American journal of human genetics最新文献

{"title":"Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders.","authors":"Julian Fuhrer, Alexey A Shadrin, Timothy Hughes, Nadine Parker, Guy Hindley, Evgeniia Frei, Dat Nguyen, Olav B Smeland, Srdjan Djurovic, Ole A Andreassen, Anders M Dale, Oleksandr Frei","doi":"10.1016/j.ajhg.2026.08.012","DOIUrl":"10.1016/j.ajhg.2026.08.012","url":null,"abstract":"<p><p>The genetic architecture of complex traits spans a continuum of polygenicity, yet it remains unclear how differences in polygenicity relate to the functional localization of SNP heritability across the genome. We use a MiXeR-based framework to partition heritability across 74 functional annotations covering exonic, intronic, and intergenic regions for 34 complex traits and introduce a likelihood-based annotation contribution score that quantifies annotation-specific impact on heritability. Exons account for a minority of heritability, and their contribution decreases with increasing polygenicity, from an average of 22% in less-polygenic somatic diseases and biomarkers to 13% in highly polygenic psychiatric and cognitive phenotypes. Intergenic fractions show the opposite trend, whereas intronic fractions remain relatively stable. Analysis of the broader set of functional annotations also reveals systematic differences along the polygenicity axis: highly polygenic traits show stronger contributions from comparative genomics and variant-effect scores, whereas less-polygenic traits show stronger contributions from promoter, transcription, and chromatin annotations. Together, these results indicate that the functional partitioning of heritability systematically varies with polygenicity, shifting from gene-proximal regulatory architectures to architectures shaped by numerous dispersed regulatory effects.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2055-2067"},"PeriodicalIF":7.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890729","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":"MMACHC burden variants are associated with higher circulating vitamin B12 in the All of Us cohort","authors":"Ling Cai,Ralph J. DeBerardinis","doi":"10.1016/j.ajhg.2026.08.015","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.015","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"8 1","pages":"2202-2204"},"PeriodicalIF":9.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090476","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":"This month in The Journal","authors":"Paul W. Hook,Alyson B. Barnes","doi":"10.1016/j.ajhg.2026.09.004","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.004","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"82 1","pages":"2023-2024"},"PeriodicalIF":9.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090478","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":"Integrating clinical diagnostics with interventional genetics for neurodevelopmental disorders.","authors":"Julia Macintosh, Khadijé Jizi, Ying Zhang, Charles-Olivier Martin, Malak Abuzgaya, Xin Zhang, Emily Ducharme, Andres Arriaga-Sierra, Huashan Peng, Anne-Marie Bélanger, Valérie K Fontaine, Chaoyi Gu, Anjie Ni, Basil Khan, Shaima Alsuwaidi, Peter Fleming, Amelia Semenak, Bavavarshini Tamilselvam, Yeqing Geng, Hooman Sadighian, Andrew G Ewing, Austen J Milnerwood, Guy A Rouleau, Jacques L Michaud, Sébastien Jacquemont, Carl Ernst","doi":"10.1016/j.ajhg.2026.09.006","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.006","url":null,"abstract":"<p><p>Interventional genetics (IG) refers to the development of therapies aimed at treating the underlying genetic cause of disease. Diagnostic sequencing has advanced to the point where genetic results can be returned within weeks, meaning that therapeutically actionable variants associated with specific diseases could be developed immediately after diagnosis. Here, we describe 81 probands with a neurodevelopmental disorder (NDD) and family matched controls with full genotype/phenotype information and biobanked stem cells, most of which are consented for sharing. We outline a rapid and scalable pipeline for induced pluripotent stem cell (iPSC) generation directly from clinical collection, without the need for peripheral blood mononuclear cell (PBMC) storage, paired with induction to neurons. We provide a proof of principle for rapid creation of oligonucleotide therapeutics for Kleefstra syndrome. This work introduces a cohort of individuals with NDDs and an implemental pipeline to integrate IG with clinical diagnostics for NDDs. This information documents our experience and provides useful details for clinical centers interested in integrating IG for NDDs with diagnostic sequencing.