American journal of human genetics最新文献

{"title":"A phenome-wide association study of CNVs genotyped from genome sequencing read depth in the UK Biobank.","authors":"Paras Garg, Bharati Jadhav, Mariya Shadrina, Alejandro Martin-Trujillo, Andrew J Sharp","doi":"10.1016/j.ajhg.2026.04.013","DOIUrl":"10.1016/j.ajhg.2026.04.013","url":null,"abstract":"<p><p>We developed a read-depth-based approach that allows accurate and scalable copy-number genotyping from genome sequencing data, including mosaic, recurrent, and multiallelic copy-number variants (CNVs) that are difficult to genotype using other methods. We genotyped each 5-kb segment throughout the genome in the UK Biobank cohort and performed phenome-wide association studies (PheWASs) using 13,215 traits under three different association models, identifying 501 CNVs associated with 1,537 traits. Of these, almost 75% were not found by comparable single-nucleotide variant (SNV)-based PheWASs. We detected signals with multiallelic CNVs, including a coding repeat within MUC1 (mucin 1, cell-surface associated) associated with stomach/duodenal polyps (p = 7.7 × 10^-24), copy number of AMY1 (amylase alpha) genes associated with denture use (p = 2.4 × 10^-29), and a multiallelic coding CNV within NEB, encoding muscle sarcomere protein, associated with muscle mass (p = 9.7 × 10^-24). We also identified intergenic CNVs with effects on traits known to be regulated by nearby genes. For example, carriers of rare non-coding deletions ∼100 kb upstream of MC4R, coding mutations in which are the most common cause of monogenic obesity, were, on average, ∼14 kg heavier than control subjects. In some cases, non-coding CNVs encompassed regulatory elements of the adjacent candidate gene. Using burden tests, we identified an excess of rare damaging non-coding SNVs within some of these regulatory elements associated with the same traits observed in CNV carriers. Our study provides a detailed map of functional CNVs, including complex loci that are recalcitrant to other methods, providing numerous insights into their effects on human traits.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1297-1318"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13241002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Principled measures and estimates of trait polygenicity.","authors":"Luke J O'Connor, Guy Sella","doi":"10.1016/j.ajhg.2026.04.009","DOIUrl":"10.1016/j.ajhg.2026.04.009","url":null,"abstract":"<p><p>While quantitative and statistical genetic studies often invoke the \"polygenicity\" of traits and sometimes quantify it, the meaning of the term is not always clear. We propose a principled definition of polygenicity that encompasses a range of measures. We show that these measures satisfy mathematical properties that are sensible and, conversely, that measures that satisfy these properties meet our definition. We consider four specific measures in greater detail, describe how they differ, and show that three of them can be estimated from genome-wide association studies summary statistics using Fourier mixture regression. We then estimate these measures for 36 human traits. This analysis reveals a lack of traits with polygenicity values that fall in the large gap between Mendelian and highly polygenic traits. We discuss the generality of this finding and the evolutionary and cellular processes that may explain it.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1347-1356"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13231060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating data sharing in research.","authors":"Anna C F Lewis, Ellen W Clayton, Hana Bangash, Harris T Bland, Katherine E Bonini, James J Cimino, John J Connolly, Robert R Freimuth, Stephanie M Fullerton, Hakon Hakonarson, Ingrid A Holm, Gail P Jarvik, Atlas Khan, Krzysztof Kiryluk, Jodell E Linder, Yuan Luo, John A Lynch, Kathleen F Mittendorf, Jennifer A Pacheco, Luke V Rasmussen, Susannah L Rose, Robb Rowley, Richard R Sharp, Theresa L Walunas, Wei-Qi Wei, Chunhua Weng, Maya Sabatello","doi":"10.1016/j.ajhg.2026.04.004","DOIUrl":"10.1016/j.ajhg.2026.04.004","url":null,"abstract":"<p><p>Sharing biomedical research data can accelerate scientific discovery, leading funders and journals to increasingly mandate sharing. However, data openness must be balanced with protecting research participants from harm in an evolving legal and social landscape. Drawing on experiences from the Electronic Medical Records and Genomics (eMERGE-IV) Network-a US-based, multi-site consortium gathering genomic and medical data focused on underrepresented groups to refine disease risk prediction-we examine challenges in implementing data sharing that are \"as open as possible, as closed as necessary.