Heritable polygenic editing: the next frontier in genomic medicine?

Nature, Год журнала: 2025, Номер 637(8046), С. 637 - 645

Опубликована: Янв. 8, 2025

Abstract Polygenic genome editing in human embryos and germ cells is predicted to become feasible the next three decades. Several recent books academic papers have outlined ethical concerns raised by germline opportunities that it may present 1–3 . To date, no attempts been made predict consequences of altering specific variants associated with polygenic diseases. In this Analysis, we show could theoretically yield extreme reductions disease susceptibility. For example, a relatively small number genomic make substantial difference an individual’s risk developing coronary artery disease, Alzheimer’s major depressive disorder, diabetes schizophrenia. Similarly, large changes factors, such as low-density lipoprotein cholesterol blood pressure, could, theory, be achieved editing. Although heritable (HPE) still speculative, completed calculations discuss underlying issues. Our modelling demonstrates how putatively positive gene at individual level deepen health inequalities. Further, single or multiple can increase some diseases while decreasing others, HPE raises challenges related pleiotropy genetic diversity. We conclude arguing for collectivist perspective on issues HPE, which accounts its effects individuals, their families, communities society 4

Язык: Английский

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Polygenic risk score for blood pressure and lifestyle factors with overall and CVD mortality: a prospective cohort study in a Japanese population

Hypertension Research, Год журнала: 2024, Номер 47(9), С. 2284 - 2294

Опубликована: Июль 3, 2024

Язык: Английский

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Functional genomics of human skeletal development and the patterning of height heritability

Cell, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Underlying variation in height are regulatory changes to chondrocytes, cartilage cells comprising long-bone growth plates. Currently, we lack knowledge on epigenetic regulation and gene expression of chondrocytes sampled across the human skeleton, therefore cannot understand basic mechanisms controlling biology. We first rectify this issue by generating extensive transcriptomic maps from different plates developing skeletons, discovering novel networks shaping bone/joint development. Next, using these tandem with genome-wide association study (GWAS) signals, disentangle impacts that skeletal element-specific versus global-acting variants have growth, revealing prime importance pleiotropy variation. Finally, as is highly heritable, thus often test case for complex-trait genetics, leverage datasets within a testable omnigenic model framework discover chondrocyte developmental modules peripheral-acting factors biology growth.

Язык: Английский

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MTHFR Polymorphisms, Homocysteine Elevation, and Ischemic Stroke Susceptibility in East Asian and European Populations

Neurology, Год журнала: 2025, Номер 104(3)

Опубликована: Янв. 9, 2025

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme that regulates folate and homocysteine metabolism. Genetic variation in We proxied reduced MTHFR function using the C677T missense variant impairs consequently increases levels of total plasma (tHcy) both East Asian European populations. Summary data for IS its subtypes (small vessel stroke [SVS], large artery [LAS], cardioembolic [CES]) were obtained from largest available genome-wide association studies. MR estimates calculated Wald ratio random-effects inverse-variance-weighted methods. performed sensitivity analyses to evaluate confounding due linkage disequilibrium. Genetically downregulated activity, associated with consequent SD increase tHcy levels, was an increased risk SVS (odds [OR] 1.20, 95% CI 1.08-1.34, Our findings provide genetic evidence activity selectively These warrant further investigation genotype-guided nutritional supplementation prevention SVS.

Язык: Английский

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Multi-ancestry genome-wide meta-analysis with 472,819 individuals identifies 32 novel risk loci for psoriasis

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 30, 2025

Psoriasis is a common chronic, recurrent, immune-mediated disease involved in the skin or joints both. However, deeper insight into genetic susceptibility of psoriasis still unclear. Here we performed largest multi-ancestry meta-analysis genome-wide association study including 28,869 cases and 443,950 healthy controls. We identified 74 significant loci for psoriasis. Of loci, 32 were novel risk loci. Across 801 likely causal genes are indicated 164 prioritized. SNP-based heritability analyses demonstrated that variants explain 15% Gene-set correlation revealed psoriasis-related have positive correlations with autoimmune diseases such as ulcerative colitis, inflammatory bowel diseases, Crohn's disease. Gene-drug interaction analysis suggested psoriasis-associated overlapped targets current medications Finally, used to explore drug repurposing potential Based on provided new biological insights etiology clinical interest, gave some hints 76

Язык: Английский

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Using omics data and genome editing methods to decipher GWAS loci associated with coronary artery disease

