American journal of human genetics最新文献

Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions.

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2025-04-03 Epub Date: 2025-03-07 DOI: 10.1016/j.ajhg.2025.02.011

Suraj Upadhya, Jenny A Klein, Anna Nathanson, Kristina M Holton, Lindy E Barrett

{"title":"Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions.","authors":"Suraj Upadhya, Jenny A Klein, Anna Nathanson, Kristina M Holton, Lindy E Barrett","doi":"10.1016/j.ajhg.2025.02.011","DOIUrl":"10.1016/j.ajhg.2025.02.011","url":null,"abstract":"Interindividual variation in phenotypic penetrance and severity is found in many neurodevelopmental conditions, although the underlying mechanisms remain largely unresolved. Within individuals, homogeneous cell types (i.e., genetically identical and in similar environments) can differ in molecule abundance. Here, we investigate the hypothesis that neurodevelopmental conditions can drive increased variability in gene expression, not just differential gene expression. Leveraging independent single-cell and single-nucleus RNA sequencing datasets derived from human brain-relevant cell and tissue types, we identify a significant increase in gene expression variability driven by the autosomal aneuploidy trisomy 21 (T21) as well as autism-associated chromodomain helicase DNA binding protein 8 (CHD8) haploinsufficiency. Our analyses are consistent with a global and, in part, stochastic increase in variability, which is uncoupled from changes in transcript abundance. Highly variable genes tend to be cell-type specific with modest enrichment for repressive H3K27me3, while least variable genes are more likely to be constrained and associated with active histone marks. Our results indicate that human neurodevelopmental conditions can drive increased gene expression variability in brain cell types, with the potential to contribute to diverse phenotypic outcomes. These findings also provide a scaffold for understanding variability in disease, essential for deeper insights into genotype-phenotype relationships.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"876-891"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584357","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}

引用次数: 0

Variability in proliferative and migratory defects in Hirschsprung disease-associated RET pathogenic variants.

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2025-04-03 Epub Date: 2025-02-25 DOI: 10.1016/j.ajhg.2025.02.004

Lauren E Fries, Sree Dharma, Aravinda Chakravarti, Sumantra Chatterjee

{"title":"Variability in proliferative and migratory defects in Hirschsprung disease-associated RET pathogenic variants.","authors":"Lauren E Fries, Sree Dharma, Aravinda Chakravarti, Sumantra Chatterjee","doi":"10.1016/j.ajhg.2025.02.004","DOIUrl":"10.1016/j.ajhg.2025.02.004","url":null,"abstract":"Hirschsprung disease (HSCR) exhibits extensive genetic heterogeneity, with 72% of cases involving pathogenic variants in 10 genes forming a gene regulatory network (GRN) essential for enteric nervous system (ENS) development. The receptor tyrosine kinase gene RET is the most significant contributor, implicated in 12%-50% of individuals depending on the phenotype. RET plays a critical role in ENS precursor proliferation and migration, and defects in these processes lead to HSCR. However, the functional impact of RET pathogenic variants and their mechanisms of disease remain poorly understood. To address this, we investigated proliferative and migratory phenotypes in a RET-dependent neural crest-derived cell line harboring one of five missense (c.166C>A [p.Leu56Met]; c.532G>C [p.Glu178Gln]; c.2372A>T [p.Tyr791Phe]; c.2765C>A [p.Ser922Tyr]; or c.2994T>A [p.Phe998Leu]) or three nonsense (c.612C>A, c.2308C>T, or c.2943C>G) heterozygous pathogenic RET variants. Using cDNA- and CRISPR-based prime reverse insertion mechanism engineering (PRIME) editing coupled with quantitative proliferation and migration assays, we observed significant losses in proliferation and migration in three missense (c.612C>A [p.Tyr204∗]; c.2308C>T [p.Arg770∗]; and c.2943C>G [p.Tyr981∗]) and all nonsense variants. Notably, the c.2372A>T (p.Tyr791Phe) missense variant, whose pathogenicity has been debated, appears benign. Importantly, the severity of migration loss did not consistently correlate with proliferation defects, and the phenotypic severity of nonsense variants was independent of their position within the RET protein. This study highlights the necessity of targeted functional assays to accurately assess the pathogenicity of HSCR-associated variants rather than relying solely on bioinformatics predictions, which could be refined by incorporating functional data.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"863-875"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514245","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}

引用次数: 0

Human leukocyte antigen variation is associated with cytomegalovirus serostatus in healthy individuals.

