Annals of Human Genetics最新文献

{"title":"Identification of PSMA4 as a Therapeutic Target for Atherosclerosis: A Comprehensive Multiomics Mendelian Randomization Analysis","authors":"Yongchao Yu,&nbsp;Yuan Zhu,&nbsp;Qian Tian,&nbsp;Lijuan Shao,&nbsp;Jiao Zeng,&nbsp;Dandan Xu,&nbsp;Xiangang Mo","doi":"10.1111/ahg.70039","DOIUrl":"10.1111/ahg.70039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>Atherosclerosis (AS) is a leading cause of cardiovascular disease, and current treatments often fail to induce plaque regression. This study aims to identify novel, genetically supported therapeutic targets for AS to enable more effective drug development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed an integrative multiomics framework, primarily using summary-data-based Mendelian randomization (SMR) to assess causal relationships between druggable genes and AS. We combined GWAS data for AS with blood cis-expression quantitative trait loci (cis-eQTL) data from three independent cohorts. Promising candidates were rigorously validated using external AS datasets, cross-tissue cis-eQTLs, two-sample MR, colocalization, and linkage disequilibrium score regression (LDSC). Further multiomics validation incorporated cis-methylation QTL (cis-mQTL) and cis-splicing QTL (cis-sQTL) data. We evaluated target safety via phenome-wide association study (PheWAS) and characterized cellular expression in atherosclerotic plaques using single-cell RNA sequencing (scRNA-seq). Finally, we predicted candidate therapeutics using the DGIdb database.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>SMR screening nominated PSMA4 as a top candidate, a finding consistently replicated across external cohorts and tissues. Two-sample MR confirmed a causal effect of PSMA4 on AS risk, which was supported by strong colocalization evidence (PP.H4 = 0.941). Multiomics analyses revealed that a specific methylation site and a splicing site of PSMA4 influence AS risk by regulating its expression. LDSC indicated a significant shared genetic basis. PheWAS suggested a favorable safety profile, and scRNA-seq pinpointed high PSMA4 expression in plaque immune cells like macrophages and dendritic cells. Drug prediction identified several proteasome inhibitors, including carfilzomib and bortezomib, as potential therapeutics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study establishes PSMA4 as a promising therapeutic target for AS, with robust genetic causality and a potential path for drug repurposing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 4","pages":"228-239"},"PeriodicalIF":1.2,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147760354","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":"Hip Bone Marrow Adiposity as a Risk Factor for Alzheimer's Disease: Insights From Mendelian Randomization Analysis","authors":"Wei Shi,&nbsp;Zhenhua Zhu,&nbsp;Minghui Wu,&nbsp;Wenjun Cheng,&nbsp;Haijun Xu","doi":"10.1111/ahg.70041","DOIUrl":"10.1111/ahg.70041","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The bone–brain axis has emerged as a critical framework linking skeletal metabolism to neurodegeneration. Within this axis, bone marrow adipose tissue (BMAT) represents a unique fat depot with distinct endocrine and hematopoietic functions, yet its contribution to Alzheimer's disease (AD) remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics to assess the causal effects of six fat depots—abdominal subcutaneous, visceral, spinal, femoral head, total hip, and femoral diaphysis fat—on AD risk. Mediation analysis was further performed to evaluate whether femoral neck bone mineral density (BMD) mediates these associations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among the six depots, only total hip BMAT showed a significant causal association with AD risk (OR = 1.28, 95% CI: 1.09–1.51, <i>p</i> = 0.003). Total hip BMAT was inversely related to femoral neck BMD (<i>β</i> = –0.43, 95% CI: –0.61 to –0.24, <i>p</i> &lt; 0.001), whereas no causal relationship was detected between BMD and AD (OR = 1.01, 95% CI: 0.89–1.15, <i>p</i> = 0.849), excluding bone loss as a mediator.