American journal of human genetics最新文献

{"title":"Reply to Zaslavsky et al.","authors":"Mathieu Quinodoz, Bart P Leroy","doi":"10.1016/j.ajhg.2026.06.010","DOIUrl":"10.1016/j.ajhg.2026.06.010","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"113 8","pages":"1771-1773"},"PeriodicalIF":7.7,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683199","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":"Cell villages and Dirichlet modeling map human cell fitness genetics","authors":"Chloe Hanson,Timothy Derebenskiy,Ana Rodriguez Vega,Yashika S. Kamte,Rachel G. Fox,Laila Sathe,Hannah Lambing,Tyler E. Dietterich,Derek Hawes,Ralda Nehme,Olli Pietiläinen,Aarno Palotie,Patrick Allard,Harold Pimentel,Michael F. Wells","doi":"10.1016/j.ajhg.2026.07.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.07.005","url":null,"abstract":"The capacity of cells to proliferate and survive is central to development and disease. Assays that measure cell fitness are therefore a cornerstone of biology, but traditional techniques lack donor diversity and have high technical variability that impedes scale and reproducibility. To overcome these barriers, we designed and validated a “cell village”-based fitness screening approach using pooled cultures of 12–39 genetically distinct human neural progenitor cell (NPC) lines. We also developed Townlet to establish a foundational statistical framework based on Dirichlet regression for analyzing proportional data from cell villages. Applying these systems, we identified hyperproliferation in NPCs harboring the autism risk factor chromosome 16p11.2 deletion, mapped common genetic variants near ZFHX3 associated with NPC proliferation rate, and discovered genetic modifiers of lead (Pb) sensitivity implicating ARNT2. Together, these experimental and analytical tools advance a scalable, genetically diverse in vitro platform for dissecting human variation in cell fitness and gene-environment interactions.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"25 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148666037","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":"Additive value of polygenic risk and family history for coronary heart disease risk stratification in two diverse US cohorts.","authors":"Mohammadreza Naderian,Johanna L Smith,Ozan Dikilitas,Marwan E Hamed,Noura S Abul-Husn,John J Connolly,Josh B Cortopassi,Qiping Feng,Sarah C Hanks,Ryan Irvin,Gail P Jarvik,Eimear E Kenny,Atlas Khan,Leah C Kottyan,Nita A Limdi,Elizabeth M McNally,Emily Miller,Bahram Namjou-Khales,Megan Roy-Puckelwartz,Robb Rowley,Hemant K Tiwari,Wei-Qi Wei,Georgia Wiesner,Teri A Manolio,Richard R Sharp,Iftikhar J Kullo","doi":"10.1016/j.ajhg.2026.06.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.014","url":null,"abstract":"Whether polygenic risk, monogenic familial hypercholesterolemia (FH), and family history (FamHx) are additively informative for coronary heart disease (CHD) risk prediction across self-identified race/ethnicity (SIRE) groups has not been established. In two diverse cohorts-Electronic Medical Records and Genomics (eMERGE) phase IV (eIV; n = 19,348) and All of Us (AoU; n = 239,645)-we quantified the associations of a polygenic risk score (PRSCHD), pathogenic/likely pathogenic variants in genes associated with FH, and FamHx with CHD and evaluated their incremental value when added to the pooled cohort equations (PCEs). CHD was defined as myocardial infarction, unstable angina, or coronary revascularization. We modeled associations with multivariable logistic regression (prevalent CHD in eIV) and Cox proportional hazards (incident CHD in AoU) and characterized predictive performance with the c-statistic and reclassification and decision-curve net benefits across actionable 10-year risk thresholds. The effects of PRSCHD and FamHx were independent and additive in both cohorts and consistent across White, Black, and Latino SIRE groups. In eIV, adding PRSCHD and FamHx to the PCE increased the c-statistic for prevalent CHD from 0.719 to 0.753 (p-diff = 9.1 × 10-3) and reclassified 18.8% of participants at the 7.5% 10-year threshold, yielding approximately 4 additional true-positive CHD identifications per 1,000 screened. Net benefit gains were observed between the 7.5% and 10% thresholds across all three SIRE groups. In conclusion, PRSCHD and FamHx were independently and additively associated with CHD across major SIRE groups in two diverse cohorts in the United States (US), motivating the addition of these factors to clinical risk algorithms.