American journal of human genetics最新文献

{"title":"Sparse matrix factorization robust to sample sharing across GWASs reveals interpretable genetic components.","authors":"Ashton R Omdahl, Joshua S Weinstock, Rebecca Keener, Surya B Chhetri, Marios Arvanitis, Alexis Battle","doi":"10.1016/j.ajhg.2025.07.003","DOIUrl":"10.1016/j.ajhg.2025.07.003","url":null,"abstract":"<p><p>Complex trait-associated genetic variation is highly pleiotropic. This extensive pleiotropy implies that multi-phenotype analyses are informative for characterizing genetic associations, as they facilitate the discovery of trait-shared and trait-specific variants and pathways (\"genetic factors\"). Previous efforts have estimated genetic factors using matrix factorization (MF) applied to numerous genome-wide association studies (GWASs). However, existing methods are susceptible to spurious factors arising from residual confounding due to sample sharing in biobank GWASs. Furthermore, MF approaches have historically estimated dense factors, loaded on most traits and variants, that are challenging to map onto interpretable biological pathways. To address these shortcomings, we introduce \"GWAS latent embeddings accounting for noise and regularization\" (GLEANR), an MF method for detection of sparse genetic factors from summary statistics. GLEANR accounts for sample sharing between studies and uses regularization to estimate a data-driven number of interpretable factors. GLEANR is robust to confounding induced by shared samples and improves the replication of genetic factors derived from distinct biobanks. We used GLEANR to evaluate 137 diverse GWASs from the UK Biobank, identifying 58 factors that decompose the genetic architecture of input traits and have distinct signatures of negative selection and degrees of polygenicity. These sparse factors can be interpreted with respect to disease, cell type, and pathway enrichment. We highlight three such factors that captured platelet-measure phenotypes and were enriched for disease-relevant markers corresponding to distinct stages of platelet differentiation. Overall, GLEANR is a powerful tool for discovering both trait-specific and trait-shared pathways underlying complex traits from GWAS summary statistics.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2178-2197"},"PeriodicalIF":8.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740923","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":"Estimating gene conversion rates from population data using multi-individual identity by descent.","authors":"Sharon R Browning, Brian L Browning","doi":"10.1016/j.ajhg.2025.07.019","DOIUrl":"10.1016/j.ajhg.2025.07.019","url":null,"abstract":"<p><p>In humans, homologous gene conversions occur at a higher rate than crossovers; however, gene conversion tracts are small and often unobservable. As a result, estimating gene conversion rates is more difficult than estimating crossover rates. We present a method for multi-individual identity-by-descent (IBD) inference that allows for mismatches due to genotype error and gene conversion. We use the inferred IBD to detect alleles that have changed due to gene conversion in the recent past. We analyze data from the TOPMed and UK Biobank studies to estimate autosome-wide maps of gene conversion rates. For 10 kb, 100 kb, and 1 Mb windows, the correlation between our TOPMed gene conversion map and the deCODE sex-averaged crossover map ranges from 0.56 to 0.67. We find that the strongest gene conversion hotspots typically fall back to the baseline gene conversion rate within 1 kb. In 100 kb and 1 Mb windows, our estimated gene conversion map has higher correlation than the deCODE sex-averaged crossover map with PRDM9 binding enrichment (0.34 vs. 0.29 for 100 kb windows and 0.52 vs. 0.34 for 1 Mb windows), suggesting that the effect of PRDM9 binding is greater on gene conversion than on crossover recombination. Our TOPMed gene conversion maps are constructed from 55-fold more observed allele conversions than the recently published deCODE gene conversion maps. Our maps provide sex-averaged estimates for 10 kb, 100 kb, and 1 Mb windows, whereas the deCODE gene conversion maps provide sex-specific estimates for 3 Mb windows.