Atherosclerosis, Год журнала: 2025, Номер 401, С. 118621 - 118621

Опубликована: Фев. 1, 2025

Coronary artery disease (CAD) is due to atherosclerosis, a pathophysiological process that involves several cell-types and results in the accumulation of lipid-rich plaque disrupt normal blood flow through coronary arteries heart. Genome-wide association studies have identified 1000s genetic variants robustly associated with CAD or its traditional risk factors (e.g. pressure, lipids, type 2 diabetes, smoking). However, gaining biological insights from these discoveries remain challenging because linkage disequilibrium difficulty interpret functions non-coding regulatory elements human genome. In this review, we present different statistical methods Mendelian randomization) molecular datasets expression protein quantitative trait loci) helped connect CAD-associated genes, pathways, tissues. We emphasize various strategies make predictions, which need be validated orthologous systems. discuss specific examples where integration omics data GWAS has prioritized causal genes. Finally, review how targeted genome-wide genome editing experiments using CRISPR/Cas9 toolbox been used characterize new genes cells. Researchers now bioinformatic methods, datasets, experimental tools dissect comprehensively loci contribute humans.

Язык: Английский

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GWAS for Defining the Etiology of Hypertension: Have They Delivered?

Hypertension, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

Genome-wide association studies have identified >3500 associated single nucleotide polymorphisms and over 1000 independent loci with hypertension. These individually small effect sizes, few been experimentally tested for causal roles in hypertension using animal models or humans. Thus, methods to prioritize maximize the relevance of are critical determine their importance We propose several approaches aid these efforts, including: (1) integration genome-wide study data multiomic sets, including proteomics, transcriptomics, epigenomics, (2) utilizing linked clinical genetic sets contributions subphenotypes distinct drivers, (3) performing whole exome/genome sequencing on cohorts individuals severe enrich rare variants larger sizes. Rather than creating longer lists hypertension-associated polymorphisms, needed identify key mediators pathophysiology.

Язык: Английский

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EPAS1 and Type 2 Diabetes Mellitus: A Two-Sample Mendelian Randomization Study

Asian Case Reports in Emergency Medicine, Год журнала: 2025, Номер 13(01), С. 25 - 32

Опубликована: Янв. 1, 2025

Язык: Английский

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Adiposity and domain-specific stroke recovery: A Mendelian randomization study

European Stroke Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 15, 2025

Introduction: While adiposity is an established risk factor for incident ischemic stroke, its influence on functional recovery after stroke uncertain. We leveraged Mendelian randomization (MR) to examine the causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) post-stroke motor, cognitive, global recovery. Materials methods: Genetic proxies BMI WHR were obtained from a genome-wide association study (GWAS) meta-analysis GIANT consortium UK Biobank ( n = 806,834). The primary outcomes longitudinal trajectories three National Institutes Health Stroke Scale (NIHSS) measures assessed over 2-year period: motor function subscores, cognitive performance total NIHSS scores (as measure recovery). associations with these GWAS conducted within VISP trial mild 1270). MR estimated using inverse-variance weighted method. Results: A 1-standard deviation (SD) increase (~4.8 kg/m 2 ) in genetically predicted associated lower odds improvement (OR 0.37, 95% CI 0.19-0.72; p 0.003). Similarly, was worse (β −0.12, −0.21, −0.03; 0.009) −0.36, −0.59, −0.13; 0.002). Associations between directionally concordant but not statistically significant > 0.05). Discussions conclusions: Human genetic evidence suggests that elevated negatively impacts multiple outcomes, including function, cognition, overall biological pathways underlying warrant further investigation.

Язык: Английский

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A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

Background Gene-environment interactions may enhance our understanding of hypertension. Our previous study highlighted the importance considering psychosocial factors in gene discovery for blood pressure (BP) but was limited statistical power and population diversity. To address these challenges, we conducted a multi-population genome-wide association (GWAS) BP accounting gene-depressive symptomatology (DEPR) larger more diverse sample. Results included 564,680 adults aged 18 years or older from 67 cohorts 4 backgrounds (African (5%), Asian (7%), European (85%), Hispanic (3%)). We discovered seven novel gene-DEPR interaction loci traits. These mapped to genes implicated neurogenesis (TGFA, CASP3), lipid metabolism (ACSL1), neuronal apoptosis (CASP3), synaptic activity (CNTN6, DBI). also identified evidence at nine known loci, further suggesting links between mood disturbance regulation. Of 16 11 were derived African, Asian, populations. Post-GWAS analyses prioritized 36 genes, including involved functions (DOCK4, MAGI2) signaling (CCK, UGDH, SLC01A2). Integrative druggability druggable candidate targets, pathways linked disorders as well products targeted by antihypertensive drugs. Conclusions findings emphasize on BP, particularly non-European targets highlight biological connecting hypertension suggest opportunities drug repurposing risk factor prevention, especially individuals with DEPR.

Язык: Английский

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