\" Recent US legal developments, including the Dobbs decision and gender-affirming care bans, highlight the urgency of considering data-sharing risks and required the Network to rethink strategies to prevent individual- and group-level harms from genomic analyses. eMERGE-IV implemented several strategies to mitigate concerns, including cell suppression for race/ethnicity data and not extracting certain diagnostic codes from participants' electronic health records. These decisions balanced immediate protection and long-term scientific benefits for relevant populations. Participant agreement to broad data sharing in informed consent is often required for research participation to make data as open as possible. No consent form, however, can define the terms of \"as closed as necessary\"-a construct that is subject to sociolegal changes across the life cycle of research studies. Providing protection requires robust data governance, including engagement with prospective and actual participants. The research enterprise must reconsider its consenting approach and develop transparent, inclusive governance structures responsive to evolving vulnerabilities while maintaining scientific progress. Public trust depends on the research enterprise successfully navigating these competing demands.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1159-1167"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13222466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Signatures of pathogen-driven selection and Austronesian gene flow of Papua New Guinea HLA alleles.","authors":"Neus Font-Porterias, Neda Nemat-Gorgani, Katherine M Kichula, Dana R Al-Hindi, Genelle F Harrison, Sudan Tao, Faming Zhu, Gonzalo Montero-Martin, Marcelo A Fernández-Viña, Lisbeth A Guethlein, Peter Parham, Stephen J Oppenheimer, Alexander G Ioannidis, Andrés Moreno-Estrada, William Pomat, Alexander J Mentzer, Brenna M Henn, Paul J Norman","doi":"10.1016/j.ajhg.2026.04.006","DOIUrl":"10.1016/j.ajhg.2026.04.006","url":null,"abstract":"<p><p>Human leukocyte antigen (HLA) class I and II are cell surface proteins that display peptide antigens to immune cells, thereby mediating detection of infected cells and production of antibodies. Pathogen exposure and demographic events, including local adaptation and admixture, have driven and maintained exceptional polymorphism of HLA genes across human populations. Papua New Guinea has a complex demography, with geographically distinct populations in the highlands and lowlands and exceptional linguistic heterogeneity throughout the island. The lowland populations retain signatures of Austronesian expansion ∼3,000 years ago. Papua New Guinea populations are also differentially exposed to endemic malarial pathogens, with a greater burden in the lowlands. We analyzed genome-wide autosomal SNP data together with HLA allele sequences, linguistic, and geographical data from 337 Papuans. We find the substructure of HLA alleles to be highly correlated with altitude in Papua New Guinea, a signal that is distinct from the rest of the genome. In addition, specific HLA-B and HLA-DP alleles in lowland groups have a greater number of homozygous genotypes than expected under neutrality. Some of these HLA alleles are of Austronesian genetic ancestry. We find that the HLA-binding repertoires at candidate loci are significantly enriched for antigenic P. falciparum-derived peptides. Together, these results indicate that pathogen-driven selective pressures correlate with the observed HLA genetic substructure in Papua New Guinea, highlighting the critical importance of characterizing highly complex HLA variation in understanding differences in disease susceptibility across diverse human groups.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1175-1193"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative genomics and single-cell CRISPRi screening dissect Alzheimer GWAS non-coding variants regulating TSPAN14.","authors":"Shannon Laub, Natalia Tulina, Matthew Hoffman, Joe Bormeh Faryean, Sandhya Ramachandran, Khanh Trang, Stephanie M Lewkiewicz, Alessandra Chesi","doi":"10.1016/j.ajhg.2026.04.011","DOIUrl":"10.1016/j.ajhg.2026.04.011","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) have uncovered many associations for human complex diseases, but functional dissection of the discovered loci has lagged behind. We present a variant-to-gene (V2G) mapping effort for Alzheimer disease (AD) leveraging the most recent AD GWAS meta-analyses. In this study, we integrated ten brain-relevant genomics datasets-including promoter Capture C, ATAC-seq, and RNA-seq from microglia, neurons, and astrocytes-to fine-map AD GWAS variants and identify effector genes. We then performed a single-cell CRISPRi Perturb-seq screen targeting 74 candidate regulatory regions in the human microglial cell line HMC3. Our V2G mapping effort identified 93 candidate causal variants and 94 effector genes (72 coding) for 35 AD loci. Our CRISPRi screen across ∼97,000 cells validated 21 variant-gene pairs. We showed that an intronic region at the TSPAN14 locus containing rs7080009, rs1870138, and rs1870137 is a microglial-specific enhancer activated by the AD-risk haplotype. CRISPR-mediated deletion of this region reduced TSPAN14 expression, disrupted cell-adhesion pathways, and lowered secretion of pro-inflammatory cytokines interleukin 6 (IL-6) and IL-8. Our study provides a systematic framework for mapping GWAS signals to effector genes in a cell-type-specific manner and identifies robust leads for in-depth functional investigations.