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2167-2177"},"PeriodicalIF":8.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939143","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":"When two plus four does not equal six: Combining computational and functional evidence to classify BRCA1 key domain missense substitutions.","authors":"Scott T Pew, Madison B Wiffler, Alun Thomas, Julie L Boyle, Melissa S Cline, Nicola J Camp, David E Goldgar, Sean V Tavtigian","doi":"10.1016/j.ajhg.2025.07.011","DOIUrl":"10.1016/j.ajhg.2025.07.011","url":null,"abstract":"<p><p>Classification of genetic variants remains an obstacle to realizing the full potential of clinical genetic sequencing. Because of their ability to interrogate large numbers of variants, multiplexed assays of variant effect and computational tools are viewed as a critical part of the solution to variant classification uncertainty. However, the (joint) performance of these assays and tools on novel variants has not been established. Transformation of the qualitative classification guidelines developed by the American College of Medical Genetics and Genomics (ACMG) into a quantitative Bayesian point system enables empirical validation of strength of evidence assigned to evidence criteria. Here, we derived a maximum-likelihood estimate model that converts frequentist odds ratios calculated from case-control data to proportions pathogenic and applied this model to functional assays, alone and in combination with computational tools across several domains of BRCA1. Furthermore, we defined exceptionally conserved ancestral residues (ECARs) and interrogated the performance of assays and tools at these residues in BRCA1. We found that missense substitutions in BRCA1 that fall at ECARs are disproportionately likely to be pathogenic with effect sizes similar to that of protein-truncating variants. In contrast, for substitutions falling at non-ECAR positions, concordant predictions of pathogenicity from functional assays and computational tools often fail to meet the additive assumptions of strength in ACMG guidelines. Thus, collectively, we conclude that strengths of evidence assigned by expert opinion in the ACMG guidelines are not universally applicable and require empirical validation.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2027-2042"},"PeriodicalIF":8.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881878","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":"A clinical and genotype-phenotype analysis of MACF1 variants.","authors":"Jordy Dekker,Rachel Schot,Kimberly A Aldinger,David B Everman,Camerun Washington,Julie R Jones,Jennifer A Sullivan,Rebecca C Spillmann,Vandana Shashi,Antonio Vitobello,Anne-Sophie Denommé-Pichon,Anne-Laure Mosca-Boidron,Laurence Perrin,Stéphane Auvin,Maha S Zaki,Joseph G Gleeson,Naomi Meave,Cassidy Wallace,Sophie Nambot,Julian Delanne,Sarah M Ruggiero,Ingo Helbig,Mark P Fitzgerald,Richard J Leventer,Dorothy K Grange,Emanuela Argilli,Elliott H Sherr,Supraja Prakash,Derek E Neilson,Francesco Nicita,Antonella Sferra,Enrico S Bertini,Chiara Aiello,Knut Brockmann,Alexander B Kuranov,Silke Kaulfuss,Sulman Basit,Majed Alluqmani,Ahmad Almatrafi,Jan M Friedman,Colleen Guimond,Faruq Mohammed,Pooja Sharma,Divya Goel,Thomas Wirth,Mathieu Anheim,Paulina Bahena,Asuman Koparir,Konstantinos Kolokotronis,Barbara Vona,Thomas Haaf,Erdmute Kunstmann,Reza Maroofian,Henrike L Sczakiel,Felix Boschann,Mala Misra-Isrie,Raymond J Louie,Elliot S Stolerman,Pedro A Sanchez-Lara,Sandra Mergler,Renske Oegema,Yuri A Zarate,Ariana Kariminejad,Homa Tajsharghi,Shimriet Zeidler,Anneke J A Kievit,Arjan Bouman,Gerarda Cappuccio,Nicola Brunetti-Pierri,Kyra E Stuurman,Dayna Morel Swols,Mustafa Tekin,Jariya Upadia,Donna M Martin,Daniel Craven,Susan M Hiatt,Laura A van de Pol,Felice D'Arco,Henri Margot,Martina Wilke,Soheil Yousefi,Tahsin Stefan Barakat,Monique M van Veghel-Plandsoen,Eleonora Aronica,Jasper Anink,Stephen L Rogers,Kevin C Slep,Dan Doherty,William B Dobyns,Grazia M S