American journal of human genetics最新文献

{"title":"Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.","authors":"Zain Dardas,Laura Harrold,Daniel G Calame,Claire G Salter,Takashi Kikuma,Kevin P Guay,Bobby G Ng,Kanae Sano,Ahmad K Saad,Haowei Du,Riccardo Sangermano,Sohil G Patankar,Shalini N Jhangiani,Semra Gürsoy,Mohamed S Abdel-Hamid,Mahmoud K H Ahmed,Reza Maroofian,Rauan Kaiyrzhanov,Kamran Salayev,Wendy D Jones,Ana Pérez Caballero,Lucy McGavin,Michael Spiller,Miranda Durkie,Nick Wood,Lauren O'Grady,Paula Goldenberg,Ann M Neumeyer,Amber Begtrup,Sherif F Abdel-Ghafar,Maha S Zaki,Hilde Van Esch,Jennifer E Posey,Olivia K Wenger,Ethan M Scott,Kinga M Bujakowska,Richard A Gibbs,Davut Pehlivan,Dana Marafi,Joseph S Leslie,Nishanka Ubeyratna,Jacob Day,Martina Owens,Jessica Settle,Soher Balkhy,Abdullah Tamim,Lama Alabdi,Fowzan S Alkuraya,Yoichi Takeda,Hudson H Freeze,Daniel N Hebert,James R Lupski,Andrew H Crosby,Emma L Baple","doi":"10.1016/j.ajhg.2025.03.018","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.018","url":null,"abstract":"Congenital disorders of glycosylation (CDGs) comprise a large heterogeneous group of metabolic conditions caused by defects in glycoprotein and glycolipid glycan assembly and remodeling, a fundamental molecular process with wide-ranging biological roles. Herein, we describe bi-allelic UGGT1 variants in fifteen individuals from ten unrelated families of various ethnic backgrounds as a cause of a distinctive CDG of variable severity. The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability, seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available). The more severely affected individuals display congenital heart malformations, variable skeletal abnormalities including scoliosis, and hepatic and renal involvement, including polycystic kidneys mimicking autosomal recessive polycystic kidney disease. Clinical studies defined genotype-phenotype correlations, showing bi-allelic UGGT1 loss-of-function variants associated with increased disease severity, including death in infancy. UGGT1 encodes UDP-glucose:glycoprotein glucosyltransferase 1, an enzyme critical for maintaining quality control of N-linked glycosylation. Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention. Collectively, our data provide a comprehensive genetic, clinical, and molecular characterization of UGGT1-CDG, broadening the spectrum of N-linked glycosylation disorders.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"24 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing trends in clinical genetic testing: A single-center analysis of EHR data from 1.8 million patients over two decades.","authors":"Lisa Bastarache,Rory J Tinker,Bryce A Schuler,Lucas Richter,John A Phillips,William W Stead,Gillian W Hooker,Josh F Peterson,Douglas M Ruderfer","doi":"10.1016/j.ajhg.2025.03.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.009","url":null,"abstract":"A lack of structural data in electronic health records (EHRs) makes assessing the impact of genetic testing on clinical practice challenging. We extracted clinical genetic tests from the EHRs of more than 1.8 million patients seen at Vanderbilt University Medical Center from 2002 to 2022. With these data, we quantified the use of clinical genetic testing in healthcare and described how testing patterns and results changed over time. We assessed trends in types of genetic tests, tracked usage across medical specialties, and introduced a new measure, the genetically attributable fraction (GAF), to quantify the proportion of observed phenotypes attributable to a genetic diagnosis over time. We identified 104,392 tests and 19,032 molecularly confirmed diagnoses. The proportion of patients with genetic testing in their EHRs increased from 1.0% in 2002 to 6.1% in 2022, and testing became more comprehensive with the growing use of multi-gene panels. The number of unique diseases diagnosed with genetic testing increased from 51 in 2002 to 509 in 2022, and there was a rise in the number of variants of uncertain significance. The phenome-wide GAF for 6,505,620 diagnoses made in 2022 was 0.46%, and the GAF was greater than 5% for 74 phenotypes, including pancreatic insufficiency (67%), chorea (64%), atrial septal defect (24%), microcephaly (17%), paraganglioma (17%), and ovarian cancer (6.8%). Our study provides a comprehensive quantification of the increasing role of genetic testing at a major academic medical institution and demonstrates its growing utility in explaining the observed medical phenome.