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1253-1278"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidance on communication and informed consent with patients and their families for experimental individualized treatments.","authors":"Annemieke Aartsma-Rus, Claudio M de Gusmao, Scott Demarest, Matias Wagner, Georg Marckmann, Charlotte Kogel, Roseline Favresse, Rebecca Schuele, Matthis Synofzik, Holm Graessner, Lynn Bush, Timothy W Yu","doi":"10.1016/j.ajhg.2026.05.002","DOIUrl":"10.1016/j.ajhg.2026.05.002","url":null,"abstract":"<p><p>With advanced tools and techniques, it is now possible to genetically diagnose an increasing number of individuals with rare diseases for which no disease-modifying treatment exists. For a subset of affected individuals, it is possible to develop individualized interventions to modulate and/or correct the underlying genetic defect. Communicating to such individuals and their guardians about the potential risks and benefits of such experimental therapies poses special challenges. In addition to typical procedures used for consenting subjects of clinical trials or off-label therapy, individualized therapy protocols involve a complex interplay between biological plausibility, preclinical data, risks, uncertainties, and ethical considerations of equipoise, especially since individualized treatments are usually developed for serious conditions. While no formal guidance exists, this perspective was drafted from the shared experience of clinicians and developers involved in treating affected individuals with individualized antisense oligonucleotides (ASOs) to provide preliminary guidance on communication and consent. As additional experience and expertise accrue over time, we anticipate that these principles will evolve with subsequent modifications to this document.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1168-1174"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HiFi sequencing accurately identifies clinically relevant variants in paralogous genes.","authors":"Bart van der Sanden, Christian Betz, Katharina Herzog, Esther Schamschula, Katharina Wimmer, Inga Vater, Saranya Balachandran, Xiao Chen, Jordi Corominas Galbany, Raoul Timmermans, Ronny Derks, Malte Spielmann, Michael A Eberle, Christian Gilissen, Lisenka E L M Vissers, Johannes Zschocke, Hanno J Bolz, Alexander Hoischen","doi":"10.1016/j.ajhg.2026.04.014","DOIUrl":"10.1016/j.ajhg.2026.04.014","url":null,"abstract":"<p><p>Short-read sequencing (SRS) methods have improved the detection of small genetic variants but remain limited in highly homologous genomic regions, such as segmental duplications with gene-pseudogene pairs. These paralogous regions often require complex, locus-specific assays for accurate analysis. Long-read genome sequencing (lrGS) technologies, such as PacBio HiFi sequencing, can span these regions but still face challenges in variant calling due to alignment ambiguities. Here, we evaluated PacBio HiFi lrGS combined with Paraphase, a dedicated haplotype-based variant caller, in 86 individuals with 125 known clinically relevant variants across 11 paralogous loci. Standard HiFi variant callers detected 95/125 variants, while the remaining 30 variants were only identified by Paraphase. Together, the standard variant callers and Paraphase detected all known variants, including single-nucleotide variants (SNVs), insertions or deletions (InDels), copy-number variants (CNVs), structural variants (SVs), and gene conversions. In addition, lrGS allowed for accurate phasing and gene-pseudogene copy-number detection. We demonstrate that PacBio HiFi lrGS, particularly when integrated with Paraphase, enables comprehensive variant detection in previously difficult-to-assess genomic regions. These results also suggest that lrGS is ready for a wider implementation, possibly as a first-tier diagnostic approach for individuals with suspected variants in these paralogous regions. Ideally, clinical adoption is guided by prospectively designed clinical utility studies, alongside evaluation of sensitivity, specificity, and cost-effectiveness.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"113 6","pages":"1357-1363"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patricia A. Jacobs (1934-2026).","authors":"S Ennis, S L Sherman, T J Hassold, P A Hunt, J A Crolla","doi":"10.1016/j.ajhg.2026.05.