Mancini","doi":"10.1016/j.ajhg.2025.08.010","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.08.010","url":null,"abstract":"Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"14 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025702","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 analysis of human fibrous dysplasia bone reveals a fibrotic transcriptome and GNAS variants in endothelial, perivascular, and stromal cells","authors":"Kelly L. Wentworth, Fernando A. Fierro, Tania A. Moody, Bryan Le, Zachary Michel, Alison Boyce, Michael Collins, Vardit Kram, Luis F. de Castro, Eric D. Chow, Amir Qorbani, Edward C. Hsiao","doi":"10.1016/j.ajhg.2025.07.018","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.07.018","url":null,"abstract":"Genetic mosaicism is a leading cause of human disease across the lifespan. Improving the tools to detect somatic mosaicism and applying them to understand the cellular and molecular mechanisms that contribute to disease is of critical importance for improving human health. Fibrous dysplasia (FD) is a prototypical disease of G<ce:inf loc=\"post\">s</ce:inf>-GPCR activation caused by somatic, mosaic <ce:italic>GNAS</ce:italic> variants (c.602G&gt;A [p.Arg201His] or c.601C&gt;T [p.Arg201Cys]) that result in fibrotic bone. Utilizing single-cell RNA sequencing and a <ce:italic>GNAS</ce:italic> genotyping strategy, we analyzed non-hematopoietic cells from FD and non-FD human bone. FD bone showed an altered fibroblast composition with an FD-specific osteoblastic cluster. Surprisingly, in addition to the skeletal stromal lineages, endothelial and perivascular cells also expressed <ce:italic>GNAS</ce:italic> c.602G&gt;A and c.601C&gt;T variants, which was confirmed using BaseScope, suggesting that these variants are present in multiple non-osteogenic cell lineages. We also identified a common fibrotic transcriptomic signature across FD cell lineages. Our results highlight the effects of <ce:italic>GNAS</ce:italic> mosaicism on the cellular and transcriptomic landscapes of FD, identify previously unrecognized cell types that may be relevant to FD pathogenesis, and reframe our understanding of <ce:italic>GNAS</ce:italic> c.602G&gt;A (p.Arg201His) and c.601C&gt;T (p.Arg201Cys) function in bone.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"21 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898182","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":"SPINK1-related chronic pancreatitis: A model that encapsulates the spectrum of variant effects, genetic complexity, and classificatory challenges","authors":"Yuan-Chen Wang, Emmanuelle Masson, Qi-Wen Wang, Emmanuelle Génin, Gérald Le Gac, Yann Fichou, David N. Cooper, Zhuan Liao, Claude Férec, Wen-Bin Zou, Jian-Min Chen","doi":"10.1016/j.ajhg.2025.07.013","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.07.013","url":null,"abstract":"The widely used American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) variant classification system is inherently limited by its binary categorization of variants as “pathogenic” or “benign,” failing to account for the full spectrum of variant effects within the complex genetic architecture of human disease. Although various refinements have been proposed, a framework that adequately captures this continuum remains to be established. To address this limitation, we conducted an in-depth analysis of <ce:italic>SPINK1</ce:italic> variants associated with chronic pancreatitis (CP), a disorder ranging from Mendelian to environmentally influenced forms. We collated and reviewed <ce:italic>SPINK1</ce:italic> variants identified in both genome-wide association studies (GWASs) and non-GWASs. Focusing on predicted loss-of-function (LoF) and experimentally characterized variants, we demonstrated through aggregation analysis that complete- or near-complete-LoF <ce:italic>SPINK1</ce:italic> variants cause autosomal-dominant disease with moderate penetrance (∼55%). This finding establishes a critical baseline for comprehensively deciphering the genetic complexity underlying <ce:italic>SPINK1</ce:italic>-related CP. Concentrating on two well-characterized partial-LoF (hypomorphic) variants, c.194+2T&gt;C and c.