American journal of human genetics最新文献

{"title":"Genome-wide association study and predictors of neonatal blood cell traits in Hispanic newborns.","authors":"Yunqi Li,Benjamin Alonzo,Zixuan E Zhang,Jalen Langie,Swe Swe Myint,Michaela Ince,Rong Lu,Charleston W K Chiang,Steven Gazal,Nicholas Mancuso,Linda Kachuri,Adam J de Smith","doi":"10.1016/j.ajhg.2026.06.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.008","url":null,"abstract":"The role of heritable genetic variation in hematologic traits in adults is well established, yet the genetic architecture of neonatal blood cell traits is unknown. Leveraging flow cytometry profiling in cord blood samples from 382 Hispanic newborns, we conducted genome-wide association studies (GWASs) of 24 blood cell phenotypes to assess the impact of genetic and birth-related characteristics. We identified six genome-wide significant loci, including a signal at chromosome 2p11.2 spanning CD8A and CD8B that was associated with CD4+CD8+ double-positive T cells (rs35505884-C: p = 6.83 × 10-26). The lead variant showed strongly differentiated allele frequencies between European (22.1%) and admixed American (11.8%) populations and was associated with global (p = 2.51 × 10-6) and local (p = 2.01 × 10-8) Indigenous American ancestry. Colocalization with single-cell expression quantitative trait loci (eQTLs) revealed convergence of GWAS effects with regulation of CD8A expression in natural killer cells and CD4+ effector memory T cells with posterior probability (PPH4) >0.85. A locus at 6p21.33 was associated with CD4-CD8+ cytotoxic T cells (rs2853973-C, p = 3.90 × 10-8) and colocalized with MICA-AS1 expression across multiple immune cell types (PPH4 > 0.85). Additional nominal genome-wide significant loci were detected for total CD45+ lymphocytes, CD19+CD56+CD16+ natural killer cells, and CD4+CD8- helper T cells. C-section delivery and biological sex significantly altered blood cell profiles, with the largest magnitudes of association observed between C-section and total CD3+ T cells (β = 0.39) and CD4+ helper T cells (β = 0.39), and between female sex and CD4+CD8- (β = 0.39) and CD4-CD8+ T cells (β = -0.36). Our study demonstrates that blood cell composition at birth is under strong genetic regulation in Hispanic newborns, highlighting the value of studying complex traits in early life.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"62 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148365101","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":"Linkage disequilibrium and allelic heterogeneity explain variation in coronary artery disease risk at 9p21 across populations and reduced effect in Africans.","authors":"Hasan Alkhairo,Satoshi Koyama,Kruthika Iyer,Austin T Hilliard,Pik Fang Kho,Shoa Clarke,Firdous M Abdulwahab,Themistocles L Assimes,Julie A Lynch,Michèle Ramsay, , ,Kyong-Mi Chang,Philip S Tsao,Fowzan S Alkuraya,Kaoru Ito,Neil Risch,Catherine Tcheandjieu","doi":"10.1016/j.ajhg.2026.06.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.007","url":null,"abstract":"Locus 9p21.3 was the first genome-wide significant locus for coronary artery disease (CAD) and replicates across multiple non-African populations, yet it is absent in African-ancestry cohorts. We analyzed multi-ancestry data from European, East Asian, South Asian, Middle Eastern, African, and admixed American groups. Ancestry was inferred using both global and local-ancestry inference (LAI) approaches. Within each ancestry, we performed CAD associations at 9p21.3 with common and rare variants, conditional and haplotype analyses, and pleiotropy assessments. CAD associations at 9p21.3 were robust in European, East Asian, Middle Eastern, and admixed American ancestry groups, nominal in South Asians, and absent in Africans despite similar allele frequencies for lead-associated SNPs. LAI-stratified analyses showed strong signals in African heterozygotes carrying 9p21.3 European chromosomes but not in homozygous Africans. The association is due to highly common variants; rare variants did not explain the locus signal. Linkage disequilibrium (LD) blocks were extended in non-Africans but fragmented into smaller blocks in Africans. Fine-mapping identified multiple independent signals, including an East Asian-specific haplotype absent in Europeans and Africans. Hamming-distance analyses revealed that risk alleles are dispersed across multiple haplotypes in homozygous-African groups. Phenome-wide association study (PheWAS) mirrored these ancestry-specific patterns across metabolic traits. The non-replication of 9p21.3 in African ancestry is not due to absent risk alleles, reduced power, or poorer imputation of risk alleles due to weaker LD; rather, it reflects greater haplotype diversity that disperses risk alleles across configurations, attenuating case-control contrast. These findings illustrate how ancestry-specific LD and multi-causal haplotype architecture modulate association detectability.