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.05.003","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"113 6","pages":"1127-1130"},"PeriodicalIF":8.1,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161288","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 next-generation episignature for Kabuki syndrome enables fine mapping of the impact of KMT2D variants to inform precision medicine.","authors":"Mengqi Wang, Shaimaa Helal, Arteen Torabi-Marashi, Sarah Goodman, Prajkta Kallurkar, Tina K Truong, Emma Mizrahi-Powell, Gilad D Evrony, Inara Chacon-Fonseca, Irene Valenzuela Palafoll, Peter Kannu, Amélie Piton, David Chitayat, Cornelius F Boerkoel, Robert Mendoza-Londono, Juan Dario Ortigoza-Escobar, Michael Kwint, Dmitrijs Rots, Tjitske Kleefstra, Monica H Wojcik, Stephen W Scherer, Brian Hon-Yin Chung, Jung Min Ko, Hans T Bjornsson, Jacqueline R Harris, Sanaa Choufani, Rosanna Weksberg","doi":"10.1016/j.ajhg.2026.04.010","DOIUrl":"10.1016/j.ajhg.2026.04.010","url":null,"abstract":"<p><p>Episignatures are increasingly valuable for variant interpretation in rare neurodevelopmental disorders, especially when optimized to capture the impact of specific variant types and locations across a gene. Here, we generated a next-generation DNA methylation (DNAm) episignature for Kabuki syndrome type 1 (KS1) using the largest cohort studied to date, aiming to clarify the epigenomic and phenotypic effects of diverse KMT2D variant types and positions. Genome-wide DNAm profiles were obtained for 110 individuals with KMT2D variants and 854 controls using microarrays and long-read sequencing (LRS). Differentially methylated loci were enriched in genes involved in embryonic and nervous system development and were leveraged to construct a support-vector machine classifier for detecting pathogenic KMT2D variants. The classifier achieved 97% sensitivity and 100% specificity in validation cohorts and outperformed in silico tools, demonstrating stronger concordance with clinical presentation. Missense variants in the C-terminal region (exon 48) of KMT2D and the N-terminal plant homeodomain (PHD)-type zinc fingers were predominantly classified as pathogenic, highlighting regions enriched for pathogenic variants. Missense variants in the central region (exons 31-39) were more often predicted benign for KS1, consistent with potential association with a different syndrome, highlighting the classifier's specificity for KS1. Test performance was consistent across array and LRS platforms, and classifier scores reflected levels of mosaicism detected by LRS. The KS1 episignature also positively classified pathogenic KDM6A variants associated with KS2. These findings represent a significant advance in the evolution of episignature development, demonstrating diagnostic and interpretive value of a KS1 signature in resolving uncertain or complex cases.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1233-1252"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-ancestry transcriptome-wide association study reveals shared and population-specific genetic effects in Alzheimer disease.","authors":"Xinyu Sun, Makaela Mews, Nicholas R Wheeler, Penelope Benchek, Tianjie Gu, Lissette Gomez, Nicholas Ray, Christiane Reitz, Adam C Naj, Jennifer Elizabeth Below, Giuseppe Tosto, Mario Cornejo-Olivas, Goldie S Byrd, Briseida E Feliciano-Astacio, Katrina Celis, Farid Rajabli, Brian W Kunkle, Margaret A Pericak-Vance, Jonathan L Haines, Anthony J Griswold, William S Bush","doi":"10.1016/j.ajhg.2026.04.007","DOIUrl":"10.1016/j.ajhg.2026.04.007","url":null,"abstract":"<p><p>Alzheimer disease (AD) risk differs across ancestral populations, yet most genetic studies have focused on non-Hispanic White (NHW) cohorts. We conducted a multi-population transcriptome-wide association study (TWAS) using whole-blood RNA sequencing (RNA-seq) and genotype data from NHW (n = 235), African American (AA; n = 224), and Hispanic (HISP; n = 292) Multi-Ancestry Genomics, Epigenomics, and Transcriptomics of Alzheimer's (MAGENTA) participants. Using sum of shared single effects (SuShiE) for multi-population cis-eQTL fine-mapping, we identified credible sets for 8,748 genes, improving fine-mapping precision relative to analyses using fewer populations. cis-eQTL effects were largely shared across populations, with a subset showing population-specific regulation. We performed population-stratified TWAS of AD and inverse-variance-weighted meta-analysis, followed by gene-level TWAS fine-mapping (MA-FOCUS), prioritizing nine genes (false discovery rate [FDR] <0.05, posterior inclusion probability [PIP] >0.8), including established AD loci (BIN1, PTK2B, DMPK) with broadly consistent effects across populations. At BIN1, fine-mapped cis-eQTL variants used in the TWAS prediction model highlighted rs11682128, which is only modestly correlated with the genome-wide association study (GWAS) index SNP rs6733839 (r² ≈ 0.34), demonstrating how integrating eQTL fine-mapping with TWAS can refine signals beyond sentinel GWAS variants. We also identified an association between COG4 expression and AD in NHW, implicating Golgi-related pathways. Using independent SuShiE-derived models from TOPMed MESA (PBMC), several signals replicated directionally across ancestries, with the strongest statistical support in NHW. Overall, multi-population eQTL fine-mapping improves model interpretability and helps resolve shared and population-specific regulatory mechanisms relevant to AD.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1279-1296"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13247992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}