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"46 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A non-syndromic orofacial cleft risk locus links tRNA splicing defects to neural crest cell pathologies.","authors":"Michaela Bartusel,Skylar X Kim,Rizwan Rehimi,Alicia M Darnell,Miloš Nikolić,Julia Heggemann,Petros Kolovos,Wilfred F J van Ijcken,Jade Varineau,Giuliano Crispatzu,Elisabeth Mangold,Samantha A Brugmann,Matthew G Vander Heiden,Magdalena Laugsch,Kerstin U Ludwig,Alvaro Rada-Iglesias,Eliezer Calo","doi":"10.1016/j.ajhg.2025.03.017","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.017","url":null,"abstract":"Orofacial clefts are the most common form of congenital craniofacial malformation worldwide. The etiology of these birth defects is multifactorial, involving genetic and environmental factors. However, in most cases, the underlying causes remain unexplained, precluding a molecular understanding of disease mechanisms. Here, we integrated genome-wide association data, targeted resequencing of case and control cohorts, tissue- and cell-type-specific epigenomic profiling, and genome architecture analyses to molecularly dissect a genomic locus associated with an increased risk of non-syndromic orofacial cleft. We found that common and rare risk variants associated with orofacial cleft intersect with an enhancer (e2p24.2) that is active in human embryonic craniofacial tissue. We mapped e2p24.2 long-range interactions to a topologically associated domain harboring MYCN, DDX1, and CYRIA. We found that MYCN and DDX1, but not CYRIA, are required during craniofacial development in chicken embryos. We investigated the role of DDX1, a key component of the tRNA splicing complex, in cranial neural crest cells (cNCCs). The loss of DDX1 in cNCCs resulted in the accumulation of unspliced tRNA fragments, depletion of mature intron-containing tRNAs, and ribosome stalling at codons decoded by these tRNAs. This was accompanied by defects in both global protein synthesis and cNCC migration. We further showed that the induction of tRNA fragments is sufficient to disrupt craniofacial development. Together, these results uncovered a molecular mechanism in which impaired tRNA splicing affects cNCCs and craniofacial development and positioned MYCN, DDX1, and tRNA processing defects as risk factors in the pathogenesis of orofacial clefts.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"49 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational and functional prioritization identifies genes that rescue behavior and reduce tau protein in fly and human cell models of Alzheimer disease.","authors":"Morgan C Stephens,Jiayang Li,Megan Mair,Justin Moore,Katy Zhu,Akash Tarkunde,Bismark Amoh,Alma M Perez,Arya Bhakare,Fangfei Guo,Joshua M Shulman,Ismael Al-Ramahi,Juan Botas","doi":"10.1016/j.ajhg.2025.03.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.012","url":null,"abstract":"Genome-wide association studies (GWASs) in Alzheimer disease (AD) have uncovered over 70 loci significantly associated with AD risk, but identifying the true causal gene(s) at these loci requires systematic functional validation that is rarely performed due to limitations of time and cost. Here, we integrate transcriptome-wide association study (TWAS) with colocalization analysis, fine-mapping, and additional annotation of AD GWAS variants to identify 123 genes at known and suggestive AD risk loci. A comparison with human AD brain transcriptome data confirmed that many of these candidate genes are dysregulated in human AD and correlate with neuropathology. We then tested all available orthologs in two well-established Drosophila AD models that express either wild-type tau or secreted β-amyloid (β42). Experimental perturbation of the 60 available candidates pinpointed 46 that modulated neuronal dysfunction in one or both fly models. The effects of 18 of these genes were concordant with the TWAS prediction, such that the direction of misexpression predicted to increase AD risk in humans exacerbated behavioral impairments in the AD fly models. Reversing the aberrant down- or upregulation of 11 of these genes (MTCH2, ELL, TAP2, HDC, DMWD, MYCL, SLC4A9, ABCA7, CSTF1, PTK2B, and CD2AP) proved neuroprotective in vivo. We further studied MTCH2 and found that it regulates steady-state tau protein levels in the Drosophila brain and reduces tau accumulation in human neural progenitor cells. This systematic, integrative approach effectively prioritizes genes at GWAS loci and reveals promising AD-relevant candidates for further investigation as risk factors or targets for therapeutic intervention.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"17 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions.","authors":"Suraj Upadhya, Jenny A Klein, Anna Nathanson, Kristina M Holton, Lindy E Barrett","doi":"10.1016/j.ajhg.2025.02.011","DOIUrl":"10.1016/j.ajhg.2025.02.011","url":null,"abstract":"<p><p>Interindividual variation in phenotypic penetrance and severity is found in many neurodevelopmental conditions, although the underlying mechanisms remain largely unresolved. Within individuals, homogeneous cell types (i.e., genetically identical and in similar environments) can differ in molecule abundance. Here, we investigate the hypothesis that neurodevelopmental conditions can drive increased variability in gene expression, not just differential gene expression. Leveraging independent single-cell and single-nucleus RNA sequencing datasets derived from human brain-relevant cell and tissue types, we identify a significant increase in gene expression variability driven by the autosomal aneuploidy trisomy 21 (T21) as well as autism-associated chromodomain helicase DNA binding protein 8 (CHD8) haploinsufficiency. Our analyses are consistent with a global and, in part, stochastic increase in variability, which is uncoupled from changes in transcript abundance. Highly variable genes tend to be cell-type specific with modest enrichment for repressive H3K27me3, while least variable genes are more likely to be constrained and associated with active histone marks. Our results indicate that human neurodevelopmental conditions can drive increased gene expression variability in brain cell types, with the potential to contribute to diverse phenotypic outcomes. These findings also provide a scaffold for understanding variability in disease, essential for deeper insights into genotype-phenotype relationships.