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study provides the first genetic evidence that excessive hip BMAT increases the risk of AD, supporting the bone–brain axis hypothesis. These findings highlight BMAT as a novel target for understanding and potentially preventing AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 4","pages":"249-255"},"PeriodicalIF":1.2,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969974","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":"Epigenetic Shifts in MTNR1A, MTNR1B and Fn14 and Their Links to Preeclampsia Risk","authors":"Sana Kashif Shahid,&nbsp;Syeda Sadia Fatima,&nbsp;Sabah Farhat,&nbsp;Shah Jabeen Khan,&nbsp;Mehir un Nisa Iqbal","doi":"10.1111/ahg.70042","DOIUrl":"10.1111/ahg.70042","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Preeclampsia (PE) is a complex pregnancy disorder associated with early placental hypoxia, oxidative stress, and impaired angiogenic signaling. Melatonin and soluble tumor necrosis factor like weak inducer of apoptosis (sTWEAK) contribute to antioxidant and vascular pathways, whereas their receptors, melatonin receptor 1A (<i>MTNR1A</i>), melatonin receptor 1B (<i>MTNR1B</i>), and fibroblast growth factor-inducible 14 (<i>Fn14)</i>, may be subject to epigenetic regulation. This study assessed serum melatonin and sTWEAK levels in parallel with promoter methylation of <i>MTNR1A</i>, <i>MTNR1B</i>, and <i>Fn14</i> in early gestation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A mixed design cohort was recruited between 13 and 20 weeks of gestation. A total of 198 pregnant women were categorized as pregnant control, high risk, or preeclamptic at enrollment time. Serum melatonin and sTWEAK were measured by enzyme-linked immunosorbent assay (ELISA). Promoter methylation of <i>MTNR1A</i>, <i>MTNR1B</i>, and <i>Fn14</i> was assessed using methylation-specific PCR with semi quantitative densitometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Serum sTWEAK levels were significantly lower in high-risk and preeclamptic women, whereas melatonin levels showed a downward trend without reaching statistical significance. Promoter methylation of <i>MTNR1A</i> and <i>Fn14</i> was elevated in both high-risk and preeclamptic groups, whereas <i>MTNR1B</i> showed no notable differences. Multivariate analysis revealed that lower sTWEAK (OR 0.837; 95% confidence interval [CI] 0.782–0.896; <i>p</i> &lt; 0.001) and higher <i>Fn14</i> methylation (OR 0.935; 95% CI 0.882–0.992; <i>p</i> = 0.027) were independently associated with hypertensive outcomes.  Additionally, higher <i>Fn14</i> methylation in early pregnancy was observed in high-risk women who later developed hypertensive disorders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Early pregnancy hypermethylation of <i>MTNR1A</i> and <i>Fn14, but not MTNR1B</i>, was observed in high-risk and PE women and co-occurred with a significantly reduced sTWEAK level and non-significantly reduced serum melatonin, suggesting epigenetic modulation of antioxidant and angiogenic pathways in women at risk for PE. These findings establish associations rather than causation and require validation using quantitative assays in multicenter cohorts before clinical translation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 4","pages":"256-265"},"PeriodicalIF":1.2,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197129","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":"A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency","authors":"Mohsine-Ali El-Hamri,&nbsp;Zineb Sabky,&nbsp;Nada Benyahya,&nbsp;Oualid Abboussi,&nbsp;Jaber Lyahyai,&nbsp;Abdelaziz Seffiani","doi":"10.1111/ahg.70040","DOIUrl":"10.1111/ahg.70040","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Inborn errors of immunity (IEI) refer to a heterogeneous group of monogenic disorders caused by germline variants that disrupt immune function. Among these conditions, immunodeficiency 92 (IMD92), an extremely rare autosomal recessive disorder due to c Rel deficiency that results from pathogenic variants of the REL gene. c Rel is a key actor of the NF-κB pathway with major implications in the immune response. Up untill now, only two patients with confirmed pathogenic REL variants have been reported.