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2025-04-03 Epub Date: 2025-03-05 DOI: 10.1016/j.ajhg.2025.02.007

Juliano A Boquett, Jürgen Sauter, Alexander H Schmidt, Martin Maiers, Jill A Hollenbach

{"title":"Human leukocyte antigen variation is associated with cytomegalovirus serostatus in healthy individuals.","authors":"Juliano A Boquett, Jürgen Sauter, Alexander H Schmidt, Martin Maiers, Jill A Hollenbach","doi":"10.1016/j.ajhg.2025.02.007","DOIUrl":"10.1016/j.ajhg.2025.02.007","url":null,"abstract":"Cytomegalovirus (CMV) is a common β-herpes virus worldwide with an estimated seroprevalence among the general population of 83%. Primary infection is usually benign; however, CMV can cause severe morbidity in newborns in whom it is acquired congenitally, as well as immunocompromised individuals. Understanding the role of immunogenetic variation in risk for CMV infection can provide insight into the immune control of this ubiquitous pathogen. Here, we evaluated the association of human leukocyte antigen (HLA) genetic variation with CMV seropositivity in more than 518,000 individuals from two independent cohorts. We found three HLA class II alleles (HLA-DRB1∗04:03 with risk; HLA-DRB1∗01:03 and HLA-DRB1∗07:01 with protection) to be significantly associated with CMV serostatus across both cohorts and in multiple population subgroups. Interestingly, HLA-DRB1∗04:03 and HLA-DRB1∗01:03, the alleles with the strongest observed effect, are relatively rare, while common homologous alleles show no association with CMV. We show that these differences are mediated by changes in charge and volume to two key pockets in the peptide-binding groove of the HLA molecule, providing a structural basis for the observed association. Our results provide population-scale evidence for the role of HLA in mediating infection with this ubiquitous human virus and a framework for understanding immunological conditions necessary for efficient viral control.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"913-926"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571872","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}

引用次数: 0

Actionable genetic variants in 4,198 Scottish participants from the Orkney and Shetland founder populations and implementation of return of results.

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2025-04-03 Epub Date: 2025-03-14 DOI: 10.1016/j.ajhg.2025.02.018

Shona M Kerr, Lucija Klaric, Marisa D Muckian, Kiera Johnston, Camilla Drake, Mihail Halachev, Emma Cowan, Lesley Snadden, John Dean, Sean L Zheng, Prisca K Thami, James S Ware, Gannie Tzoneva, Alan R Shuldiner, Zosia Miedzybrodzka, James F Wilson

{"title":"Actionable genetic variants in 4,198 Scottish participants from the Orkney and Shetland founder populations and implementation of return of results.","authors":"Shona M Kerr, Lucija Klaric, Marisa D Muckian, Kiera Johnston, Camilla Drake, Mihail Halachev, Emma Cowan, Lesley Snadden, John Dean, Sean L Zheng, Prisca K Thami, James S Ware, Gannie Tzoneva, Alan R Shuldiner, Zosia Miedzybrodzka, James F Wilson","doi":"10.1016/j.ajhg.2025.02.018","DOIUrl":"10.1016/j.ajhg.2025.02.018","url":null,"abstract":"The benefits of returning clinically actionable genetic results to participants in research cohorts are accruing, yet such a genome-first approach is challenging. Here, we describe the implementation of return of such results in two founder populations from Scotland. Between 2005 and 2015, we recruited >4,000 adults with grandparents from Orkney and Shetland into the Viking Genes research cohort. The return of genetic data was not offered at baseline, but in 2023, we sent invitations to participants for consent to return of actionable genetic findings. We generated exome sequence data from 4,198 participants and used the American College of Medical Genetics and Genomics (ACMG) v.3.2 list of 81 genes, ClinVar review, and pathogenicity status, plus manual curation, to develop a pipeline to identify potentially actionable variants. We identified 104 individuals (2.5%) with 108 actionable genotypes at 39 variants in 23 genes and validated these. Working with the NHS Clinical Genetics service, which provided genetic counseling and clinical verification of the research results, and after expert clinical review, we notified 64 consenting participants (or their next of kin) of their actionable genotypes. Ten actionable variants across seven genes (BRCA1, BRCA2, ATP7B, TTN, KCNH2, MUTYH, and GAA) have risen 50- to >3,000-fold in frequency through genetic drift in ancestral island localities. Viking Genes is one of the first UK research cohorts to return actionable findings, providing an ethical and logistical exemplar of return of results. The genetic structure in the Northern Isles of Scotland with multiple founder effects provides a unique opportunity for a tailored approach to disease prevention through genetic screening.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"793-807"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633352","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}

引用次数: 0

Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2025-04-03 Epub Date: 2025-03-04 DOI: 10.1016/j.ajhg.2025.02.005