-4141G&gt;T (enhancer), we present converging evidence for a distinct variant category that neither aligns with the ACMG/AMP binary classifications nor fits the recently proposed “risk alleles” category. Although some variants remain classified as variants of uncertain significance (VUSs), we propose a refined classificatory framework that integrates “risk,” “predisposing,” and “pathogenic” variants to accommodate the full spectrum of clinically relevant <ce:italic>SPINK1</ce:italic> variants. This refined framework is expected to serve as a model for variant interpretation beyond <ce:italic>SPINK1</ce:italic>, providing insights into the issue of “missing heritability” and fostering further exploration of variant effects and genetic complexity across different contexts of human disease.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"23 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898188","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":"Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants of MVP, FinnGen, and UK Biobank","authors":"Shanlee M. Davis, Aoxing Liu, Craig C. Teerlink, Dana M. Lapato, Bryan Gorman, Giulio Genovese, Madhurbain Singh, Mary P. Reeve, Amanda E. Gentry, Kati M. Donner, Timo P. Sipilä, Awaisa Ghazal, Meghana S. Pagadala, Matthew S. Panizzon, Eva E. Lancaster, FinnGen, Chris Chatzinakos, Andrea Ganna, Tim B. Bigdeli, Mark J. Daly, Julie A. Lynch, Judith Ross, Roseann E. Peterson, Richard L. Hauger","doi":"10.1016/j.ajhg.2025.07.017","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.07.017","url":null,"abstract":"Sex chromosome trisomies (SCTs) are the most common whole-chromosome aneuploidy in humans. Yet, our understanding of the prevalence and associated health outcomes is largely driven by observational studies of clinically diagnosed individuals, resulting in a disproportionate focus on 47,XXY and associated hypogonadism. We analyzed microarray intensity data of sex chromosomes for 1.5 million individuals enrolled in three large cohorts—the Million Veteran Program, FinnGen, and UK Biobank—to identify individuals with 47,XXY, 47,XYY, and 47,XXX. We examined disease conditions associated with each SCT by performing phenome-wide association studies using electronic health records for each cohort, followed by meta-analysis across cohorts. We identified 2,769 individuals with SCTs (47,XXY: 1,319; 47,XYY: 1,108; and 47,XXX: 342), most of whom had no documented clinical diagnosis (47,XXY: 73.8%; 47,XYY: 98.6%; and 47,XXX: 93.6%). The identified phenotypic associations with SCT spanned all examined disease categories except neoplasms. Many associations are shared among three SCT subtypes, particularly for vascular diseases (e.g., chronic venous insufficiency [odds ratio (OR) (95% confidence interval [CI]) for 47,XXY: 4.7 (3.9,5.8), 47,XYY: 5.6 (4.5,7.0), and 47,XXX: 4.6 (2.7,7.6)]; venous thromboembolism [47,XXY: 4.6 (3.7–5.6), 47,XYY: 4.1 (3.3–5.0), and 47,XXX: 8.1 (4.2–15.4)]; and glaucoma [47,XXY: 2.5 (2.1–2.9), 47,XYY: 2.4 (2.0–2.8), and 47,XXX: 2.3 (1.4–3.5)]). A third sex chromosome confers an increased risk for systemic comorbidities, even if the SCT is not documented. SCT phenotypes largely overlap, suggesting that one or more X/Y homolog genes, possibly in the pseudoautosomal region, may underlie pathophysiology and comorbidities across SCTs.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"43 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898598","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":"Hearing restoration by gene replacement therapy for a multisite-expressed gene in a mouse model of human DFNB111 deafness","authors":"Luoying Jiang, Shao Wei Hu, Zijing Wang, Yi Zhou, Honghai Tang, Yuxin Chen, Daqi Wang, Xintai Fan, Lei Han, Huawei Li, Dazhi Shi, Yingzi He, Yilai Shu","doi":"10.1016/j.ajhg.2025.08.