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>Here, a third case is described of a 5-year-old Moroccan child with combined immunodeficiency presenting with chronic diarrhea and recurrent opportunistic infections, alongside newly reported features including craniosynostosis, language delay, and epilepsy. Clinical exome sequencing, confirmed by Sanger sequencing, identified a novel homozygous frameshift variant (NM_001291746.4) <i>REL</i>:c.24del p.(Tyr9Ilefs*2). This variant introduces a very early premature stop codon. Western blot analysis of peripheral blood mononuclear cells demonstrated a severe reduction of c Rel protein expression with preserved p65 levels, confirming its functional impact.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This report expands the mutational spectrum of <i>REL</i> and further supports the critical, non-redundant role of c-Rel in human immune homeostasis. It also highlights the central role of next generation sequencing, particularly clinical exome approaches, in the diagnosis and evolving genetic classification of IEI, enabling earlier recognition, refined subclassification, and more personalized management of affected patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 4","pages":"240-248"},"PeriodicalIF":1.2,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873080","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":"Genetic Insights Into Hypertension and Breast Cancer Risk in African Women: A Mendelian Randomization and Colocalization Analyses","authors":"Emmanuel Owusu Ansah,&nbsp;Emmanuel Boateng Agyenim,&nbsp;Andrews Danquah,&nbsp;Stephen Kumi Addo,&nbsp;Daniel Sakyi Agyirifo,&nbsp;Kwadwo Fosu,&nbsp;Foster Kyei","doi":"10.1111/ahg.70038","DOIUrl":"10.1111/ahg.70038","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Breast cancer (BC) is a major global health concern. Although observational studies have reported an association between hypertension and BC risk, the causal nature of this relationship remains unclear.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We performed a univariate two-sample Mendelian randomization (MR) analysis to investigate the causal effect of genetically predicted hypertension on overall BC risk and its molecular subtypes. Summary-level genetic data for hypertension were obtained from the Africa Wits-INDEPTH Partnership for Genomic Research (AWI-Gen) study conducted in sub-Saharan Africa (&lt;i&gt;n&lt;/i&gt; = 10,775). Single-nucleotide polymorphisms (SNPs) for exposure and outcome were harmonized before analysis. Causal estimates were primarily derived using the inverse-variance weighted (IVW) method with random effects, complemented by MR-Egger, weighted median, weighted mode, simple mode, and MR-robust adjusted profile score (RAPS) approaches. Sensitivity analyses assessed heterogeneity and horizontal pleiotropy, and reverse MR analyses evaluated potential causal effects of overall BC on hypertension. Additionally, colocalization analyses were conducted to determine whether hypertension- and BC-associated variants share common causal signals across genomic loci.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;After Bonferroni correction for multiple testing (&lt;i&gt;p&lt;/i&gt; &lt; 0.003), no statistically significant associations were observed between genetically predicted hypertension and overall BC or its molecular subtypes: overall BC (odds ratio [OR] = 1.26, 95% confidence interval [CI]: 0.86–1.83, &lt;i&gt;p&lt;/i&gt; = 0.23), estrogen receptor–positive BC (OR = 1.29, 95% CI: 0.81–2.06, &lt;i&gt;p&lt;/i&gt; = 0.28), estrogen receptor–negative (ER&lt;sup&gt;−&lt;/sup&gt;) BC (OR = 1.90, 95% CI: 1.06–3.41, &lt;i&gt;p&lt;/i&gt; = 0.03), and triple-negative BC (OR = 1.98, 95% CI: 1.95–4.14, &lt;i&gt;p&lt;/i&gt; = 0.07). The nominal association observed for ER&lt;sup&gt;−&lt;/sup&gt; BC did not withstand correction for multiple testing. Colocalization analyses revealed generally low posterior probabilities for shared causal variants (PP.H4 &lt; 0.5) across all BC subtypes. Findings were consistent across sensitivity analyses, and reverse MR provided no evidence of causality in the opposite direction.