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"54 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148365155","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":"Comparison of methods for assessing effects of risk factors on disease progression in Mendelian randomization under index event bias.","authors":"Linxuan Zhang,Ixavier Alonzo Higgins,Qile Dai,Apostolos Gkatzionis,Jocelyn Quistrebert,Nasir Bashir,Gopuraja Dharmalingam,Pallav Bhatnagar,Dipender Gill,Yushi Liu,Stephen Burgess","doi":"10.1016/j.ajhg.2026.06.004","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.004","url":null,"abstract":"Mendelian randomization has emerged as a transformative approach for inferring causal relationships between risk factors and disease outcomes. However, applying Mendelian randomization to disease progression-a critical step in validating therapeutic targets-is hampered by index event bias. This form of selection bias occurs because analyses of disease progression are necessarily restricted to individuals who have already experienced the disease event. Here, we present a comprehensive evaluation of statistical methods designed to mitigate index event bias, including inverse-probability weighting, Heckman's method, the Slope-Hunter method, and multivariable methods. We compare their performance in simulations and applied examples. Inverse-probability weighting methods reduce bias but require individual-level data and will only fully eliminate bias when the disease event model is correctly specified. The Slope-Hunter method performed poorly in all simulation scenarios, even when its assumptions were fully satisfied. Multivariable methods worked best when including genetic variants that affect the incident disease event. However, if these genetic variants also affect disease progression directly, then the analysis will suffer from pleiotropy. Hence, if the same biological mechanisms affect disease incidence and progression, then multivariable methods will have little utility. In such a case, however, analyses of disease progression are less critical, as conclusions reached from analyses of disease incidence are likely to hold for disease progression. Our findings indicate that no single method is a universal solution to provide reliable results for the investigation of disease progression. Instead, we propose a strategic framework for method selection based on data availability and biological context.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"29 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148348924","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":"Deciding \"what\" to screen for and \"when\": The importance of natural history information.","authors":"Jahnelle Jackson,Jonathan S Berg","doi":"10.1016/j.ajhg.2026.06.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.06.001","url":null,"abstract":"Genomic medicine promises to leverage research on human genetic variation to improve health. As technology improves, our increasing ability to determine an individual's genomic sequence must be matched with increased understanding of underlying mechanisms of disease and how phenotypes arise because of genetic variation. Knowledge about the etiology of rare monogenic conditions can be leveraged for medical and public health purposes through diagnostic testing and predictive screening. However, policy decisions about the use of genetic and genomic analysis in a predictive setting must consider the penetrance and expressivity of each monogenic condition and how these factors influence the timing of genomic screening and its potential benefits and harms. This means that high-quality data are required on the nature of genetic diseases and how they impact human health across populations. The objective of this paper is to address the inherent challenges in determining the onset of symptoms for rare monogenic conditions and underscore the importance of curating natural history data. By elucidating the natural progression of rare monogenic conditions, we can optimize screening strategies and guide clinical decision-making. Detailed information about natural history is critical to understanding the optimal timing of population screening and subsequent intervention for any given condition.