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"876-891"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variability in proliferative and migratory defects in Hirschsprung disease-associated RET pathogenic variants.","authors":"Lauren E Fries, Sree Dharma, Aravinda Chakravarti, Sumantra Chatterjee","doi":"10.1016/j.ajhg.2025.02.004","DOIUrl":"10.1016/j.ajhg.2025.02.004","url":null,"abstract":"<p><p>Hirschsprung disease (HSCR) exhibits extensive genetic heterogeneity, with 72% of cases involving pathogenic variants in 10 genes forming a gene regulatory network (GRN) essential for enteric nervous system (ENS) development. The receptor tyrosine kinase gene RET is the most significant contributor, implicated in 12%-50% of individuals depending on the phenotype. RET plays a critical role in ENS precursor proliferation and migration, and defects in these processes lead to HSCR. However, the functional impact of RET pathogenic variants and their mechanisms of disease remain poorly understood. To address this, we investigated proliferative and migratory phenotypes in a RET-dependent neural crest-derived cell line harboring one of five missense (c.166C>A [p.Leu56Met]; c.532G>C [p.Glu178Gln]; c.2372A>T [p.Tyr791Phe]; c.2765C>A [p.Ser922Tyr]; or c.2994T>A [p.Phe998Leu]) or three nonsense (c.612C>A, c.2308C>T, or c.2943C>G) heterozygous pathogenic RET variants. Using cDNA- and CRISPR-based prime reverse insertion mechanism engineering (PRIME) editing coupled with quantitative proliferation and migration assays, we observed significant losses in proliferation and migration in three missense (c.612C>A [p.Tyr204^∗]; c.2308C>T [p.Arg770^∗]; and c.2943C>G [p.Tyr981^∗]) and all nonsense variants. Notably, the c.2372A>T (p.Tyr791Phe) missense variant, whose pathogenicity has been debated, appears benign. Importantly, the severity of migration loss did not consistently correlate with proliferation defects, and the phenotypic severity of nonsense variants was independent of their position within the RET protein. This study highlights the necessity of targeted functional assays to accurately assess the pathogenicity of HSCR-associated variants rather than relying solely on bioinformatics predictions, which could be refined by incorporating functional data.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"863-875"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human leukocyte antigen variation is associated with cytomegalovirus serostatus in healthy individuals.","authors":"Juliano A Boquett, Jürgen Sauter, Alexander H Schmidt, Martin Maiers, Jill A Hollenbach","doi":"10.1016/j.ajhg.2025.02.007","DOIUrl":"10.1016/j.ajhg.2025.02.007","url":null,"abstract":"<p><p>Cytomegalovirus (CMV) is a common β-herpes virus worldwide with an estimated seroprevalence among the general population of 83%. Primary infection is usually benign; however, CMV can cause severe morbidity in newborns in whom it is acquired congenitally, as well as immunocompromised individuals. Understanding the role of immunogenetic variation in risk for CMV infection can provide insight into the immune control of this ubiquitous pathogen. Here, we evaluated the association of human leukocyte antigen (HLA) genetic variation with CMV seropositivity in more than 518,000 individuals from two independent cohorts. We found three HLA class II alleles (HLA-DRB1^∗04:03 with risk; HLA-DRB1^∗01:03 and HLA-DRB1^∗07:01 with protection) to be significantly associated with CMV serostatus across both cohorts and in multiple population subgroups. Interestingly, HLA-DRB1^∗04:03 and HLA-DRB1^∗01:03, the alleles with the strongest observed effect, are relatively rare, while common homologous alleles show no association with CMV. We show that these differences are mediated by changes in charge and volume to two key pockets in the peptide-binding groove of the HLA molecule, providing a structural basis for the observed association. Our results provide population-scale evidence for the role of HLA in mediating infection with this ubiquitous human virus and a framework for understanding immunological conditions necessary for efficient viral control.