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"31 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148440925","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":"Landscape of parental postzygotic mutations across >11,000 rare disease trios.","authors":"O Isaac Garcia-Salinas,Katrina A Andrews,Rashesh Sanghvi,John A Sayer,Maria Torra I Benach,My H Pham,Aylwyn Scally,Hilary C Martin,Raheleh Rahbari","doi":"10.1016/j.ajhg.2026.06.015","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.015","url":null,"abstract":"Early postzygotic mutations (PZMs) that arise after fertilization but prior to primordial germ cell specification may be present in both somatic and germ cells, causing mosaicism in a parent and constitutive inheritance in their offspring. In clinical family-trio whole-genome sequencing (WGS), such variants are systematically missed because their sub-heterozygous variant allele fraction (VAF) prevents heterozygous calling in the parent, while residual parental allele support disqualifies the variant as a candidate germline de novo mutation (DNM) in the child. Here, we developed a bioinformatic approach to ascertain parental PZMs from unfiltered DNM candidates in standard-depth (∼30×) trio WGS and applied it to 12,015 trios from the Genomics England 100,000 Genomes Project. We identified 1,015 high-confidence early autosomal parental PZMs, a large single-source catalog of this mutation class. These exhibited a monomodal VAF distribution centered around 5% in parental blood, consistent with empirically characterized ascertainment boundaries imposed by standard-depth sequencing and germline variant calling. PZMs showed no parental age or sex bias and displayed a mutational spectrum distinct from that of DNMs, with enrichment for C>A and T>A substitutions and depletion of T>C. Mutational signature analysis revealed that both mutation types are shaped by clock-like signatures SBS1 and SBS5 in similar proportions, suggesting that spectral differences reflect shifts within shared mutagenic processes. Exploratory genomic distribution analysis revealed a negative PZM association with GC content, in contrast to the positive association for DNMs. Among these, we found variants in DYNC1H1 and WT1 with potential clinical relevance that were missed by routine diagnostic pipelines.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"75 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432639","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":"Likelihood-based calibration improves the clinical utility of JAG1 functional data for variant classification.","authors":"Tristan J Hayeck,Christopher J Sottolano,Justin J Blair,Markos N Xenakis,Nancy B Spinner,Melissa A Gilbert","doi":"10.1016/j.ajhg.2026.06.016","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.016","url":null,"abstract":"Multiplexed assays of variant effects (MAVEs) represent a powerful approach to providing functional information for variants at scale. To harness the full utility of these systems, assay readout must be translated into a language that is accommodating to the clinical genomics community. We previously performed a MAVE to characterize variants in JAG1, the primary cause of the autosomal-dominant, multisystemic disease Alagille syndrome. Using this existing dataset, we calculated log-likelihood ratios of pathogenicity for each variant score, allowing for direct translation of variant data into recognized evidence weights utilized by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in clinical variant classification. Calibration resulted in improved separation of known benign and pathogenic variants and increased the classification rate of abnormal missense variants from 486 to 610, providing clear binning for strong (n = 1), moderate (n = 340), and supporting (n = 269) evidence toward pathogenicity. Retrospective application of this evidence to a cohort of 29 individuals with a JAG1 variant of uncertain significance (VUS) identified from clinical diagnostic sequencing yielded nine (31%) variants with abnormal data meeting supporting (n = 3) and moderate (n = 6) weight for pathogenicity, of which six (21%) were upgraded to likely pathogenic or pathogenic. Calibration of MAVE data to comply with the ACMG/AMP variant classification framework improves the diagnostic yield for JAG1 variants for Alagille syndrome. Moreover, our results support the broader application of these models to additional MAVEs, suggesting that they are likely to strongly impact variant classification across genes associated with disease.