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Impact&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study represents the first MR and colocalization investigation of hypertension and BC risk in a sub-Saharan African population. Although no evidence of a direct genetic causal relationship was identified, the combined MR and colocalization findings suggest that previously reported associations may be driven by nongenetic","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 4","pages":"217-227"},"PeriodicalIF":1.2,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687769","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":"Association Between Different Types of Lipids and Alzheimer's Disease, Parkinson's Disease, and Epilepsy: A Mendelian Randomization and Bioinformatics Analysis","authors":"Jiayu Zhang,&nbsp;Anqi Song,&nbsp;Yi Xiang,&nbsp;Jiaqi Liu,&nbsp;Baixiang Li,&nbsp;Xueting Li","doi":"10.1111/ahg.70025","DOIUrl":"10.1111/ahg.70025","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;With the increasing prevalence of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy (EP) worldwide, there is a growing burden on medical and healthcare resources. Therefore, it is crucial to identify the etiology of these diseases and implement targeted preventive, diagnostic, and treatment measures to address the existing shortage of medical resources. Lipids are integral components of biological membranes. They not only function in energy storage and maintaining cell structure but also play a pivotal role in intercellular communication and signal transmission. Hence, lipids may hold significant implications in the pathogenesis and progression of the aforementioned disorders.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Utilizing two-sample Mendelian randomization (MR) in this investigation, the IEU OpenGWAS database was analyzed to explore the potential causal association between 159 lipids and the mentioned conditions, with sensitivity analysis being performed. Differentially expressed genes (DEGs) were obtained through data analysis of these three diseases in the GEO database, followed by enrichment analysis and protein–protein interaction (PPI) network analysis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The findings indicated a potential causal association between the onset and progression of these disorders and 20 lipids categorized into six groups, which include sterol esters (SEs), ceramides (Cer), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and triacylglycerol (TAG). Furthermore, these lipids were found to regulate biological processes and pathways associated with endocytosis, synaptic vesicular circulation, signal release, MAPK signaling pathway, PI3 kinase (PI3K)–AKT signaling pathway, dopaminergic synapses, and malaria infection. It is worth noting that based on the comprehensive scores of protein interactions in the STRING database, as well as their connectivity and association strength with other proteins in the network, heat shock factor binding protein 1 (HSPB1), which is closely related to lipids and has a relatively close relationship with diseases, was identified as a key protein for AD. Similarly, RAB3A was identified as a key protein for PD. CD160 serves as the key protein of EP.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study, by combining MR with bioinformatics analysis, discovered the potential lipid-based biological processes, pathways, and biomarkers of AD, PD, and EP, respectively, suggesting new therapeutic targets for us, deepening our understanding of the mech","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 3","pages":"121-135"},"PeriodicalIF":1.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136078","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":"Construction of a Prognostic and Diagnostic Gene Signature Based on the Characteristics of Cancer Stem-Like Cells for the Treatment Guidance of Hepatocellular Carcinoma","authors":"Xiawei Li,&nbsp;Min Wang,&nbsp;Xiang Zhang,&nbsp; Bilige,&nbsp;Zhiye Du,&nbsp;Yongqi Yang,&nbsp;Baotong Zhang","doi":"10.1111/ahg.70032","DOIUrl":"10.1111/ahg.70032","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is a highly aggressive cancer with significant intratumoral heterogeneity, likely contributed by the differentiation of cancer stem-like cells (CSCs) into multiple cancer cell lineages, resulting in therapeutic resistance and increased patient mortality. However, there is limited evidence from patient samples regarding the critical role of CSCs in treatment efficacy and patient outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, through the analysis of single-cell transcriptomic data of HCC patient samples, we identify a rare population of cells with cancer stem-like features. Next, we constructed a 12-gene signature that accurately predicts patient survival. Furthermore, based on the expression levels of the 12-gene signature of CSCs, a CAncer stem-like cell Risk Score (CARS) is computed.