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, Yuan Zhu, Qian Tian, Lijuan Shao, Jiao Zeng, Dandan Xu, Xiangang Mo","doi":"10.1111/ahg.70039","DOIUrl":"https://doi.org/10.1111/ahg.70039","url":null,"abstract":"<p><strong>Purpose: </strong>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><p><strong>Methods: </strong>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><p><strong>Results: </strong>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><p><strong>Conclusion: </strong>This study establishes PSMA4 as a promising therapeutic target for AS, with robust genetic causality and a potential path for drug repurposing.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.2,"publicationDate":"2026-04-24","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":"Genetic Insights Into Hypertension and Breast Cancer Risk in African Women: A Mendelian Randomization and Colocalization Analyses.","authors":"Emmanuel Owusu Ansah, Emmanuel Boateng Agyenim, Andrews Danquah, Stephen Kumi Addo, Daniel Sakyi Agyirifo, Kwadwo Fosu, Foster Kyei","doi":"10.1111/ahg.70038","DOIUrl":"https://doi.org/10.1111/ahg.70038","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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 (n = 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.</p><p><strong>Results: </strong>After Bonferroni correction for multiple testing (p < 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, p = 0.23), estrogen receptor-positive BC (OR = 1.29, 95% CI: 0.81-2.06, p = 0.28), estrogen receptor-negative (ER^-) BC (OR = 1.90, 95% CI: 1.06-3.41, p = 0.03), and triple-negative BC (OR = 1.98, 95% CI: 1.95-4.14, p = 0.07). The nominal association observed for ER^- BC did not withstand correction for multiple testing. Colocalization analyses revealed generally low posterior probabilities for shared causal variants (PP.H4 < 0.5) across all BC subtypes. Findings were consistent across sensitivity analyses, and reverse MR provided no evidence of causality in the opposite direction.</p><p><strong>Impact: </strong>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 metabolic or vascular mechanisms rather than shared inherited genetic determinants. Further studies in larger and more diverse populations are warranted to confirm these findings and explore underlying biological pathways.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.2,"publicationDate":"2026-04-14","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":"Mitonuclear Discordance and Gout, Type 2 Diabetes and Chronic Kidney Disease in Aotearoa New Zealand Indigenous Māori and Pacific People","authors":"Rachel R. Dickerson,&nbsp;Riku Takei,&nbsp;Murray Cadzow,&nbsp;Theodore G. Schurr,&nbsp;Phillip L. Wilcox,&nbsp;Nicola Dalbeth,&nbsp;Lisa K. Stamp,&nbsp;Rinki Murphy,&nbsp;Janak R. de Zoysa,&nbsp;Stephane E. Castel,&nbsp;Anne-Katrin Emde,&nbsp;Kaja A. Wasik,&nbsp;Tony R. Merriman,&nbsp;Anna L. Gosling","doi":"10.1111/ahg.70033","DOIUrl":"10.1111/ahg.70033","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mitochondrial proteins are encoded by both mitochondrial- and nuclear-encoded genes. Because mitochondrial DNA (mtDNA) is maternally inherited, admixed individuals may have different ancestral sources for their nuclear and mitochondrial genomes. The potential incompatibility between these genomic components may cause suboptimal mitochondrial function and result in energy-related pathologies. This incompatibility, or ‘mitonuclear discordance’, is defined as the proportion of the nuclear genome not derived from the same ancestral source as the mtDNA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Based on this understanding, we hypothesized that increased mitonuclear discordance would be associated with lower mitochondrial copy number and increased risk of gout, type 2 diabetes and chronic kidney disease. We tested this prediction using genomic data from a cohort of 2301 New Zealanders with Polynesian ancestry (Indigenous Māori and Pacific peoples living in Aotearoa New Zealand).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed that increased mitonuclear discordance was correlated with a decreased chance of gout (<i>p</i> = 5.08 × 10⁻⁵) and a decreased chance of diagnosis with type 2 diabetes, specifically in individuals having haplogroup B4a1a (<i>p</i> = 4.20 × 10⁻⁹), which was present in 86.0% of the Polynesian study cohort. No significant association was found between mitonuclear discordance and mitochondrial copy number (<i>p</i> = 0.93), risk of chronic kidney disease (<i>p</i> = 0.084) or gout flare frequency (<i>p</i> = 0.53).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overall, while these results contradicted our hypothesis, they can potentially be explained by a higher prevalence of disease-associated alleles for gout and type 2 diabetes in Polynesian genomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 3","pages":"189-201"},"PeriodicalIF":1.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103363","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}

