DNA methylation as a possible causal mechanism linking childhood adversity and health: Results from two-sample mendelian randomization study DOI
Isabel K. Schuurmans, Erin C. Dunn, Alexandre A. Lussier

et al.

American Journal of Epidemiology, Journal Year: 2024, Volume and Issue: 193(11), P. 1541 - 1552

Published: May 17, 2024

Abstract Childhood adversity is an important risk factor for adverse health across the life course. Epigenetic modifications, such as DNA methylation (DNAm), are a hypothesized mechanism linking to disease susceptibility. Yet, few studies have determined whether adversity-related DNAm alterations causally related future outcomes or if their developmental timing plays role in these relationships. Here, we used 2-sample mendelian randomization obtain stronger causal inferences about association between adversity-associated loci development (ie, birth, childhood, adolescence, and young adulthood) 24 mental, physical, behavioral outcomes. We identified particularly strong associations attention-deficit/hyperactivity disorder, depression, obsessive-compulsive suicide attempts, asthma, coronary artery disease, chronic kidney disease. More of were birth childhood DNAm, whereas adolescent adulthood more closely linked mental health. also had primarily risk-suppressing relationships with outcomes, suggesting that might reflect compensatory buffering mechanisms against rather than acting solely indicator risk. Together, our results suggest both physical impacts differences emerging earlier development.

Language: Английский

Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease DOI
Wei Zhou, Masahiro Kanai, Kuan-Han Wu

et al.

Cell Genomics, Journal Year: 2022, Volume and Issue: 2(10), P. 100192 - 100192

Published: Oct. 1, 2022

Language: Английский

Citations

239
Genotyping and population characteristics of the China Kadoorie Biobank DOI Creative Commons
Robin Walters, Iona Y. Millwood, Kuang Lin

et al.

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(8), P. 100361 - 100361

Published: July 20, 2023

The China Kadoorie Biobank (CKB) is a population-based prospective cohort of >512,000 adults recruited from 2004 to 2008 10 geographically diverse regions across China. Detailed data questionnaires and physical measurements were collected at baseline, with additional three resurveys involving ∼5% surviving participants. Analyses genome-wide genotyping, for >100,000 participants using custom-designed Axiom arrays, reveal extensive relatedness, recent consanguinity, signatures reflecting large-scale population movements Chinese history. Systematic association studies incident disease, captured through electronic linkage death disease registries the national health insurance system, replicate established loci identify 14 novel associations. Together candidate drug targets risk factors contributions international genetics consortia, these demonstrate breadth, depth, quality CKB data. Ongoing high-throughput omics assays biosamples planned whole-genome sequencing will further enhance scientific value this biobank.

Language: Английский

Citations

75
Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts DOI Creative Commons
Ying Wang, Shinichi Namba, Esteban A. Lopera-Maya

et al.

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(1), P. 100241 - 100241

Published: Jan. 1, 2023

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies thoroughly investigated their best practices global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance 9 biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning thresholding (P + T) PRS-continuous shrinkage (CS). For both methods, a European-based linkage disequilibrium (LD) reference panel resulted comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P T method, especially endpoints SNP-based heritability. Notably, is heterogeneous endpoints, biobanks, ancestries, asthma, which has known variation prevalence populations. Overall, provide lessons construction, evaluation, interpretation GBMI resources highlight importance of biobank-scale genomics era.

Language: Английский

Citations

73
Genomic findings in schizophrenia and their implications DOI Creative Commons
Michael J. Owen, Sophie E. Legge, Elliott Rees

et al.

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(9), P. 3638 - 3647

Published: Sept. 1, 2023

Abstract There has been substantial progress in understanding the genetics of schizophrenia over past 15 years. This revealed a highly polygenic condition with majority currently explained heritability coming from common alleles small effect but additional contributions rare copy number and coding variants. Many specific genes loci have implicated that provide firm basis upon which mechanistic research can proceed. These point to disturbances neuronal, particularly synaptic, functions are not confined brain regions circuits. Genetic findings also nature schizophrenia’s close relationship other conditions, bipolar disorder childhood neurodevelopmental disorders, provided an explanation for how risk persist population face reduced fecundity. Current genomic approaches only potentially explain around 40% heritability, proportion this is attributable robustly identified loci. The extreme polygenicity poses challenges biological mechanisms. high degree pleiotropy points need more transdiagnostic shortcomings current diagnostic criteria as means delineating biologically distinct strata. It inferring causality observational experimental studies both humans model systems. Finally, Eurocentric bias needs be rectified maximise benefits ensure these felt across diverse communities. Further advances likely come through application new emerging technologies, such whole-genome long-read sequencing, large samples. Substantive will require parallel functional genomics proteomics applied developmental stages. For efforts succeed identifying disease mechanisms defining novel strata they combined sufficiently granular phenotypic data.