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102914","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":"Effect heterogeneity reveals complex pleiotropic effects of rare coding variants","authors":"Wenhan Lu, Siwei Chen, Chiara Auwerx, Jack Fu, Danielle Posthuma, Benjamin M. Neale, Luke J. O’Connor, Konrad J. Karczewski","doi":"10.1016/j.ajhg.2026.09.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.007","url":null,"abstract":"Recent expansion of large-scale biobank resources has enabled rare-variant association studies (RVASs) and systematic investigation of rare-variant pleiotropy across thousands of phenotypes simultaneously. However, existing statistical frameworks for dissecting pleiotropy were largely developed for common-variant association signals and are not well suited to gene-based rare-variant burden signals, limiting the interpretation of cross-phenotype associations. Here, we develop Allelic Spectrum of Pleiotropy Informed Correlated Effects (ALLSPICE), a likelihood-based method that tests whether rare coding variant effects in genes exhibiting cross-phenotype associations are proportional or heterogeneous across continuous traits while accounting for phenotypic correlation using summary statistics. ALLSPICE is well calibrated in simulations and is implemented as an R package for scalable analysis of gene-level rare-variant burden associations. We applied ALLSPICE to RVAS of 359 continuous traits in the UK Biobank and identified 124 significant heterogeneous events among 11,810 pairs of gene-trait associations. By identifying effect heterogeneity within genes associated with multiple phenotypes, ALLSPICE extends analysis of allelic heterogeneity to biobank-scale RVASs, clarifies shared and heterogeneous rare-variant architectures underlying cross-phenotype burden associations, and provides insight into rare-variant pleiotropy.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"16 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149085150","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":"Monoallelic variants in BRSK1 are associated with a neurodevelopmental disorder with or without epilepsy","authors":"Mingxi Deng,Mengqi Ma,Vanessa Andrea Gomez,Jinghan Zhao,Shenzhao Lu,Shabab Bin Hannan,Stephanie Baskin,Amjad Khan,Donald R. Latner,Susan M. Hiatt,Gregory M. Cooper,Michael J. Parker,Thomas Carroll,Saskia B. Wortmann,Johannes A. Mayr,Nicole J. Boczek,Kristen Rasmussen,Eva Kahn,Brendan Lanpher,Caroline Nava,Thomas Courtin,Mingxue Gu,Liwen Ma,Yun Zhao,Hirokazu Hashimoto,Shinya Yamamoto,Zhandong Liu,Joshua M. Shulman,The Community Texome,Michael F. Wangler,Hugo J. Bellen","doi":"10.1016/j.ajhg.2026.09.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.005","url":null,"abstract":"Brain-specific serine/threonine kinase (BRSK1; synapses of amphids defective [SAD]-B) encodes an AMP-activated protein kinase (AMPK)-related serine/threonine kinase required for neuronal polarization and synaptic function. An individual with a variant in BRSK1 was identified in the Texome Project, which provides genomic diagnosis to financially disadvantaged individuals in Texas, using AI-MARRVEL. We subsequently found nine individuals harboring rare heterozygous BRSK1 variants through GeneMatcher. Affected individuals present with developmental delay and variable phenotypes including anxiety, attention-deficit hyperactivity disorder (ADHD), autism, and seizures. All variants (missense and nonsense) are predicted to be deleterious by pathogenicity prediction tools. We utilized Drosophila to model three missense variants to assess the impact of the variants in vivo. We show that Drosophila sff (sugar-free frosting; ortholog of BRSK1) is expressed in neurons of the larval central nervous system (CNS) and adult brain. Loss of sff leads to viable flies with severe locomotor impairment, bang and heat sensitivity, and a short lifespan. In addition, the third-instar neuromuscular junctions (NMJs) in sff null mutants display a significant overgrowth, associated with elevated levels of Futsch (MAP1B), a microtubule-associated protein. Expression of the human reference BRSK1 cDNA in the sff null mutant rescues the behavioral, NMJ morphology, and Futsch phenotypes, showing that the human gene is functional in flies. In contrast, the three individual-derived alleles (BRSK1p.Ile202Val, BRSK1p.Arg237Cys, and BRSK1p.Thr406Ile) provide only a partial rescue and fail to normalize NMJ morphology and Futsch levels, suggesting that they are partial loss-of-function alleles. In summary, our data support a model that heterozygous loss of BRSK1 leads to a neurodevelopmental syndrome with variable phenotypes.