Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension

van Duijvenboden, Stefan; Ramírez, Julia; Young, William J.; Olczak, Kaya J.; Ahmed, Farah; Alhammadi, Mohammed J.A.Y.; Bell, Christopher G.; Morris, Andrew P.; Munroe, Patricia B.

doi:10.1016/j.ajhg.2023.08.009

Cited by 6 publications

(1 citation statement)

References 91 publications

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“…The transition from identifying genetic variants associated with diseases through GWAS to understanding their functional impacts presents a significant challenge, especially as most GWAS variants are located in the genome's noncoding regions. Munroe's team 4 has highlighted a path forward by integrating diverse data sets-including mouse models, human genetic disorders, gene expression profiles, tissue-specific gene abundance, and extensive literature reviews-to nominate 436 blood pressure candidate genes for functional validation. This validation process is essential for bridging the gap between genetic discovery and clinical application.…”

Section: Functional Validation Of Gwas-identified Variantsmentioning

confidence: 99%

Beyond Genome-Wide Scans: Advancing Hypertension Genomics Into the Future

Padmanabhan,

Delles,

Dominiczak

2024

Hypertension

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Section: Functional Validation Of Gwas-identified Variantsmentioning

confidence: 99%

Beyond Genome-Wide Scans: Advancing Hypertension Genomics Into the Future

Padmanabhan,

Delles,

Dominiczak

2024

Hypertension

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Epigenomic insights into common human disease pathology

Bell

2024

Cell. Mol. Life Sci.

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The epigenome—the chemical modifications and chromatin-related packaging of the genome—enables the same genetic template to be activated or repressed in different cellular settings. This multi-layered mechanism facilitates cell-type specific function by setting the local sequence and 3D interactive activity level. Gene transcription is further modulated through the interplay with transcription factors and co-regulators. The human body requires this epigenomic apparatus to be precisely installed throughout development and then adequately maintained during the lifespan. The causal role of the epigenome in human pathology, beyond imprinting disorders and specific tumour suppressor genes, was further brought into the spotlight by large-scale sequencing projects identifying that mutations in epigenomic machinery genes could be critical drivers in both cancer and developmental disorders. Abrogation of this cellular mechanism is providing new molecular insights into pathogenesis. However, deciphering the full breadth and implications of these epigenomic changes remains challenging. Knowledge is accruing regarding disease mechanisms and clinical biomarkers, through pathogenically relevant and surrogate tissue analyses, respectively. Advances include consortia generated cell-type specific reference epigenomes, high-throughput DNA methylome association studies, as well as insights into ageing-related diseases from biological ‘clocks’ constructed by machine learning algorithms. Also, 3rd-generation sequencing is beginning to disentangle the complexity of genetic and DNA modification haplotypes. Cell-free DNA methylation as a cancer biomarker has clear clinical utility and further potential to assess organ damage across many disorders. Finally, molecular understanding of disease aetiology brings with it the opportunity for exact therapeutic alteration of the epigenome through CRISPR-activation or inhibition.

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