Human Genomics最新文献

Background: Inherited retinal diseases (IRDs) are highly diverse and rare genetic disorders causing mild to complete vision loss across different age groups, with a notably higher disease burden in India. Although genetic testing has improved diagnostic accuracy, India's distinct genetic landscape, shaped by diverse racial backgrounds, admixtures, endogamy, and consanguinity, presents unique challenges. Additionally, phenotype overlaps, non-canonical presentations, genetic heterogeneity, and insufficient literature evidence contribute to clinically and genetically unsolved cases. Since genetic variant reporting commonly relies on information from non-Indian population databases, it is important to build comprehensive knowledge from published Indian data for its unbiased representation in relevant clinical resources. This review aims to assess the current state of Indian IRD research and its lacunae, as this understanding is essential to gauge the readiness of research institutions and tertiary centres for maximizing accessibility to genetic testing and potential treatment options.

Methods: We screened 764 PubMed-sourced Indian IRD articles until October 2023 and analysed 21,158 IRD cases from 287 publications reporting clinical and/or genetic data, and further found that 80 publications (n = 628 cases) reported genetic variants (v = 686 variants). Relevant literature was analysed to assess demographic distribution, genetic trends and the research landscape in India.

Results and clinical significance: Our analyses draw a comprehensive sketch of publication-derived demographics and genetic insights into major IRDs reported in India. They emphasize the urgent need for comprehensive and timely clinical and genetic reporting, since Indian IRD research remains fragmented. This calls for integrated nationwide efforts in systematic reporting through an extensive national IRD case registry for improving diagnostic accuracy, enhancing patient recruitment for clinical trials, and expanding access to emerging therapeutics.

While genome-wide association studies (GWAS) have linked common genetic variants to COVID-19 susceptibility and severity, rare high-impact variants may also contribute to phenotypic heterogeneity. Inborn errors of type I interferon immunity (IFN-I-IEIs), including X-linked TLR7 deficiency, account for ~ 2% of critical COVID-19 cases. In this study, we investigated rare potentially deleterious variants in IFN-I-IEI and GWAS-prioritized genes in young, severely affected COVID-19 patients from the German National Pandemic Cohort Network (NAPKON). Genome sequencing was performed on 110 hospitalized COVID-19 patients, including 82 males and 28 females, all under 60 years of age and without relevant pre-existing medical conditions. Rare potentially deleterious variants in TLR7 and 25 additional IFN-I-IEI genes, as well as 23 GWAS risk genes for COVID-19 severity, were analyzed based on allele frequency, predicted functional impact, and inheritance pattern models and subsequently classified based on the American College of Medical Genetics and Genomics (ACMG) criteria. Polygenic Risk Scores (PRS) were additionally calculated as an exploratory and case-only analysis to assess the contribution of common variant-derived genetic predisposition for severe COVID-19. Consistent with prior findings from other studies in German cohorts, no candidate variants or large deletions were identified in TLR7. However, 7 variants of uncertain significance in IFN-I-IEI genes as well as 13 candidate variants of potential deleterious effect in GWAS risk genes were present in 19 individuals (17.3%). We observed nominally significant differences in PRS distributions, with younger individuals (< 40 years) having higher PRS (p = 0.045) compared to older individuals, and carriers of rare variants having lower PRS compared to non-carriers (p = 0.037). These patterns are consistent with an age-dependent contribution of polygenic risk to severe COVID-19 and a potentially lower polygenic burden among rare-variant carriers, although confirmation in larger well-controlled cohorts will be required. The candidate variants identified in IFN-I-IEI and GWAS risk genes represent targets for further functional studies to clarify their potential contribution to disease risk. These findings highlight the need for future integrative genomic approaches to better understand the joint contribution of common and rare variants to COVID-19 severity.

The interaction between the genome and the exposome is increasingly recognized as central to human health and disease. While exposome research has generally focused on adverse exposures such as pollutants and toxins, the concept of the beneficial exposome-positive environmental exposures that promote health-remains underexplored. Among the most promising beneficial exposures are plant-derived phytochemicals, a rich class of bioactive compounds with therapeutic potential. Phytoncides, a specific subset of volatile organic compounds released by plants, exemplify this beneficial potential through their antimicrobial, anti-inflammatory, antioxidant, and neuroprotective effects. Historically utilized in traditional medicine across cultures, plant-based remedies containing these compounds are now being examined through modern genomics, exposomics, and systems biology approaches to understand the specific contributions of phytoncides and other bioactive constituents. Emerging data suggest that phytochemicals modulate gene expression, immune function, and metabolic pathways across multiple organ systems, contributing to immune, neurological, endocrine, cardiovascular, respiratory, integumentary, and mental health improvements. However, the evidence base is predominantly preclinical, with limited human validation, considerable heterogeneity in plant-extract composition, and incompletely characterized molecular mechanisms. This review synthesizes current evidence on genome-exposome interactions (GxE) related to plant-derived compounds, highlighting recent mechanistic insights and exploring translational applications-including forest bathing, green space integration in urban design, and bioengineering approaches-while addressing the challenges of clinical translation. As environmental change accelerates, understanding beneficial GxE offers new opportunities for preventative and precision public health interventions and calls for integrating nature-based solutions into modern healthcare paradigms.

