Mammalian Genome最新文献

{"title":"Exploring the genetic footprints of high altitude adapted humans and livestock.","authors":"Manish Tiwari, Gayatri Gujar, Siriluck Ponsuksili, C G Shashank, Shweta Sharma, Monika Sodhi, Manishi Mukesh","doi":"10.1007/s00335-025-10161-9","DOIUrl":"https://doi.org/10.1007/s00335-025-10161-9","url":null,"abstract":"<p><p>High-altitude environments such as the Himalayas, Andes, and Ethiopian regions pose extreme environmental challenges like hypobaric hypoxia, cold stress, and extreme UV radiation. This prompts both short-term physiological and long-term genetic adaptations in resident human and livestock populations. Various genetic studies suggest that candidate genes, such as HIF1A, EPAS1, EGLN1, MITF, ITPR2, VEGFA etc. are involved in hypoxia response, erythropoiesis, angiogenesis and metabolic regulation that results in high altitude adaptation. Phylogenetic comparisons of HIF family genes, suggest evolutionary divergence between humans and livestock, however, closer relationships exist among the ruminants suggesting shared adaptive pressures. The present study revealed that despite of the different evolutionary history, both humans and livestock across the different geographical regions show similar type of traits, driven by certain genes (either the same genes or different genes working in similar ways). These genes have been naturally selected over the time and helped the humans and livestock to survive at extreme environments. Furthermore, enrichment analysis suggests convergent evolution at the gene and pathway levels, supporting the genetic adaption in humans and livestock across the different geographical regions. This review will serve as a valuable information source for researchers working in the fields of high-altitude environments, evolutionary biology and environmental genomics.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired immune metabolism in COPD driven by dysfunction of CXCL16 + alveolar macrophages: multivariate causal evidence.","authors":"Xianqiang Zhou, Yixin Zhang, Jie Yang, Zhengjie Jin, Zhancheng Gao, Cuiling Feng","doi":"10.1007/s00335-025-10163-7","DOIUrl":"https://doi.org/10.1007/s00335-025-10163-7","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a leading global cause of mortality, with alveolar macrophages (AMs) dysfunction implicated in pathogenesis, though key molecular drivers remain unclear. This study integrated multi-omics approaches to identify causal AMs-derived factors in COPD. Single-cell RNA sequencing (scRNA-seq) of human lung tissues revealed a significantly increased proportion of macrophages, particularly enriched AMs clusters (0, 1, 5), in COPD patients versus controls. Two-sample Mendelian randomization (MR) analysis of 1,283 AMs-specific genes identified CXCL16 as having a robust negative causal relationship with COPD risk across European (IVW OR = 0.944, P = 0.039) and East Asian (Weighted median OR = 0.858, P = 0.008) populations. Bulk RNA-seq confirmed decreased CXCL16 expression in COPD lungs. Cell-cell chat analysis indicated that CXCL16 + AMs mediated critical immune interactions via pathways like MIF-CD74/CD44. Critically, CXCL16 deficiency in AMs drives COPD progression by disrupting immune-metabolic homeostasis. These findings establish CXCL16 downregulation in AMs as a novel causal mechanism in COPD and highlight its potential as a therapeutic target for restoring macrophage function and halting disease advancement.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring genome, transcriptome, and microbiome interactions related to feed efficiency and methane emissions in Bos indicus through multi-omics network analysis.","authors":"Tainã Figueiredo Cardoso, Jennifer Jessica Bruscadin, Juliana Afonso, Liliane Costa Conteville, Bruno Gabriel Nascimento Andrade, Jessica Moraes Malheiros, Anna Carolina Fernandes, Wellison J S Diniz, Priyanka Banerjee, Priscila S N de Oliveira, Adhemar Zerlotini, Gerson Barreto Mourão, Luiz Lehmann Coutinho, Luciana Correia de Almeida Regitano","doi":"10.1007/s00335-025-10160-w","DOIUrl":"https://doi.org/10.1007/s00335-025-10160-w","url":null,"abstract":"<p><p>The minor effects of many SNP interactions often determine complex traits. This interaction, known as epistasis, represents a non-additive genetic effect in which the influence of one variant