans tend to have more genetic variants compared to Caucasians; therefore, using genetic information to distinguish the disease subtypes for this group of people is relatively challenging, but we were able to identify two subtypes whose cardiac mechanics have statistically different distributions using the proposed process. The research gives a promising direction in using statistical methods to select genetic information and identify subgroups of diseases, which may inform the development and trial of novel targeted therapies.

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Over 1000 genetic loci influencing blood pressure with multiple systems and tissues implicated

Cited by 50 publications

References 85 publications

Integrative genomic analysis of blood pressure and related phenotypes in rats

Integrative genomic analysis of blood pressure and related phenotypes in rats

Identifying genetic variants associated with cerebellar volume in 33,265 individuals from the UK-Biobank

Genetic-Based Hypertension Subtype Identification Using Informative SNPs

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