Language: Английский

Citations

61
Decoding the genetic and epigenetic basis of asthma DOI Creative Commons
Bernard Stikker, Rudi W. Hendriks, Ralph Stadhouders

et al.

Allergy, Journal Year: 2023, Volume and Issue: 78(4), P. 940 - 956

Published: Feb. 2, 2023

Abstract Asthma is a complex and heterogeneous chronic inflammatory disease of the airways. Alongside environmental factors, asthma susceptibility strongly influenced by genetics. Given its high prevalence our incomplete understanding mechanisms underlying susceptibility, frequently studied in genome‐wide association studies (GWAS), which have identified thousands genetic variants associated with development. Virtually all these reside non‐coding genomic regions, has obscured functional impact asthma‐associated their translation into disease‐relevant mechanisms. Recent advances genomics technology epigenetics now offer methods to link gene regulatory elements embedded within started unravel molecular (epi)genetics asthma. Here, we provide an integrated overview (epi)genetic asthma, focusing on efforts associations biological insight pathophysiology using state‐of‐the‐art methodology. Finally, perspective as how decoding epigenetic basis potential transform clinical management predict risk

Language: Английский

Citations

47
Effect of air pollution on asthma DOI Creative Commons
Xiaoying Zhou, Vanitha Sampath, Kari C. Nadeau

et al.

Annals of Allergy Asthma & Immunology, Journal Year: 2024, Volume and Issue: 132(4), P. 426 - 432

Published: Jan. 21, 2024

Language: Английский

Citations

26
Gene–environment interactions in human health DOI

Esther Herrera-Luis,

Kelly S. Benke, Heather E. Volk

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(11), P. 768 - 784

Published: May 28, 2024

Language: Английский

Citations

21
Multi-omics approaches for understanding gene-environment interactions in noncommunicable diseases: techniques, translation, and equity issues DOI Creative Commons

Robel Alemu,

Nigussie Tadesse Sharew,

Yodit Y. Arsano

et al.

Human Genomics, Journal Year: 2025, Volume and Issue: 19(1)

Published: Jan. 31, 2025

Non-communicable diseases (NCDs) such as cardiovascular diseases, chronic respiratory cancers, diabetes, and mental health disorders pose a significant global challenge, accounting for the majority of fatalities disability-adjusted life years worldwide. These arise from complex interactions between genetic, behavioral, environmental factors, necessitating thorough understanding these dynamics to identify effective diagnostic strategies interventions. Although recent advances in multi-omics technologies have greatly enhanced our ability explore interactions, several challenges remain. include inherent complexity heterogeneity multi-omic datasets, limitations analytical approaches, severe underrepresentation non-European genetic ancestries most omics which restricts generalizability findings exacerbates disparities. This scoping review evaluates landscape data related NCDs 2000 2024, focusing on advancements integration, translational applications, equity considerations. We highlight need standardized protocols, harmonized data-sharing policies, advanced approaches artificial intelligence/machine learning integrate study gene-environment interactions. also opportunities translating insights (GxE) research into precision medicine strategies. underscore potential advancing enhancing patient outcomes across diverse underserved populations, emphasizing fairness-centered strategic investments build local capacities underrepresented populations regions.

Language: Английский

Citations

2
Chronic Inflammation in Asthma: Looking Beyond the Th2 Cell DOI Creative Commons

Simone E. M. Olsthoorn,

Anneloes van Krimpen, Rudi W. Hendriks

et al.

Immunological Reviews, Journal Year: 2025, Volume and Issue: 330(1)

Published: Feb. 27, 2025

ABSTRACT Asthma is a common chronic inflammatory disease of the airways. A substantial number patients present with severe and therapy‐resistant asthma, for which underlying biological mechanisms remain poorly understood. In most asthma patients, airway inflammation characterized by activation type 2 immunity. CD4 + T helper (Th2) cells are canonical producers cytokines that fuel inflammation: interleukin (IL)‐4, IL‐5, IL‐9, IL‐13. However, more recent findings have shown other lymphocyte subsets, in particular group innate lymphoid (ILC2s) CD8 cytotoxic (Tc2) cells, can also produce large amounts cytokines. Importantly, inflammation, despite high sensitivity Th2 suppression corticosteroids—the mainstay drugs asthma. Emerging evidence indicates ILC2s Tc2 abundant adopt corticosteroid‐resistance states. Moreover, many do not overt implicating non‐type immunity as driver disease. this review, we will discuss pathophysiology focus on roles played ILC2s, lymphocytes, placing special emphasis forms.

Language: Английский

Citations

2
Meta-analysis fine-mapping is often miscalibrated at single-variant resolution DOI
Masahiro Kanai, Roy Elzur, Wei Zhou

et al.

Cell Genomics, Journal Year: 2022, Volume and Issue: 2(12), P. 100210 - 100210

Published: Nov. 4, 2022

Language: Английский

Citations

58