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"9 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148304940","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":"Homologous recombination deficiency-driven genomic instability in ovarian cancer as an indicator of BRCA1 and BRCA2 variant pathogenicity.","authors":"Simon Schnaiter,Frédéric R Santer,Katalin A Csanaky,Louise Adel Jensen,Alain G Zeimet,Kyriaki Michailidou,Amanda B Spurdle,Mads Thomassen","doi":"10.1016/j.ajhg.2026.05.015","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.05.015","url":null,"abstract":"Homologous recombination deficiency (HRD) drives oncogenesis and therapeutic vulnerability in high-grade ovarian cancer (HGOC). While HRD testing is widely used to guide platinum- and especially poly(ADP-ribose) polymerase (PARP)-inhibitor-based therapies, its potential to provide evidence for BRCA1 and BRCA2 variant classification under the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) framework has not been assessed. In this Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium project, a literature review identified four independent HGOC cohorts reporting details on both BRCA1 and BRCA2 pathogenic variant (BRCApv) status and HRD-related genomic instability scores (HRD-GISs), all determined by the Myriad MyChoice HRD+ CDx assay. Likelihood ratios (LRs) were calculated to assess the probability that a BRCA1 or BRCA2 variant is pathogenic with a given HRD-GIShigh (≥42) or HRD-GISlow (<42) tumor status, and these LRs were mapped to ACMG/AMP evidence strength categories defined by Bayesian modeling. Across the pooled dataset of 4,943 tumors (765 BRCApv and 4,178 BRCA1 or BRCA2 wild type [BRCAwt]), 91.0% of BRCApv and 30.0% of BRCAwt tumors were HRD-GIShigh. The LR for a BRCA1 or BRCA2 variant being pathogenic in an HRD-GIShigh HGOC was 3.03 (95% confidence interval [CI]: 2.88-3.19), corresponding to supporting pathogenic evidence. Conversely, the pooled LR for a variant being pathogenic in an HRD-GISlow HGOC was 0.13 (95% CI: 0.10-0.16), corresponding to moderate benign evidence. The HGOC HRD-GIS determined by the MyChoice HRD+ CDx assay provides statistically robust evidence for BRCA1 and BRCA2 variant interpretation. This approach may refine variant classification, particularly for variants of uncertain significance, and enhance clinical decision-making in hereditary and tumor-based cancer risk assessment.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"35 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148304949","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 social determinants of health and genetic risk in disease risk models.","authors":"Abhijith Biji,Kathleen Ferar,Vikas Pejaver,Eimear E Kenny,Bian Liu,Samira Asgari","doi":"10.1016/j.ajhg.2026.05.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.05.014","url":null,"abstract":"Complex diseases are shaped by heritable factors and non-genetic environmental, behavioral, and social determinants of health, but these are rarely modeled together. The growing availability of large-scale, multimodal biobanks creates new opportunities to integrate diverse data types into more accurate disease risk models. Here, we apply multiple correspondence analysis (MCA) to over 100 environmental, behavioral, and social variables from the All of Us biobank (n = 413,457 individuals) to generate low-dimensional embeddings that quantify non-genetic risk for six common chronic conditions: asthma, chronic kidney disease, coronary heart disease, hypercholesterolemia, prostate cancer, and breast cancer. These embeddings recovered known risk factors such as economic status and smoking but also pointed to others such as loneliness and spirituality. Including MCA axes in addition to demographics and polygenic scores (PGSs) consistently improved disease-risk prediction, with improvement in area under the receiver operating characteristic curve (ΔROC-AUC) ranging from 0.007 to 0.027. For four of six diseases, the gains in model predictive power from MCA embeddings surpassed those attributable to PGS. Genetic and non-genetic risks combined additively, with little evidence of interaction effects (ΔROC-AUC ≤ 0.001) and highly stable variant effect sizes when embeddings were included in genetic association models (r > 0.98). In summary, we introduce a scalable, interpretable framework that summarizes survey-based environmental, behavioral, and social factors without prior assumptions about disease-specific variables. Our results demonstrate that these non-genetic contexts improve prediction but show limited evidence of interaction with genome-wide polygenic disease risk. Our results underscore the importance of incorporating social, behavioral, and environmental factors into clinical models of disease risk.