depends on the presence of others. In this study, we tested for epistatic effects on the residual feed intake (RFI) and residual methane emission (RME) traits of Nelore cattle. Additionally, we evaluated the impact of these interactions in other omics layers (i.e., microorganism profiles in the rumen content and feces and mRNA and miRNA expression in the rumen wall). The genomic interaction modules identified 14 and 10 significant SNP-SNP modules associated with RME and RFI traits, respectively. The majority of these SNPs were located in intronic and intergenic regions. The top pathways and processes associated with the SNP-SNP modules were identified, with several pathways related to the immune system and actin cytoskeleton organization. Furthermore, many other omics data were correlated with these SNP-SNP modules. Our findings suggest that the immune response and cilium organization may play important roles in feed efficiency. These insights not only provide novel candidates for enhancing these traits through microbiota composition and transcriptional regulation but also underscore the power of network analysis in uncovering new functional interactions. This research provides new insights and highlights candidate features for improving cattle feed efficiency and methane emissions.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of plasma genetic markers mediating lung cancer-induced cardiovascular disorders based on genome wide association studies.","authors":"Tongyu Wang, Xinge Miao, Yin Wang, Sadees Clarance Chandran, Yunlong Xia","doi":"10.1007/s00335-025-10158-4","DOIUrl":"https://doi.org/10.1007/s00335-025-10158-4","url":null,"abstract":"<p><p>Lung cancer is strongly associated with increased cardiovascular disease (CVD) risk, yet the molecular mechanisms remain poorly understood. Batched two-sample Mendelian randomization (MR) analysis was performed to investigate cancer types and CVDs with significant associations. Local genetic correlation analyses were performed to identify meaningful genetic regions. Genomic Structural Equation Modeling (gSEM) was applied to identify latent factors shared between selected cancer types and CVDs. A transcriptome-wide association study (TWAS) was performed to identify relevant genetic markers. A two-stage MR analysis was performed to investigate potential mediators. Colocalization analysis was performed to assess the sensitivity of the results. Seventeen cancer types were positively associated with CVD risk, with lung cancer exhibiting the strongest link. Using LAVA and ρ-HESS, we identified local genetic correlations between lung cancer and specific CVDs, including coronary artery disease (CAD), heart failure (HF), abdominal aortic aneurysm (AAA), and atrial fibrillation (AF). Weighted median MR analysis identified a negative effect for IREB2 (OR = 0.9; 95% CI 0.84-0.95; P < 0.05), and positive effects for both KRTCAP2 (OR = 1.1; 95% CI 1.02-1.21; P < 0.05) and MTX1P1 (OR = 1.1; 95% CI 1.02-1.21; P < 0.05), on lung cancer-induced AAA. ZBTB7B exhibited a positive mediating effect in the association between lung cancer and HF risk (OR = 1.04; 95% CI 1.01-1.07; P < 0.05). This study highlights IREB2, KRTCAP2, MTX1P1, and ZBTB7B as potential therapeutic targets for cancer-related CVD risk, emphasizing the importance of considering genetic factors in understanding and managing cardiovascular complications associated with lung cancer.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and functional analysis of Rattus norvegicus Mammary carcinoma susceptibility 1b (Mcs1b) nominated variants.","authors":"Jennifer Sanders, Theodore S Kalbfleisch, Sasha Le, Xin Xu, Timothy D Cummins, David W Powell, David J Samuelson","doi":"10.1007/s00335-025-10157-5","DOIUrl":"https://doi.org/10.1007/s00335-025-10157-5","url":null,"abstract":"<p><p>Rattus norvegicus (a.k.a. laboratory rat or Brown Rat) Mammary carcinoma susceptibility 1b (Mcs1b) is a concordant ortholog of a female breast cancer risk allele at human 5q11.2. Previously, Mcs1b was delimited to a 1.8 Mb interval of RNO2 and Map3k1 along with Mier3 were determined to be Mcs1b-nonminated genes. This conclusion was based on shared synteny with human 5q11.2 and differential gene expression between cancer susceptible and Mcs1b resistant mammary glands. In this study, targeted genome sequencing of cancer