\u0000</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results show that patients with a higher CARS exhibit increased resistance to sorafenib but greater sensitivity to immune checkpoint inhibitors (ICI). The identification of CSCs in the single-cell transcriptome also provides a unique opportunity to study the microenvironmental characteristics of CSCs in HCC. HCC samples with higher CARS show a substantial infiltration of B cells, and the glycoprotein signaling of GRN and PSAP is specifically associated with the crosstalk between B cells and CSCs, rather than other tumor cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings develop CARS of potential prognostic and predictive value in HCC management.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 3","pages":"176-188"},"PeriodicalIF":1.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145970425","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":"Downregulation of EPAS1 and EGLN1 mRNA Expression Associated With High-Altitude Adaptive Genetic Variants in Sherpa Highlanders","authors":"Yunden Droma,&nbsp;Fengming Yue,&nbsp;Masao Ota,&nbsp;Nobumitsu Kobayashi,&nbsp;Yoshiaki Kitaguchi,&nbsp;Masayuki Hanaoka","doi":"10.1111/ahg.70034","DOIUrl":"10.1111/ahg.70034","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Sherpa highlanders exhibit remarkable tolerance to hypoxia, most likely due to genetic adaptations shaped by natural selection at high altitude. This study examined the roles of <i>endothelial PAS domain protein 1</i> (<i>EPAS1</i>) and <i>egl-9 family hypoxia-inducible factor 1</i> (<i>EGLN1</i>) in the genetic mechanisms underlying this adaptation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Blood samples were collected from 56 Sherpa highlanders residing in Namche Bazaar (3440 m) and 25 non-Sherpa lowlanders in Kathmandu (1300 m). Samples were measured for serum erythropoietin (EPO) concentrations, genetic variants of <i>EPAS1</i> (rs13419896:G&gt;A; rs4953354:A&gt;G) and <i>EGLN1</i> (rs1435166:G&gt;A; rs2153364:A&gt;G), and mRNA expression levels of the <i>EPAS1</i> and <i>EGLN1</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Oxygen saturation (SpO₂) was significantly lower in Sherpas at high altitude than in non-Sherpas at low altitude, consistent with a hypoxic state. However, serum EPO concentrations in Sherpas were comparable to those of non-Sherpas, despite the expected hypoxia-driven stimulation of EPO production. Genotyping revealed significantly lower frequencies of the wild-type alleles of <i>EPAS1</i> and <i>EGLN1</i> in Sherpas compared with non-Sherpas. These genetic patterns were linked to markedly reduced mRNA expression levels of both genes in Sherpa highlanders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>High-altitude adaptive genetic variants in <i>EPAS1</i> and <i>EGLN1</i> are associated with reduced systemic mRNA expression of these genes and a blunted EPO response in Sherpa highlanders, suggesting transcriptional modulation of the hypoxia-induced factor pathway under chronic hypoxia. This attenuated hypoxic response manifests as the tolerance to hypoxia in Sherpa highlanders, enabling Sherpas to adapt to high-altitude hypoxia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 3","pages":"202-214"},"PeriodicalIF":1.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13040315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140680","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}