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"40 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067343","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":"Genomic Analyses Reveal Mutational Signatures and Frequently Altered Genes in Esophageal Squamous Cell Carcinoma","authors":"Ling Zhang,Yong Zhou,Caixia Cheng,Heyang Cui,Le Cheng,Pengzhou Kong,Jiaqian Wang,Yin Li,Wenliang Chen,Bin Song,Fang Wang,Zhiwu Jia,Lin Li,Yaoping Li,Bin Yang,Jing Liu,Ruyi Shi,Yanghui Bi,Yanyan Zhang,Juan Wang,Zhenxiang Zhao,Xiaoling Hu,Jie Yang,Hongyi Li,Zhibo Gao,Gang Chen,Xuanlin Huang,Xukui Yang,Shengqing Wan,Chao Chen,Bin Li,Yongkai Tan,Longyun Chen,Minghui He,Sha Xie,Xiangchun Li,Xuehan Zhuang,Mengyao Wang,Zhi Xia,Longhai Luo,Jie Ma,Bing Dong,Jiuzhou Zhao,Yongmei Song,Yunwei Ou,Enming Li,Liyan Xu,Jinfen Wang,Yanfeng Xi,Guodong Li,Enwei Xu,Jianfang Liang,Xiaofeng Yang,Jiansheng Guo,Xing Chen,Yanbo Zhang,Qingshan Li,Lixin Liu,Yingrui Li,Xiuqing Zhang,Huanming Yang,Dongxin Lin,Xiaolong Cheng,Yongjun Guo,Jun Wang,Qimin Zhan,Yongping Cui","doi":"10.1016/j.ajhg.2026.09.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.012","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"150 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149019701","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":"Genetic data sharing by clinical laboratories in Canada: A position statement by the Canadian College of Medical Geneticists","authors":"Jordan Lerner-Ellis,Yael Fisher,Ma’n H. Zawati,Ronald Agatep,Nick Antonishyn,Ian Bosdet,Kym M. Boycott,Ian King,Ryan E. Lamont,Christian R. Marshall,Victor D. Martinez,Tanya N. Nelson,Darren O’Rielly,Stephen Yip,Barbara Shantz,Andrea Herscovich,E. Magda Price,Canadian College of Medical Geneticists,,Taila Hartley,Kathy Chun","doi":"10.1016/j.ajhg.2026.09.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.001","url":null,"abstract":"Next-generation sequencing has transformed diagnosis, prognosis, and treatment across rare disease, cancer, immunology, and infectious disease. As variant interpretation may evolve with emerging evidence, sharing genetic data is essential to improve diagnostic accuracy and advance genomic medicine. However, practical guidance for implementing clinical genetic data sharing remains limited. The Canadian College of Medical Geneticists (CCMG), therefore, developed national guidance to support secure, ethical, and effective genetic data sharing by Canadian clinical laboratories. An ad hoc CCMG working group with broad geographic and disciplinary representation developed the initial framework of this guidance through six meetings. Members included clinical laboratory geneticists, genomics specialists, a legal expert, a clinical geneticist, and a genetic counselor. The process drew on expert consensus (including patient and family perspectives), existing frameworks, and relevant peer-reviewed evidence, followed by iterative external review. Reporting was informed by the Appraisal of Guidelines for Research and Evaluation II (AGREE II) framework. The guidance provides recommendations to support genetic data sharing by Canadian clinical laboratories. It addresses benefits, risks, and ethical considerations, with emphasis on proportionality, privacy, and governance. Recommendations include approaches to sharing diverse genetic data types, establishing institutional policies, and addressing implementation barriers. This guidance aims to align Canadian clinical laboratory data-sharing practices with international standards and improve diagnostic accuracy, equity, and innovation in genomic medicine. By emphasizing ethical principles, proportionality, and governance, it seeks to enable responsible data sharing; strengthen trust among patients, families, and professionals; and contribute to the broader global genomic data ecosystem.