susceptible and Mcs1b resistance associated alleles was used to identify three Mcs1b-nominated quantitative trait nucleotides (QTNs) in noncoding DNA. In vitro approaches, luciferase activity and electromobility shift assays, were used to suggest these variants reside in potential gene regulatory elements. One of these variants, UL-A74-SNV-17, resulted in luciferase activities that were 2.6× higher for the susceptibility associated variant compared to the resistance associated variant. These results recapitulated Mcs1b nominated gene transcript level differences between Mcs1b genotypes in mammary epithelial cells (MECs), where Map3k1 and Mier3 were 1.5- to 2.0-fold higher for the susceptible genotype compared to the Mcs1b resistance-associated genotype. Evidence of a chromatin loop in Mcs1b that may position Mcs1b QTNs near distal genes was uncovered using chromosome confirmation capture (3C). Rat Mcs1b was also functionally characterized by determining that Mcs1b genotype had effects on the amount of luminal MECs in adult mammary glands. In conclusion, UL-A74-SNV-17 is a priority candidate Mcs1b QTN with a hypothesized mechanistic role in the differential regulation of Mcs1b nominated genes, Mier3 and Map3k1.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide association analysis highlights genomic regions and genes potentially associated with anestrus in crossbred gilts.","authors":"Monike Willemin Quirino, Cleverson Hebbel, Adriana Mércia Guaratini Ibelli, Mônica Corrêa Ledur, Maurício Egídio Cantão, Jane de Oliveira Peixoto, Marcos Antonio Zanella Mores, Pricila Baldessar, Rafael Keith Ono, Mariana Groke Marques, Vanessa Peripolli, Rafael da Rosa Ulguim, Bernardo Garziera Gasperin, Ivan Bianchi","doi":"10.1007/s00335-025-10159-3","DOIUrl":"https://doi.org/10.1007/s00335-025-10159-3","url":null,"abstract":"<p><p>Anestrus, an infertility condition that affects several animal' species, is characterized by failing to display estrus. In pig production, it leads to the culling of 5 to 15% of the replacement gilts, resulting in significant losses impairing the swine female longevity. Despite that, little is known about the genetic mechanisms involved with anestrus in pigs. Hence, this study evaluated cyclic and non-cyclic F1 Landrace × Large White gilts to identify genomic regions associated with failure to display pubertal estrus through a genome-wide association study (GWAS), highlighting possible candidate genes involved with this condition in swine. Tissue samples were collected at 219.8 ± 4.7 days of age and genotyped with the PorcineSNP50 BeadChip from Illumina. In the GWAS, a SNP in the EML4 gene located on chromosome 3 (SSC3) was moderately associated with anestrus. The other 14 SNPs suggestively associated with anestrus were identified on SSCs 1, 3, 6, 7, 9 and 15. Investigating the regions close to those SNPs, new candidate genes for anestrus occurrence, such as EML4, DST, SRTB, MEAF, PHF1, PPMIB and PREPL, including 11 lncRNAs and a snoRNA were identified. Therefore, our study highlighted novel genetic mechanisms involved with the failure to display pubertal estrus in pigs, contributing to unraveling the genetic architecture of anestrus in pigs and other species. The use of genomic methodologies is a promising tool to help the early identification of gilts with potential reproductive problems associated with anestrus.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harmonizing mouse anatomy terminology: a common language?","authors":"Jesús Ruberte, Paul N Schofield, John P Sundberg, Sergi Olvera-Maneu, Ana Carretero","doi":"10.1007/s00335-025-10156-6","DOIUrl":"https://doi.org/10.1007/s00335-025-10156-6","url":null,"abstract":"<p><p>The mouse remains the principal animal model for investigating human diseases due, among other reasons, to its anatomical similarities to humans. Despite its widespread use, the assumption that mouse anatomy is a fully established field with standardized and universally accepted terminology is misleading. Many phenotypic anatomical annotations do not refer to the authority or origin of the terminology used, while others inappropriately adopt outdated or human-centric nomenclature. This inconsistency is further exacerbated by the limited availability of comprehensive anatomical references, often compelling researchers to rely on \"do-it-yourself\" anatomical interpretations when characterizing disease models-an approach that increases the risk of inaccuracies in the absence of expert anatomical guidance. To address this critical gap, we propose the formation of expert working groups comprising comparative anatomists and disease model developers. These groups would be responsible for systematically reviewing the anatomical literature of each mouse organ system and producing consensus-based terminologies aligned with the Nomina Anatomica Veterinaria (NAV), the authoritative standard for quadrupedal species. Such harmonization efforts would not only improve the consistency and reliability of anatomical descriptions in mouse models but also enhance the integration and interoperability of anatomical data across biomedical ontologies and databases, facilitating more robust data mining and translational research.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kangayam and Tharparkar cattle exhibit higher duplications in innate immune genes compared to Sahiwal, Gir, Karan Fries, and Holstein Friesian: insights from an array comparative genomic hybridization.","authors":"Mayank Roshan, Ashutosh Vats, Kamlesh Kumari Bajwa, Sanjay Sharma, Menaka Thambiraja, Monika Sodhi, Dheer Singh, Ragothaman M Yennamalli, Suneel Kumar Onteru","doi":"10.1007/s00335-025-10136-w","DOIUrl":"10.1007/s00335-025-10136-w","url":null,"abstract":"<p><p>Innate immunity, the primary defence mechanism, encompasses a range of protective processes like anatomical barriers, cytokine secretion, and the action of various immune cells. Cattle breeds might differ in these processes because of their genetic differences such as copy number variations (CNVs). Therefore, the present investigation employed an array comparative genomic hybridisation (aCGH) approach on breed representative pooled DNA samples to evaluate CNVs across six cattle breeds: four indigenous Indian breeds, Kangayam (KNG), Tharparkar (TP), Sahiwal (SW), Gir (GIR), one crossbred Karan Fries (KF), and one exotic breed, Holstein Friesian (HF). In aCGH, HF DNA was used as control, while test DNA was from the other breeds. Each pooled test DNA sample was a representative of 18 animals belonging to three distinct geographical locations of India. The study using Aberration Detection Method 2 (ADM-2) of Agilent Genomic Workbench revealed the highest number of duplications in KNG (1189 genes), followed by TP (534 genes), and the greatest number of deletions in SW (774 genes). Among these genes, 183 and 76 innate immune genes with hub genes TGF-β1, CD79A, and IL4 showed duplications in KNG and TP, respectively. In SW, 113 innate immune genes with hub genes PSMC5, MAPK1, and AXIN1 showed deletions. In contrast, KF and HF showed no genes with deletions and fewer duplicated innate immunity genes, reflecting either lower genetic variability in their immune gene repertoire or a potential bias due to HF DNA as a control in aCGH. Functional enrichment of innate immune genes revealed duplications in KNG enriched in interleukin-1 receptor (IL1R) activity (p = 9.9 × 10^-3) and nucleobase metabolism (p = 2.88 × 10⁻¹¹), while duplications in TP were linked to DNA-binding transcription factor activity (p = 2.34 × 10⁻¹⁴). The KEGG pathway analysis highlighted Th17 cell differentiation (p = 1.3 × 10⁻⁴) in KNG and Hippo signalling (p = 3.7 × 10^-2) in TP. Overall, these findings highlight the importance of genetic diversity in shaping innate immunity in indigenous Indian cattle breeds, favouring a balanced crossbreeding to sustain the Indian dairy sector.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"812-826"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic advancements in goat breeding: enhancing productivity, disease resistance, and sustainability in India's rural economy.","authors":"Manjit Panigrahi, Sonali Sonejita Nayak, Divya Rajawat, Anal Bose, Nishu Bharia, Shivani Das, Anurodh Sharma, Triveni Dutt","doi":"10.1007/s00335-025-10138-8","DOIUrl":"10.1007/s00335-025-10138-8","url":null,"abstract":"<p><p>Goats are vital to the rural economy of India, contributing significantly to livelihoods, nutrition, and agricultural sustainability. With a population of 148.88 million, India holds the world's largest goat population, comprising 41 recognized indigenous breeds. These goats provide milk, meat, and