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.08.011","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"23 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898137","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":"Data sharing in the PRIMED Consortium: Design, implementation, and recommendations for future policymaking.","authors":"Johanna L Smith, Quenna Wong, Whitney Hornsby, Matthew P Conomos, Benjamin D Heavner, Iftikhar J Kullo, Bruce M Psaty, Stephen S Rich, Adrienne M Stilp, Bamidele Tayo, Yuji Zhang, Pradeep Natarajan, Sarah C Nelson","doi":"10.1016/j.ajhg.2025.06.004","DOIUrl":"10.1016/j.ajhg.2025.06.004","url":null,"abstract":"<p><p>Sharing diverse genomic and other biomedical datasets is critical to advancing scientific discoveries and their equitable translation to improve human health. However, data sharing remains challenging in the context of legacy datasets, evolving policies, multi-institutional consortium science, and international stakeholders. The NIH-funded Polygenic Risk Methods in Diverse Populations (PRIMED) Consortium was established to improve the performance of polygenic risk estimates for a broad range of health and disease outcomes with global impacts. Improving polygenic risk score performance across genetically diverse populations requires access to large, diverse cohorts. We report on the design and implementation of data-sharing policies and procedures developed in PRIMED to aggregate and analyze data from multiple heterogeneous sources while adhering to pre-existing data-sharing policies for each integrated dataset and respecting participant preferences and informed consent. Specifically, we describe two primary data-sharing mechanisms-coordinated dbGaP applications and a Consortium Data Sharing Agreement-and provide alternatives when individual-level data cannot be shared within the Consortium (e.g., federated analyses). We also describe technical implementation of Consortium data sharing in the NHGRI Analysis Visualization and Informatics Lab-space (AnVIL) cloud platform to share derived individual-level data, genomic summary results, and methods workflows with appropriate permissions. As a consortium making secondary use of pre-existing data sources, we also discuss challenges and propose solutions for release of individual- and summary-level data products to the broader scientific community. We make recommendations for ongoing and future policymaking with the goal of informing future consortia and other research activities.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1754-1768"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590267","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":"Genetic predisposition for immunoglobulin E production explains atopic risk in children: Tohoku Medical Megabank cohort study.","authors":"Yoichi Sutoh, Tsuyoshi Hachiya, Yayoi Otsuka-Yamasaki, Shohei Komaki, Shiori Minabe, Hideki Ohmomo, Kozo Tanno, Atsushi Hozawa, Naoki Nakaya, Aoi Noda, Masatsugu Orui, Mami Ishikuro, Taku Obara, Shinichi Kuriyama, Makoto Sasaki, Atsushi Shimizu","doi":"10.1016/j.ajhg.2025.06.015","DOIUrl":"10.1016/j.ajhg.2025.06.015","url":null,"abstract":"<p><p>The atopic march lacks early identification methods for high-risk children. In this study, we assessed whether the risk of atopic diseases in infants could be predicted using a polygenic score (PGS) for total immunoglobulin E (IgE) levels. The PGS estimated using the polygenic model generated by PRS-CS was significantly correlated with log-transformed IgE levels (ρ = 0.200, p < 2.2 × 10^-16). Assessment of the risk from birth to 2 years of age in a Japanese birth cohort (n = 17,154) applying the estimated PGS revealed significantly elevated incidence risk ratios in the highest PGS quintile (Q5) compared with those in the reference quintiles (Q1-Q3) for food allergy (1.51-fold; 95% confidence interval: 1.30-1.76), atopic dermatitis (1.30-fold; 1.12-1.51), and both conditions (1.88-fold; 1.46-2.43). These findings address critical gaps in allergy and PGS research among non-European populations, suggesting the contribution of genetic predisposition to IgE production in early-onset allergic diseases and supporting the use of PGS in early intervention.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1852-1863"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688671","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}