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"24 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149013588","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":"Robust cis-by-trans epistasis in the human plasma proteome highlights an ABO-centered interaction network","authors":"Jinghui Li,Xuanyao Liu","doi":"10.1016/j.ajhg.2026.09.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.003","url":null,"abstract":"Detecting and interpreting epistatic effects in the human genome is essential for a complete understanding of the genetic architecture of gene regulation and complex traits. Progress in this area, however, has been hindered by limited discovery power and an abundance of false positives. Here, leveraging large-scale plasma proteomic data from the UK Biobank (UKB) Pharma Proteomics Project (PPP), we systematically map high-confidence cis-by-trans epistatic effects regulating protein expression. To reduce the multiple-testing burden, we focus on protein-level rather than variant-level interaction effects, and we employ a sandwich variance estimator to control false positives, as validated by extensive simulations. We applied the approach to identify cis-by-trans interactions across all proteins assayed in UKB-PPP and detected seven significant epistatic effects. Incorporating these interactions into protein-wide association studies is highly prone to false positives. We thus developed a principled framework but found that they offered little improvement in trait mapping power, likely because their effects on protein-expression variance are outweighed by additive effects. Analysis of the biological and evolutionary context of our detected epistatic interactions pointed to ABO as a central regulator that appears to modulate mean protein expression for several trans-chromosomal targets through its effects on blood type, potentially driving long-term balancing selection on loci within its epistatic network. Together, our results clarify both the biological relevance and the practical limitations of epistasis-aware analysis in human proteomic regulation.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"15 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149013589","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 rare recurring gain-of-function variant in BMPR2 causes neurodevelopmental phenotypes in humans and flies","authors":"Jung-Wan Mok,Carrie L. Welch,Haley A. Dostalik,Zhi Tan,Ariel Brautbar,Maria DesCartes,Erica T. Gray,Alejandro Iglesias,Scott D. McLean,Morgan Nutter,Olivia Daugherty,Amber Begtrup,Ingrid M. Wentzensen,Yufeng Shen,Damian W. Young,Martin M. Matzuk,Baylor College of Medicine Center for Precision Medicine Models,Oguz Kanca,Michael F. Wangler,Hugo J. Bellen,Wendy K. Chung,Shinya Yamamoto","doi":"10.1016/j.ajhg.2026.08.019","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.019","url":null,"abstract":"Bone morphogenetic protein receptor type 2 (BMPR2) encodes an evolutionarily conserved serine/threonine kinase that phosphorylates type-1 BMP receptors to mediate intercellular communication upon ligand binding. Loss-of-function variants in BMPR2 are known to cause pulmonary arterial hypertension and other cardiovascular disorders. Here, we report a rare recurrent missense variant in BMPR2 (c.1126G>A [GenBank: NM_001204] [p.Glu376Lys]) identified in six individuals, who all present with neurodevelopmental phenotypes including autism spectrum disorder and global developmental delay. Trio analysis demonstrates de novo occurrence of this variant in at least five of the individuals. Using the fruit fly Drosophila melanogaster, we show that this variant behaves as a gain-of-function allele that acts in a ligand-independent but type-1 BMP receptor-dependent manner. BMPR2-specific inhibitors suppress excessive BMP activation induced by p.Glu376Lys variant expression in Drosophila, demonstrating its hypermorphic property. Finally, we show that this variant causes neurodevelopmental defects in flies when expressed in neurons or glial cells. Given that BMPR2 is expressed in various neural cell types in the human brain, ectopic activation of BMP signaling in multiple cell types is likely to contribute to the neurodevelopmental phenotypes observed in the probands.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"46 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149010172","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}