American journal of human genetics最新文献

{"title":"Principled measures and estimates of trait polygenicity.","authors":"Luke J O'Connor, Guy Sella","doi":"10.1016/j.ajhg.2026.04.009","DOIUrl":"https://doi.org/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":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants.","authors":"Marcy E Richardson, Megan Holdren, Terra Brannan, Miguel de la Hoya, Amanda B Spurdle, Sean V Tavtigian, Colin C Young, Lauren Zec, Susan Hiraki, Michael J Anderson, Logan C Walker, Shannon McNulty, Clare Turnbull, Marc Tischkowitz, Katherine Schon, Thomas Slavin, William D Foulkes, Melissa Cline, Alvaro N Monteiro, Tina Pesaran, Fergus J Couch","doi":"10.1016/j.ajhg.2026.03.016","DOIUrl":"10.1016/j.ajhg.2026.03.016","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1123"},"PeriodicalIF":8.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525317","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":"Putting polygenic scores in context: How intersectional factors affect relative and absolute genetic risk.","authors":"Mihael Cudic, Justin D Tubbs, Tian Ge, Jordan W Smoller","doi":"10.1016/j.ajhg.2026.03.013","DOIUrl":"10.1016/j.ajhg.2026.03.013","url":null,"abstract":"<p><p>The clinical utility of polygenic scores (PGSs) is known to vary when training and test samples differ in ancestry, with recent work suggesting that sociodemographic differences can also impact PGS performance. However, the impact of belonging to multiple intersecting contexts on genetic risk remains understudied. We analyzed lifetime disease odds ratio (OR) and absolute risk (AR) estimates in high-PGS individuals across 106 two-way intersections of sociodemographic factors (sex, age, alcohol intake, smoking, income, and deprivation). Seven diseases were assessed: atrial fibrillation, coronary artery disease, type 2 diabetes, hypercholesterolemia, asthma, obesity, and major depression. Primary analyses were performed in the UK Biobank (UKB; n = 375,054, British-European-like ancestry), with replication in All of Us (AoU; n = 36,552, African-like ancestry and n = 99,477, European-like ancestry). ORs varied significantly across contexts, with greater variation observed across intersectional contexts. On average, the maximal OR varied across two-way contexts by 56%. AR deviations were more moderate after adjusting for context prevalence but still showed intersectional effects. For example, high-PGS, low-income individuals had an average 1.0 percentage-point drop in estimated AR across phenotypes using a context-aware vs. context-unaware PGS, while those additionally reporting low alcohol intake had a 3.1-point lower AR estimate for major depression in the UKB. Results were generally consistent across datasets, with strongest replication in European-like AoU samples. Our findings show that intersectional contexts can have a sizable impact on genetic risk effect estimates. Future clinical applications may need to incorporate these contextual effects to improve accuracy and fairness for individual-specific genetic risk assessment.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"966-977"},"PeriodicalIF":8.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13120731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687693","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":"Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder.","authors":"James Lambton, Shotaro Asano, Yuxiang Huang, Fumi Suomi, Tomoya Eguchi, Cassidy Petree, Kevin Huang, Magali Prigent, Aliza Imam, Thomas J McCorvie, Daniel Warren, Emma Hobson, Helen McCullagh, Doriana Misceo, Anna Bjerre, Marie F Smeland, Claus Klingenberg, Eirik Frengen, Swati Naik, Gavin Ryan, Annapurna Sudarsanam, Katherine Foster, Pradeep Vasudevan, Rajib Samanta, Fatima Rahman, Shazia Maqbool, Vrajesh Udani, Stephanie Efthymiou, Henry Houlden, Robert McFarland, Jack J Collier, Reza Maroofian, Wyatt W Yue, Gaurav K Varshney, Daniel J Klionsky, Renaud Legouis, Thomas G McWilliams, Noboru Mizushima, Monika Oláhová, Charlotte L Alston, Robert W Taylor","doi":"10.1016/j.ajhg.2026.03.002","DOIUrl":"10.1016/j.ajhg.2026.03.002","url":null,"abstract":"<p><p>Autophagy is an essential developmental and homeostatic process, defined by the endolysosomal degradation of intracellular components and pathogens. Dysfunctional autophagy is implicated in complex human disease, yet reports of congenital autophagy disorders were considered exceedingly rare until the recent report of several unrelated families with bi-allelic variants in the core autophagy effector ATG7, complementing the report of two individuals harboring ATG5 variants. We now report six affected individuals from five families with bi-allelic ATG12 variants with complex neurological phenotypes overlapping those seen in individuals with pathogenic variants in ATG5 and ATG7: developmental delay, intellectual disability, congenital ataxia, hypotonia, and seizures with cerebellar vermis hypoplasia evident on neuroradiological imaging. Structural modeling implicated a potential disruption of the ATG12-ATG5-ATG16N-ATG3 complex. Biochemical analyses of primary fibroblasts confirmed the loss of stable ATG12-ATG5 conjugate in one family and altered autophagic flux in one unrelated family. The HaloTag processing assay in HeLa cells demonstrated a decrease in ATG12-ATG5 conjugate and reduced autophagic flux in response to starvation. Complementation studies demonstrated that equivalent missense atg12 variants were unable to fully recover the biochemical defect in atg12-null yeast, with microscopy analysis demonstrating a reduced delivery of autophagy substrates to the yeast's degradative compartment. Zebrafish studies confirmed that Atg12 is required for normal growth, brain development, and neural function. Collectively, our findings underscore the pivotal role of autophagy in maintaining human neural integrity, emphasize an emerging group of congenital autophagy disorders, and expand our understanding of adaptive homeostasis in human health and disease.