fiber, particularly in marginal environments. The genomic advancements in goat research have revolutionized the understanding of genetic diversity, adaptation, and trait improvement. Whole-genome sequencing (WGS), single nucleotide polymorphism (SNP) arrays and transcriptomics have unveiled genetic markers associated with production, disease resistance, and reproductive traits. Genomic tools such as the Illumina Goat SNP50K BeadChip and high-throughput sequencing technologies have facilitated the identification of selection signatures and quantitative trait loci (QTL), influencing economically important traits like milk yield, meat quality, and prolificacy. Notably, genes such as DGAT1, GHR, BMPR1B, and HSP70 have been linked to production efficiency, reproductive performance, and climate resilience. Genome-wide association studies (GWAS) and genomic selection (GS) have enabled precision breeding, enhancing genetic gains and reducing inbreeding risks. The application of RNA sequencing has provided insights into gene expression patterns governing lactation, growth, and reproductive efficiency. Epigenomic studies, focusing on DNA methylation and histone modifications, have highlighted regulatory mechanisms underpinning prolificacy and muscle development. Conservation genomics has played a pivotal role in safeguarding native breeds by assessing genetic diversity and mitigating inbreeding depression. Indicine goat breeds, such as Jamunapari, Beetal, Barbari, and Black Bengal, exhibit unique genetic adaptations to diverse agro-climatic conditions, emphasizing the need for their conservation. Emerging technologies, including CRISPR-Cas9 gene editing, hold promise for precision breeding to enhance productivity and disease resistance. Integrating genomics with artificial intelligence (AI) and big data analytics is poised to revolutionize goat breeding and management. Future efforts should focus on expanding genomic databases, developing breed-specific reference genomes, and promoting genomic literacy among farmers to ensure sustainable goat production and improve rural livelihoods in India.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"761-786"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of genetic biomarkers of blood cholesterol levels using whole gene pathogenicity modelling.","authors":"Sharon Sunny, Guo Cheng, Joshua Haria, Iman Nazari, Jagmohan Chauhan, Sarah Ennis","doi":"10.1007/s00335-025-10140-0","DOIUrl":"10.1007/s00335-025-10140-0","url":null,"abstract":"<p><p>Elevated cholesterol increases risk of diseases such as heart disease, chronic kidney disease and diabetes and early detection and diagnosis is desirable to enable preventative intervention. This study seeks to elucidate genetic factors affecting low-density lipoprotein cholesterol (LDL-C) levels in blood, enabling development of personalised strategies for lipid management and cardiovascular disease prevention. GenePy, a gene pathogenicity scoring tool, condenses genetic variant data into a single burden score for both individuals and genes. GenePy scores were evaluated across all genes to assess their association with blood cholesterol levels, excluding participants on cholesterol-lowering medications. Nonparametric tests analysed the relationship between GenePy scores and cholesterol levels in those aged < 60 years and ≥ 60 years. GenePy was effective in identifying PCSK9, APOE, and LDLR as the genes most critically influencing plasma cholesterol at a population level. Of note, the strongest genetic effect observed was a protective loss of function effect in the PCSK9 gene. Novel significant signals driving blood LDL-C levels that are common to both age groups include: BPIFB6 that has a role in lipid binding and transport; FAIM that has a role in regulation of lipogenesis, SLAMF9 previously implicated in macrophage cholesterol loading; CLU-a component of HDL; SAA1 with a known role in cholesterol homeostasis. A gene-based analysis integrating common, rare, and private variations identifies genes influencing blood LDL-C levels. Developing effective polygenic risk scores requires a comprehensive understanding of genetic factors affecting cholesterol to improve prediction and personalise treatment plans.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"914-927"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}