{"title":"Genetic Landscape of Pediatric Dyslipidemia in a Turkish Cohort: Insights From a Single-Center Experience","authors":"Kadri Murat Erdoğan,&nbsp;Mehmet Berkay Akcan,&nbsp;Havva Yazıcı,&nbsp;Berk Özyılmaz,&nbsp;Taha Reşid Özdemir,&nbsp;Özge Özer Kaya,&nbsp;Özgür Kırbıyık,&nbsp;Esra Er,&nbsp;Yaşar Bekir Kutbay,&nbsp;Merve Saka Güvenç,&nbsp;Tuba Sözen Türk,&nbsp;Selcan Keşan,&nbsp;Fethiye Esenkaya,&nbsp;Altuğ Koç","doi":"10.1111/ahg.70028","DOIUrl":"10.1111/ahg.70028","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Dyslipidemia is a heterogeneous group of disorders that typically presents asymptomatically during childhood but increases the risk of atherosclerotic cardiovascular disease later in life. Understanding the genetic basis can provide valuable insights for early diagnosis and may support more tailored therapeutic approaches. This study aimed to investigate the genetic etiology of childhood-onset dyslipidemia and explore genotype–phenotype correlations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We retrospectively analyzed genetic data from 133 pediatric patients evaluated for suspected dyslipidemia between 2018 and 2023. Targeted next-generation sequencing (NGS) was performed using a panel covering 20 genes associated with lipid metabolism. Only pathogenic or likely pathogenic variants were included in the analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Pathogenic or likely pathogenic variants were identified in 17% of patients (<i>n</i> = 23). The most frequently affected gene was <i>LDLR</i> (74%), followed by significant variants in <i>APOB</i>, <i>APOA5</i>, <i>LDLRAP1</i>, and <i>ALMS1</i>. Three novel pathogenic variants were identified in this cohort: a splice-site variant in <i>LDLRAP1</i> (c.231+2T&gt;C) and two truncating variants in <i>APOB</i> (p.Tyr992Ter and p.Lys576Ter). Genotype–phenotype analysis revealed distinct impacts of variant types on lipid profiles. Notably, <i>APOB</i> variants were associated with both hypercholesterolemia and hypocholesterolemia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings highlight the substantial contribution of genetic factors to childhood dyslipidemia and underscore the clinical utility of genetic testing in guiding diagnostic and therapeutic decisions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 3","pages":"145-154"},"PeriodicalIF":1.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285444","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":"CFAP74 Variants Could Cause Male Infertility With the Asthenoteratozoospermia Phenotype","authors":"Guoyong Chen,&nbsp;Yulin Wang,&nbsp;Jingyi Kang,&nbsp;Xiaoyan Mei,&nbsp;Zhedan Zhang,&nbsp;Yan Zhang,&nbsp;Jun Lu,&nbsp;Yun Liu,&nbsp;Fenghua Lan,&nbsp;Wujian Huang,&nbsp;Duo Zhang","doi":"10.1111/ahg.70026","DOIUrl":"10.1111/ahg.70026","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Severe asthenozoospermia, particularly when associated with multiple morphological abnormalities of the flagella (MMAF), represents a genetically influenced disorder, although the precise pathogenic mechanisms remain incompletely characterized.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, whole-exome sequencing (WES) was performed for 44 asthenoteratozoospermia patients, and 11 pathogenic genes were detected in 20 of them (45.5%). Our investigation focused on <i>CFAP74</i> variants identified in two unrelated patients: a homozygous c.3532G&gt;A mutation in Patient P43 and novel compound heterozygous variants (c.2452C&gt;T and c.3044T&gt;C), first reported in this study, in Patient P24.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Ultrastructural analyses using scanning and transmission electron microscopy revealed characteristic flagellar defects, including a thinner midpiece, disorganized mitochondrial sheath arrangement and axonemal structural abnormalities. Immunofluorescence analysis demonstrated that CFAP74 localized at the entire flagella of control and proband spermatozoa, indicating these missense variants do not disrupt protein expression or subcellular location. Notably, the P24 couple experienced three failed intracytoplasmic sperm injection (ICSI) attempts prior to achieving successful pregnancy through donor sperm by in vitro fertilization (IVF), highlighting the clinical implications of <i>CFAP74</i>-related fertility impairments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study expands the mutational spectrum of <i>CFAP74</i> and further supports the causality between <i>CFAP74</i> mutations and male infertility.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 3","pages":"155-165"},"PeriodicalIF":1.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336173","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}