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"913-926"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Actionable genetic variants in 4,198 Scottish participants from the Orkney and Shetland founder populations and implementation of return of results.","authors":"Shona M Kerr, Lucija Klaric, Marisa D Muckian, Kiera Johnston, Camilla Drake, Mihail Halachev, Emma Cowan, Lesley Snadden, John Dean, Sean L Zheng, Prisca K Thami, James S Ware, Gannie Tzoneva, Alan R Shuldiner, Zosia Miedzybrodzka, James F Wilson","doi":"10.1016/j.ajhg.2025.02.018","DOIUrl":"10.1016/j.ajhg.2025.02.018","url":null,"abstract":"<p><p>The benefits of returning clinically actionable genetic results to participants in research cohorts are accruing, yet such a genome-first approach is challenging. Here, we describe the implementation of return of such results in two founder populations from Scotland. Between 2005 and 2015, we recruited >4,000 adults with grandparents from Orkney and Shetland into the Viking Genes research cohort. The return of genetic data was not offered at baseline, but in 2023, we sent invitations to participants for consent to return of actionable genetic findings. We generated exome sequence data from 4,198 participants and used the American College of Medical Genetics and Genomics (ACMG) v.3.2 list of 81 genes, ClinVar review, and pathogenicity status, plus manual curation, to develop a pipeline to identify potentially actionable variants. We identified 104 individuals (2.5%) with 108 actionable genotypes at 39 variants in 23 genes and validated these. Working with the NHS Clinical Genetics service, which provided genetic counseling and clinical verification of the research results, and after expert clinical review, we notified 64 consenting participants (or their next of kin) of their actionable genotypes. Ten actionable variants across seven genes (BRCA1, BRCA2, ATP7B, TTN, KCNH2, MUTYH, and GAA) have risen 50- to >3,000-fold in frequency through genetic drift in ancestral island localities. Viking Genes is one of the first UK research cohorts to return actionable findings, providing an ethical and logistical exemplar of return of results. The genetic structure in the Northern Isles of Scotland with multiple founder effects provides a unique opportunity for a tailored approach to disease prevention through genetic screening.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"793-807"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.","authors":"Huw B Thomas, Leigh A M Demain, Alfredo Cabrera-Orefice, Isabelle Schrauwen, Hanan E Shamseldin, Alessandro Rea, Thashi Bharadwaj, Thomas B Smith, Monika Oláhová, Kyle Thompson, Langping He, Namanpreet Kaur, Anju Shukla, Musaad Abukhalid, Muhammad Ansar, Sakina Rehman, Saima Riazuddin, Firdous Abdulwahab, Janine M Smith, Zornitza Stark, Hanifenur Mancilar, Sait Tumer, Fatma N Esen, Eyyup Uctepe, Vehap Topcu, Ahmet Yesilyurt, Erum Afzal, Mehri Salari, Christopher Carroll, Giovanni Zifarelli, Peter Bauer, Deniz Kor, Fatma D Bulut, Henry Houlden, Reza Maroofian, Samantha Carrera, Wyatt W Yue, Kevin J Munro, Fowzan S Alkuraya, Peter Jamieson, Zubair M Ahmed, Suzanne M Leal, Robert W Taylor, Ilka Wittig, Raymond T O'Keefe, William G Newman","doi":"10.1016/j.ajhg.2025.02.005","DOIUrl":"10.1016/j.ajhg.2025.02.005","url":null,"abstract":"<p><p>Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"952-962"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opportunities and challenges of local ancestry in genetic association analyses.","authors":"Quan Sun, Andrea R V R Horimoto, Brian Chen, Frank Ockerman, Karen L Mohlke, Elizabeth Blue, Laura M Raffield, Yun Li","doi":"10.1016/j.ajhg.2025.03.004","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.004","url":null,"abstract":"<p><p>Recently, admixed populations make up an increasing percentage of the US and global populations, and the admixture is not uniform over space or time or across genomes. Therefore, it becomes indispensable to evaluate local ancestry in addition to global ancestry to improve genetic epidemiological studies. Recent advances in representing human genome diversity, coupled with large-scale whole-genome sequencing initiatives and improved tools for local ancestry inference, have enabled studies to demonstrate that incorporating local ancestry information enhances both genetic association analyses and polygenic risk predictions. Along with the opportunities that local ancestry provides, there exist challenges preventing its full usage in genetic analyses. In this review, we first summarize methods for local ancestry inference and illustrate how local ancestry can be utilized in various analyses, including admixture mapping, association testing, and polygenic risk score construction. In addition, we discuss current challenges in research involving local ancestry, both in terms of the inference itself and its role in genetic association studies. We further pinpoint some future study directions and methodology development opportunities to help more effectively incorporate local ancestry in genetic analyses. It is worth the effort to pursue those future directions and address these analytical challenges because the appropriate use of local ancestry estimates could help mitigate inequality in genomic medicine and improve our understanding of health and disease outcomes.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 4","pages":"727-740"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}