Background: Atherosclerosis (AS) is a chronic vascular disease and the principal cause leading to ischemic cardiomyopathy (ICM). It involves complex metabolic dysregulation beyond the resolution of single-omics. Emerging evidence implicates arginine-proline metabolism (APM) in driving inflammation and impairing efferocytosis, yet the cellular basis of plaque instability remains elusive.

Methods: We employed a five-stage analytical framework. First, metabolomic profiling revealed shared pathways between AS and ICM. Second, single-cell RNA sequencing identified APM-enriched macrophage subtypes in both diseases. Pseudotime analysis, Scissor algorithm, and cell-cell communication analyses linked these subtypes to APM signaling, stroke prognosis, and key ligand-receptor interactions. Third, cNMF and unsupervised clustering defined APM-related gene signatures in macrophages, validated by survival analysis. Fourth, spatial transcriptomics confirmed their spatial distribution and colocalization within unstable plaques. Finally, key biomarkers were validated in atherosclerotic lesions using ApoE^-/- mouse.

Results: Metabolomic profiling revealed APM as a shared dysregulated pathway in AS and ICM. We identified a macrophage subset (SPP1⁺ macrophages and mono-macrophages), termed APM_high macrophages, enriched in the fibrous cap and characterized by elevated collagenase activity, heightened inflammation, and disrupted cholesterol homeostasis. Spatial and cell-cell communication analyses revealed strong interactions with dendritic cells via the MIF-(CD74 + CXCR4) axis, potentially contributing to plaque destabilization. Transcriptomic clustering uncovered a high-APM plaque subtype associated with worse ischemic outcomes. Six diagnostic biomarkers were identified through machine learning and validated across multiple cohorts and in ApoE^-/- mouse.

Conclusion: In summary, our study decodes the metabolic basis of inflammation shared between AS and ICM, suggesting an APM_high macrophage-centered regulatory axis across multiple omics layers. This work advances our understanding of the cardio-metabolic axis and suggests new avenues for targeted therapy.

Background: The Human Exposome Project (HEP) aims to chart lifelong environmental exposures and their biological consequences, furnishing the environmental counterpart to the genomic revolution. Yet the fine‑grained, multimodal data streams that fuel exposomics-biospecimens, geolocation traces, wearable‑sensor feeds, and socio‑environmental metadata-raise privacy, justice, and governance questions that may exceed the reach of conventional bioethics.

Main body: Building on lessons from genomics, biobanking, digital health, and environmental‑justice research, we identify five foundational ethical domains for exposome science: (1) privacy and data sovereignty, (2) informed consent and sustained participant engagement, (3) environmental justice, (4) governance and oversight, and (5) actionability and the responsible return of results,as well as (6)the adherence to research program goals. Similar to the "values in design" construct widely used in the socio-technical field and the "ethics by design" in the artificial intelligence (AI) field, we translate these domains into operational pillars for ethics‑by‑design research practice: dynamic or tiered consent architectures; participatory governance mechanisms such as community advisory boards; embedded ethics research programs; algorithmic‑fairness protocols for artificial‑intelligence analytics; and dedicated review bodies equipped to evaluate longitudinal, sensor‑based, multi‑omics studies. Concrete recommendations include federated data stewardship to minimize re‑identification risk, Evidence‑to‑Decision frameworks that couple exposomic evidence with societal values, and transparent pathways for communicating context‑dependent findings to individuals, communities, and policymakers.

Conclusions: Ethical preparedness and action are a prerequisite for the scientific impact and social license of exposome research. Institutionalizing the proposed roadmap-via an international Exposome Ethics Consortium, expanded training for Institutional Review Boards, harmonized regulatory guidance, and sustained community co‑governance-will help protect privacy, promote equity, and foster public trust. Embedding systematic ethical reflection as core infrastructure will enable the Human Exposome Project to realize its promise of precision public health without replicating patterns of opaque surveillance, marginalization, or data commodification. The Human Exposome Project (HEP) represents an ambitious endeavor to characterize lifelong environmental exposures in relation to health. Yet, this vision brings profound ethical challenges: from managing massive, sensitive datasets to ensuring justice for disproportionately exposed communities. This article synthesizes foundational work on exposome ethics, outlines core ethical challenges, and proposes a proactive ethical governance model that ensures scientific integrity and social legitimacy.

Changes in gene function or expression caused by epigenetic modifications may play a role in painful diabetic neuropathy. Two independent cohorts of patients deeply phenotyped for painful diabetic neuropathy underwent whole genome DNA methylation data analysis. Burden of rare site events at the global, chromosomal and gene level; epigenetic homogeneity for regions enriched in epivariants (epilesions) and functional analysis of the genes with stochastic phenomena was undertaken. This revealed significant involvement of the SLIT/ROBO signaling axis-engaged in peripheral nerve regeneration after injury, among several molecular pathways, making it an attractive therapeutic target in patients with diabetic painful neuropathy.