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1090-1107"},"PeriodicalIF":8.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525335","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":"The impact of sex on the immune system explored at the single-cell level.","authors":"Seyhan Yazar, Jose Alquicira-Hernandez, Kristof Wing, Anne Senabouth, Stacey Andersen, Kirsten A Fairfax, Alex W Hewitt, Joseph E Powell, Sara Ballouz","doi":"10.1016/j.ajhg.2026.04.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.04.003","url":null,"abstract":"<p><p>Sex has a key role in disease susceptibility (in particular, autoimmunity). Sex differences in the immune system originate from genes and their interactions with both intrinsic and extrinsic factors. However, the cellular-level factors influencing sexual dimorphism are not fully understood. We thus examined immune sex differences at single-cell resolution to dissect the genetic impacts. Female-biased sex-differentially expressed genes (sex-DEGs) in multiple immune cells were involved in tumor necrosis factor alpha (TNF-α) signaling, whereas male DEGs were enriched for ribosomal-related functions. While cis-expression trait quantitative loci (eQTLs) were less common on sex chromosomes, we identified over 1,000 sex-specific eQTLs and 51 sex-interacting eQTLs on autosomes. When we examined the effect of genetic control on sex-DEGs, we found genetic variants affecting the female-biased expression of FCGR3A in natural killer (NK) cells (rs2099684) and ITGB2 in monocytes (rs760462), both of which are associated with systemic lupus erythematosus. Our work reveals biases masked in bulk analyses and highlights sexually dimorphic genes and pathways at baseline.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"113 5","pages":"1006-1023"},"PeriodicalIF":8.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855659","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":"Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants.","authors":"Marcy E Richardson, Megan F H Bishop, Megan A Holdren, Miguel de la Hoya, Amanda B Spurdle, Sean V Tavtigian, Terra Brannan, Colin C Young, Lauren Zec, Susan Hiraki, Clare Turnbull, Marc Tischkowitz, Kara A Bernstein, Jean-Yves Masson, Shannon M McNulty, Tina Pesaran, Alvaro N Monteiro, Logan C Walker, William D Foulkes, Fergus J Couch","doi":"10.1016/j.ajhg.2026.03.015","DOIUrl":"10.1016/j.ajhg.2026.03.015","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1122"},"PeriodicalIF":8.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525339","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":"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":"https://doi.org/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":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meta-analysis across six global biobanks identifies recessive coding associations with complex traits and diseases.","authors":"Frederik H Lassen, Georgios Kalantzis, Andrea Eoli, Barney Hill, Kyuto Sonehara, Shinichi Namba, Isaac Wade, Sam Hodgson, Wei Zhou, Benjamin M Neale, Konrad J Karczewski, Yukinori Okada, David A van Heel, Sarah Finer, Cecilia M Lindgren, Henrike O Heyne, Hilary C Martin, Duncan S Palmer","doi":"10.1016/j.ajhg.2026.04.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.04.005","url":null,"abstract":"<p><p>Rare bi-allelic variation is a major contributor to human disease risk, yet its effects are difficult to study at scale in population cohorts owing to the limited number of individuals with putatively deleterious bi-allelic genotypes and the challenges of accurately phasing low-frequency variants. Here, we present recessive, gene-based analyses of rare and low-frequency variants in up to 948,690 exome- or whole-genome-sequenced individuals across six biobanks with linked electronic health records. Through statistical phasing, we inferred putatively damaging compound-heterozygous genotypes, increasing the number of bi-allelic damaging genotypes by 19%. Restricting to predicted loss-of-function (pLoF) variants, we identified 5,563 genes harboring bi-allelic genotypes, a 19.8% increase in putative knockouts. We then considered all low-frequency variants (minor allele frequency [MAF] <5%) and performed gene-based recessive association testing using putatively damaging bi-allelic genotypes, identifying 58 significant associations (false discovery rate [FDR] ≤1% or p_rec≤7.5 × 10^-7) after meta-analysis and Cauchy combination of nonsynonymous annotations. Comparing recessive and additive models, we found 17 instances where recessive effects were more pronounced, including several previously unreported associations, such as HBB with heart failure (p_rec = 2.6 × 10^-14; p_add = 0.98), LECT2 with height (p_rec = 3.7 × 10^-14; p_add = 4.1 × 10^-10), and ENSG00000267561 with height (p_rec = 2.9 × 10^-9; p_add = 0.37). This study demonstrates the potential of federated approaches to study the effects of rare bi-allelic variation.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809537","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":"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":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}