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"50 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432896","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":"Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder.","authors":"Philip M Boone,Serkan Erdin,Abucar Mohamed,Sadegheh Haghshenas,Kamli N W Faour,Emeline Kao,Jack Fu,Chiara Auwerx,Ricardo Harripaul,Bimal Jana,Danielle Springer,Grey Hallstrom,Celine E F de Esch,Erica Denhoff,Lauren Holmes,Kiana Mohajeri,John Lemanski,Jennifer Kerkhof,Haley McConkey,Jessica Rzasa,Madison J McCune,Michael A Levy,Julia Grafstein,Matthew Larson,Zsabre Wright,Roberta L Beauchamp,Diane Lucente,Rami Abou Jamra,Neena Agrawal,Pankaj B Agrawal,Erica F Andersen,Emanuela Argilli,Renee Araiza,Sonia Ballal,Megan F Baxter,Gaber Bergant,Astrid Bertsche,Riya Bhavsar,Debora R Bortola,Viktoria Bothe,Charlotte Brasch-Andersen,Dominique Braun,Ange-Line Bruel,Catherine Buchanan,Nicholas D Burt,Laura M L Carvalho,Luigi Chiriatti,Benjamin Cogne,Ryan Collins,Amy Crunk,Benjamin Currall,Andree Delahaye-Duriez,Julian Delanne,Anne-Sophie Denommé-Pichon,Koenraad Devriendt,Aloysius Domingo,Laura Duncan,Laurence Faivre,Laura Famularo,Anne Fulton,Casie A Genetti,Tamar Harel,Marketa Havlovicova,Jenny Higgs,Marine Houlier,Maria Iascone,LaDonna Immken,Bertrand Isidor,Frank J Kaiser,Kaycee Karbone,Margaret Kenna,Amjad Khan,Lara Kristina Kimmig,Tjitske Kleefstra,Eva-Maria Kraus,Ana C V Krepischi,Ilona Krey,Roger L Ladda,Louise Lanoue,Cedric Le Caignec,Zoe K Lewis,Gloria Lima,Sally Ann Lynch,Milan Macek,Olivier Maier,Silvia Maitz,Alison Male,Marcela Malikova,Victoria McKay,Oana Moldovan,Danielle Monteil,Mariana Moysés Oliveira,Jeeva Munasinghe,Sachiko Nakamori,Sonja Neuser,Mathilde Nizon,Xander Nuttle,Kathryn O'Keefe,Laura Orec,Ilaria Parenti,Borut Peterlin,Rolph Pfundt,Jill Pouncey,Francesca Clementina Radio,Leema Robert,Lance Rodan,Hallel Rosenberg-Fogler,Jill A Rosenfeld,Hana Safraou,Monica Salani,Sophia Schliesske,Eleanor G Seaby,Susan L Sell,A Eliot Shearer,Elliott Sherr,Amelle Shillington,Dorothea Siebold,Margje Sinnema,Laura Smith,Alexander P A Stegmann,Cathy A Stevens,Servi J C Stevens,Eric Surette,Marco Tartaglia,Jenny C Taylor,Michelle L Thompson,Pernille M Tørring,Frederic Tran Mau Them,Olga Tsoulaki,Muhammad Umair,Els Vanhoutte,Marie Vincent,Antonio Vitobello,Lydia von Wintzingerode,Amy Watt,Marketa Wayhelova,Ingrid M Wentzensen,William Wilson,Monica H Wojcik,Bo Yuan,Giuseppe Zampino,Siddharth Srivastava,Dominik S Westphal,Korbinian M Riedhammer,Eric Joyce,Rachita Yadav,James F Gusella,Derek J C Tai,Bekim Sadikovic,Karl E Pfeifer,Michael E Talkowski","doi":"10.1016/j.ajhg.2026.06.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.012","url":null,"abstract":"Cohesin orchestrates gene expression via three-dimensional chromosome folding. Genes encoding cohesin and cohesin loaders have been associated with Mendelian disorders, whereas genes encoding cohesin release factors, including WAPL and its binding partners PDS5A and PDS5B, have not. We explored the relevance of cohesin release factors in Mendelian disease by phenotyping individuals with heterozygous predicted damaging variants in WAPL (n = 27), PDS5A (n = 8), and PDS5B (n = 8), by modeling WAPL deficiency in human cells and mice, and by aggregating disease association statistics from consortia studies. We identified a WAPL-related disorder featuring developmental delay, intellectual disability, and risk of other developmental anomalies. Similarities between individuals with damaging WAPL variants and those with large, recurrent 10q22.3q23.2 (10q) deletions encompassing WAPL nominate WAPL as a driver gene within this genomic disorder region. While individuals with PDS5A or PDS5B variants exhibited features of developmental disorders, neither cohort-based statistics nor subject phenotyping associated these genes with specific phenotypes. We used CRISPR to generate truncating variants in WAPL and 10q deletion or duplication in human induced pluripotent stem cells (iPSCs) and induced neurons. Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes. Mice with 50% Wapl expression exhibited mild deficits of growth and learning/memory, whereas those with 25% residual Wapl displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity. In summary, we delineated a genetic condition caused by cohesin release factor deficiency, nominated WAPL as a driver gene within a genomic disorder region, and further illuminated dosage sensitivity of human cohesin.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"31 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148415858","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":"Overlapping Xq13.3 duplications define an X-linked hypotrichosis simplex and implicate TAB3 dosage sensitivity.","authors":"Qiaoyu Cao,Anqi Zhao,Jianbo Wang,Xinjie Lin,Zhoukai Long,Chaolan Pan,Kai Yang,Chun Gu,Yumeng Wang,Lu Li,Xiaoxiao Wang,Jinran Lin,Wenyu Wu,Rushan Xia,Ming Li","doi":"10.1016/j.ajhg.2026.06.013","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.013","url":null,"abstract":"Hereditary hypotrichosis comprises a group of nonsyndromic hair growth disorders for which molecularly characterized forms have been predominantly attributed to autosomal inheritance. Here, we identified three unrelated families with X-linked hypotrichosis simplex (XLHS), characterized by normal hair at birth followed by progressive scalp hair sparsity that emerges in childhood or adolescence. Affected males showed more severe and diffuse involvement, whereas affected females exhibited milder, patchy thinning, consistent with X-linked inheritance. Genomic analyses revealed partially overlapping duplications at Xq13.3 in all affected individuals, defining a shared critical interval encompassing TAB3, FTHL17, and part of DMD. Among these genes, FTHL17 is mainly expressed in the testicular system, and DMD is classically associated with muscular dystrophy, whereas neither FTHL17 nor DMD showed detectable differences in protein abundance between affected individuals and healthy control subjects in scalp tissue. In contrast, TAB3 showed increased accumulation in scalp tissue from affected individuals compared with healthy control subjects, supporting TAB3 as the most likely dosage-sensitive candidate gene. Functionally, both an inducible keratinocyte-specific Tab3-overexpressing mouse model and TAB3-overexpressing HaCaT keratinocyte models demonstrated impaired TAK1-dependent canonical NF-κB signaling. In mice, Tab3 overexpression recapitulated the human hypotrichosis phenotype and induced early pathological changes on postnatal day 31, including hyperkeratosis, thickening of the stratum corneum, and inflammatory cell infiltration. Anti-inflammatory treatment improved hair density in mice, and clinical observations in affected individuals suggested potential benefit. Together, these findings define a previously unrecognized XLHS, implicate an increase in TAB3 dosage as its genetic driver, and identify dysregulated TAK1-NF-κB signaling as a candidate pathogenic mechanism.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"9 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148415899","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 CDK20 cause a severe ciliopathy with midline brain and facial anomalies.","authors":"Gabrielle Lemire,Aren E Marshall,Tejan S Patel,Jonathan Trejo Martinez,Tally Lerman-Sagie,Wendy Mears,Xueqi Wang,Dorit Lev,Alison J Eaton,Kelly Bontempo,Brad Angle,Patrick Shannon,Susan Blaser, ,Kym M Boycott,Julie Richer,Karen Chong,Theodore G Drivas,David Chitayat","doi":"10.1016/j.ajhg.2026.06.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.009","url":null,"abstract":"CDK20, also known as CCRK, is a cyclin-dependent kinase that regulates cell growth, primary cilium structure, and Sonic Hedgehog signaling. CDK20 has not yet been associated with a known human disorder. In this report, we present a cohort of seven individuals from five unrelated families with bi-allelic variants in CDK20 and an overlapping phenotype of ventriculomegaly or hydrocephalus, midline brain anomalies, abnormal nose, midline cleft lip and/or palate, cryptophthalmos or anophthalmia, postaxial polydactyly, and a sandal toe gap. Immunoblot analysis of fibroblasts derived from two affected fetuses with a homozygous CDK20 c.687+6T>C (p.?) variant demonstrated reduced CDK20 levels. Fibroblasts derived from these affected fetuses were also significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. Our findings support that bi-allelic loss-of-function variants in CDK20 cause a severe ciliopathy with midline brain and facial anomalies.