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"277 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148299195","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":"Individuals who deviate from polygenic expectation are enriched for damaging variants in genes linked to rare disease.","authors":"Nikolas A Baya,Frederik H Lassen,Barney Hill,Samvida S Venkatesh,Hannah Currant,Cecilia M Lindgren,Duncan S Palmer","doi":"10.1016/j.ajhg.2026.05.013","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.05.013","url":null,"abstract":"Polygenic scores (PGSs) stratify disease risk but often fail to capture individual variation. \"Misaligned\" individuals, whose observed phenotypes deviate from their genetically expected values based on PGS, provide a powerful model for identifying factors beyond common-variant effects, including additional genetic factors. Here, we apply misalignment classification and enrichment testing frameworks to seven continuous traits and three diseases, assessing whether misaligned individuals in the UK Biobank are enriched for rare (minor-allele frequency [MAF] <0.1%) damaging genetic variation. We identified significant enrichment of predicted loss-of-function (pLoF) variants in COPB2 and GORAB among individuals with lower-than-expected bone mineral density. Regarding stature, shorter-than-expected individuals were enriched for pLoF variants in ACAN and IGF1, while taller-than-expected individuals showed enrichment for damaging missense variants in FBN1. Transitioning from validation to discovery, we performed an exome-wide scan for genes associated with misalignment and identified 74 significant genes, including KANK1, a gene which may have a protective role against primary ovarian insufficiency, and ACSL6, a lipid metabolism gene where damaging missense variation was associated with lower-than-expected BMI. For diseases, results supported a liability threshold model involving counteracting common and rare variant effects. Diagnosed type 2 diabetes mellitus patients with rare pathogenic variants in HNF1A and HNF4A possessed significantly lower polygenic risk than those without. Conversely, coronary artery disease controls harboring protective ANGPTL3 variants had nominally higher polygenic risk. This study highlights the power of misalignment-based analyses in complex continuous phenotypes and disease with the potential to validate known genetic contributors to traits and identify previously unassociated genes.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"30 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148299193","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":"Genetics of skeletal proportions across two different populations.","authors":"Eric Bartell, Kuang Lin, Kristin Tsuo, Wei Gan, Sailaja Vedantam, Joanne B Cole, John M Baronas, Loic Yengo, Eirini Marouli, Tiffany Amariuta, Zhengming Chen, Liming Li, Nora E Renthal, Christina M Jacobsen, Rany M Salem, Robin G Walters, Joel N Hirschhorn","doi":"10.1016/j.ajhg.2026.05.004","DOIUrl":"10.1016/j.ajhg.2026.05.004","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1364"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980252","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":"Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly.","authors":"Robin Wijngaard, Caspar I van der Made, Sema Kalkan Uçar, Gayatri Ramakrishnan, Man Wang, Johannes Brand, Jill A Rosenfeld, Tiphanie P Vogel, Sarah K Nicholas, Monika Weisz-Hubshman, Clara D M van Karnebeek, Eric J Allenspach, Taylor E Gardiner, Sumudu Perera Kimmantudawage, Zornitza Stark, Ruth K Armstrong, Janine Campbell, Stefano Volpi, Enrico Drago, Marco Gattorno, Alice Grossi, Isabella Ceccherini, Alfredo Cabrera-Orefice, Bente Siebels, Thomas Mair, Hartmut Schlüter, Ruben L Smeets, Ronald van Beek, Ingrid Goebel, Katrin Küchler, Søren W Gersting, Alexander Hoischen, Lisenka E L M