{"title":"Correction to “Recent Statistical Innovations in Human Genetics”","authors":"","doi":"10.1111/ahg.70029","DOIUrl":"10.1111/ahg.70029","url":null,"abstract":"<p>Balding, D. J., and D. Speed. “Recent Statistical Innovations in Human Genetics.” <i>Annals of Human Genetics</i> 89: 241–254. https://doi.org/10.1111/ahg.12606</p><p>The following text was omitted from the start of the Introduction:</p><p>“Developments in statistics and human genetics have long been closely linked, dating back at least to Galton (1886), spanning the enormous contributions of Fisher in the first half of the twentieth century (Fisher 1925, for instance), and the development of maximum likelihood to infer gene-based trees (Cavalli-Sforza and Edwards 1967). We will not go over those great achievements, but instead”.</p><p>The updated text should read “Developments in statistics and human genetics have long been closely linked, dating back at least to Galton (1886), spanning the enormous contributions of Fisher in the first half of the twentieth century (Fisher 1925, for instance), and the development of maximum likelihood to infer gene-based trees (Cavalli-Sforza and Edwards 1967). We will not go over those great achievements, but instead this review covers aspects of three areas of recent statistical advance in human genetics: modelling shared inheritance of DNA segments and what they can tell us about demographic history and selection, modelling relationships between DNA variants and phenotypes and what they can tell us about genetic causes and predicted phenotypes, and identification inferences from DNA profiles.”</p><p>The three cited references are already included in the References, but they are not cited in the paper as published.</p><p>We apologize for this error.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 3","pages":""},"PeriodicalIF":1.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399503","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":"The Genetic Basis of Neurological Disorders: Missense and Nonsense Variants in Three Pakistani Families With Syndromic Intellectual Disability","authors":"Kenza Javed,&nbsp;Nazif Muhammad,&nbsp;Syeda Iqra Hussain,&nbsp;Fozia Fozia,&nbsp;Muhammad Irfan Ullah,&nbsp;Shah Qiaz,&nbsp;Samin Jan,&nbsp;Salah ud Din,&nbsp;Adil U. Reman,&nbsp;Muhammad Daud Khan,&nbsp;Shamim Saleha,&nbsp;Noor Muhammad,&nbsp;Naveed Wasif,&nbsp;Saadullah Khan","doi":"10.1111/ahg.70030","DOIUrl":"10.1111/ahg.70030","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Neurological disorders affect both the central and peripheral nervous systems, exhibiting broad genetic and clinical variability and posing a significant public health concern. These conditions range from common disorders, such as attention deficit disorder and epilepsy, to rare diseases like intellectual disability (ID) and white matter disorders. Exome sequencing (ES) has emerged as a powerful tool in diagnosing the genetic underpinnings of these disorders. ES demonstrated its feasibility as a cost-effective diagnostic pathway by identifying pertinent diagnostic outcomes in 29.4% of cases and being noticeably more cost-effective than conventional genetic diagnostic techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methodology</h3>\u0000 \u0000 <p>This study investigated the genetic basis of three rare neurological disorders in three unrelated Pakistani families using ES. Each family presents with a distinct syndromic form of ID, associated with bilateral frontoparietal polymicrogyria (BFPP) (Family-1), Li–Ghorbani–Weisz–Hubshman syndrome (LIGOWS) (Family-2), or hypomyelination and congenital cataract (HCC) (Family-3). The functional consequences of the missense variants were investigated using bioinformatic prediction tools to confirm the pathogenicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In Family-1 with BFPP, ES identified a novel homozygous missense variant ((NM_001145771.3): c.1579C &gt; T; (NP_001139243.1): p.Pro527Ser) in <i>ADGRG1</i>, predicted to impact protein function. In Family-2 with LIGOWS, a novel homozygous missense variant ((NM_182958.4): c.649A &gt; C; (NP_892003.2): p.Met217Leu) was found in <i>KAT8</i>. In Family-3 with HCC, a novel homozygous nonsense variant ((NM_032581.4): c.722T &gt; G; (NP_115970.2): p.Leu241Ter) was identified in <i>FAM126A</i>, likely resulting in a truncated, nonfunctional protein. Families’ structures and segregation analysis confirm disease condition segregating with autosomal recessive mode of inheritance. The functional consequences of the <i>ADGRG1</i> and <i>KAT8</i> missense variants were revealed as deleterious using bioinformatic prediction tools.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We have identified novel pathogenic variants in <i>ADGRG1</i>, <i>KAT8</i>, and <i>FAM126A</i> in individuals with rare neurological disorders, thereby expanding the genetic and clinical spectrum of these conditions. This study reports, for the first time, an autosomal recessive inheritance pattern for a KAT8-related disorder, providing new insights into its genetic architecture.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 3","pages":"167-175"},"PeriodicalIF":1.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145675890","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}