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"36 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393331","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":"Integrative analysis of gastric tissue transcriptomes and gastric cancer GWAS implicates candidate susceptibility genes.","authors":"Beiping Hu,Min Zhang,Yuhui Yu,Yongchao Liu,Jiawei Wang,Aiping Zhang,Qian Li,Yun Gao,Zhe Li,Lijun Bian,Yuanliang Gu,Xia Zhu,Qiang She,Xuefeng Gao,Bin Deng,Haisheng Fang,Caihong Hu,Yuheng Chen,Yan Chen,Xinya Wang,Xianyong Yin,Meng Zhu,Lu Wang,Yue Jiang,Jiaping Chen,Juncheng Dai,Hongxia Ma,Yanbing Ding,Caiwang Yan,Guangfu Jin","doi":"10.1016/j.ajhg.2026.06.002","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.002","url":null,"abstract":"Genome-wide association studies (GWASs) have identified at least 17 genetic variants associated with gastric cancer risk. However, the underlying genetic regulatory mechanisms remain poorly understood. We systematically performed genome-wide analyses of expression quantitative trait loci (eQTLs), splicing QTLs (sQTLs), and alternative polyadenylation QTLs (apaQTLs) using gastric biopsy tissues from 262 Chinese individuals, and we integrated these data with GWAS results from 10,254 gastric cancer cases and 10,914 controls. We identified 4,636 eGenes, 1,422 sGenes, and 511 apaGenes, with 55.3% of sGenes and 49.5% of apaGenes being distinct from eGenes. Notably, over half of the variants associated with shared genes were unique to a specific QTL type, with these variants characterized by a wide physical separation (median distance = 25.01 kb) and weak linkage disequilibrium (median r2 = 0.42). Gastric cancer risk variants showed significant enrichment across all three QTL categories. Integrative transcriptome-wide association studies (TWASs) across expression, splicing, and alternative polyadenylation identified 34 genes at false discovery rate (FDR) <0.05; PSCA was implicated across all three regulatory layers. The candidates DIP2B and RMC1 were experimentally validated to promote gastric tumorigenesis both in vitro and in vivo. Functional analyses revealed that the rs11264361-T allele reduced FDPS exon 9 skipping, leading to increased expression of the full-length transcript, while the apaVariant rs7445 regulated UBE2L3 polyadenylation via ATXN2 binding, contributing to gastric cancer risk. Collectively, these results provide a comprehensive QTL resource in gastric tissues and demonstrate distinct regulatory mechanisms of eQTLs, sQTLs, and apaQTLs in gastric cancer development.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"169 1","pages":"1521-1542"},"PeriodicalIF":9.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148372621","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":"Trust, mistrust, and the promise of AI in genomics for African populations.","authors":"Amadou Gaye, Vence L Bonham, Tesfaye B Mersha","doi":"10.1016/j.ajhg.2026.05.009","DOIUrl":"10.1016/j.ajhg.2026.05.009","url":null,"abstract":"<p><p>Artificial intelligence (AI) is rapidly reshaping genomic medicine, yet its benefits remain unevenly distributed due to the profound under-representation of African populations in genomic datasets and persistent legacies of mistrust. These structural gaps undermine model validity, amplify bias, and limit clinical utility across the world's most genetically diverse populations. Building trustworthy AI for genomics in African populations requires transparent and interpretable systems, equitable data generation led by African institutions, culturally grounded governance, and rigorous population-specific validation. Advancing these principles is essential to ensure that AI reduces, rather than reinforces, global genomic inequities.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1367-1371"},"PeriodicalIF":7.7,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13476947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256879","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}