Vissers, Ron A Wevers, Catherine Meyer-Schwesinger, Saskia B Wortmann, Machteld M Oud, Sergio Guerrero-Castillo","doi":"10.1016/j.ajhg.2026.04.015","DOIUrl":"10.1016/j.ajhg.2026.04.015","url":null,"abstract":"<p><p>Monoallelic variants in catalytic immunoproteasome subunits have recently been linked to proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID), yet their molecular mechanisms and clinical spectra are not fully defined. In this study, seven individuals from five unrelated families carrying five distinct monoallelic PSMB8 variants were identified. Individuals presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Additional findings included leukocyte vacuolization in blood and bone marrow. Pathogenic variants in immunoproteasome subunits were analyzed to identify structural features associated with dominant-negative behavior. Immunoproteasome assembly and activity were investigated using complexome profiling, immunoblotting, and in-gel activity assays in proband-derived fibroblasts and transfected HEK293T cells, with downstream effects assessed by proteomic and RT-qPCR analyses. Mutant PSMB8 subunits were inefficiently incorporated into immunoproteasome complexes, leading to impaired assembly, including reduced fully assembled complexes and accumulation of assembly intermediates. This defect was accompanied by activation of the integrated stress response alongside impaired immune signaling. Monoallelic pathogenic variants in PSMB8, PSMB9, and PSMB10 associated with PRAAS-ID affected residues that are highly conserved and biophysically similar between the three immunoproteasome catalytic subunits. These shared structural features may help identify additional variants with similar disruptive effects on immunoproteasome assembly. Together, our data show that monoallelic PSMB8 variants disrupt immunoproteasome assembly, resulting in clinically variable disease with immunodeficiency and systemic inflammation. Our findings support immunoproteasome assembly disruption as a unifying dominant-negative mechanism underlying PRAAS-ID.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1214-1232"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986096","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 phenome-wide association study of CNVs genotyped from genome sequencing read depth in the UK Biobank.","authors":"Paras Garg, Bharati Jadhav, Mariya Shadrina, Alejandro Martin-Trujillo, Andrew J Sharp","doi":"10.1016/j.ajhg.2026.04.013","DOIUrl":"10.1016/j.ajhg.2026.04.013","url":null,"abstract":"<p><p>We developed a read-depth-based approach that allows accurate and scalable copy-number genotyping from genome sequencing data, including mosaic, recurrent, and multiallelic copy-number variants (CNVs) that are difficult to genotype using other methods. We genotyped each 5-kb segment throughout the genome in the UK Biobank cohort and performed phenome-wide association studies (PheWASs) using 13,215 traits under three different association models, identifying 501 CNVs associated with 1,537 traits. Of these, almost 75% were not found by comparable single-nucleotide variant (SNV)-based PheWASs. We detected signals with multiallelic CNVs, including a coding repeat within MUC1 (mucin 1, cell-surface associated) associated with stomach/duodenal polyps (p = 7.7 × 10^-24), copy number of AMY1 (amylase alpha) genes associated with denture use (p = 2.4 × 10^-29), and a multiallelic coding CNV within NEB, encoding muscle sarcomere protein, associated with muscle mass (p = 9.7 × 10^-24). We also identified intergenic CNVs with effects on traits known to be regulated by nearby genes. For example, carriers of rare non-coding deletions ∼100 kb upstream of MC4R, coding mutations in which are the most common cause of monogenic obesity, were, on average, ∼14 kg heavier than control subjects. In some cases, non-coding CNVs encompassed regulatory elements of the adjacent candidate gene. Using burden tests, we identified an excess of rare damaging non-coding SNVs within some of these regulatory elements associated with the same traits observed in CNV carriers. Our study provides a detailed map of functional CNVs, including complex loci that are recalcitrant to other methods, providing numerous insights into their effects on human traits.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1297-1318"},"PeriodicalIF":7.7,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13241002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}