Huw B Thomas, Leigh A M Demain, Alfredo Cabrera-Orefice, Isabelle Schrauwen, Hanan E Shamseldin, Alessandro Rea, Thashi Bharadwaj, Thomas B Smith, Monika Oláhová, Kyle Thompson, Langping He, Namanpreet Kaur, Anju Shukla, Musaad Abukhalid, Muhammad Ansar, Sakina Rehman, Saima Riazuddin, Firdous Abdulwahab, Janine M Smith, Zornitza Stark, Hanifenur Mancilar, Sait Tumer, Fatma N Esen, Eyyup Uctepe, Vehap Topcu, Ahmet Yesilyurt, Erum Afzal, Mehri Salari, Christopher Carroll, Giovanni Zifarelli, Peter Bauer, Deniz Kor, Fatma D Bulut, Henry Houlden, Reza Maroofian, Samantha Carrera, Wyatt W Yue, Kevin J Munro, Fowzan S Alkuraya, Peter Jamieson, Zubair M Ahmed, Suzanne M Leal, Robert W Taylor, Ilka Wittig, Raymond T O'Keefe, William G Newman

{"title":"Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.","authors":"Huw B Thomas, Leigh A M Demain, Alfredo Cabrera-Orefice, Isabelle Schrauwen, Hanan E Shamseldin, Alessandro Rea, Thashi Bharadwaj, Thomas B Smith, Monika Oláhová, Kyle Thompson, Langping He, Namanpreet Kaur, Anju Shukla, Musaad Abukhalid, Muhammad Ansar, Sakina Rehman, Saima Riazuddin, Firdous Abdulwahab, Janine M Smith, Zornitza Stark, Hanifenur Mancilar, Sait Tumer, Fatma N Esen, Eyyup Uctepe, Vehap Topcu, Ahmet Yesilyurt, Erum Afzal, Mehri Salari, Christopher Carroll, Giovanni Zifarelli, Peter Bauer, Deniz Kor, Fatma D Bulut, Henry Houlden, Reza Maroofian, Samantha Carrera, Wyatt W Yue, Kevin J Munro, Fowzan S Alkuraya, Peter Jamieson, Zubair M Ahmed, Suzanne M Leal, Robert W Taylor, Ilka Wittig, Raymond T O'Keefe, William G Newman","doi":"10.1016/j.ajhg.2025.02.005","DOIUrl":"10.1016/j.ajhg.2025.02.005","url":null,"abstract":"Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"952-962"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565789","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}

引用次数: 0

Opportunities and challenges of local ancestry in genetic association analyses.

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2025-04-03 DOI: 10.1016/j.ajhg.2025.03.004

Quan Sun, Andrea R V R Horimoto, Brian Chen, Frank Ockerman, Karen L Mohlke, Elizabeth Blue, Laura M Raffield, Yun Li

{"title":"Opportunities and challenges of local ancestry in genetic association analyses.","authors":"Quan Sun, Andrea R V R Horimoto, Brian Chen, Frank Ockerman, Karen L Mohlke, Elizabeth Blue, Laura M Raffield, Yun Li","doi":"10.1016/j.ajhg.2025.03.004","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.004","url":null,"abstract":"Recently, admixed populations make up an increasing percentage of the US and global populations, and the admixture is not uniform over space or time or across genomes. Therefore, it becomes indispensable to evaluate local ancestry in addition to global ancestry to improve genetic epidemiological studies. Recent advances in representing human genome diversity, coupled with large-scale whole-genome sequencing initiatives and improved tools for local ancestry inference, have enabled studies to demonstrate that incorporating local ancestry information enhances both genetic association analyses and polygenic risk predictions. Along with the opportunities that local ancestry provides, there exist challenges preventing its full usage in genetic analyses. In this review, we first summarize methods for local ancestry inference and illustrate how local ancestry can be utilized in various analyses, including admixture mapping, association testing, and polygenic risk score construction. In addition, we discuss current challenges in research involving local ancestry, both in terms of the inference itself and its role in genetic association studies. We further pinpoint some future study directions and methodology development opportunities to help more effectively incorporate local ancestry in genetic analyses. It is worth the effort to pursue those future directions and address these analytical challenges because the appropriate use of local ancestry estimates could help mitigate inequality in genomic medicine and improve our understanding of health and disease outcomes.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 4","pages":"727-740"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787520","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}

引用次数: 0

Multiple origins and phenotypic implications of an extended human pseudoautosomal region shown by analysis of the UK Biobank.

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2025-04-03 Epub Date: 2025-02-20 DOI: 10.1016/j.ajhg.2025.01.026

Nitikorn Poriswanish, James Eales, Xiaoguang Xu, David Scannali, Rita Neumann, Jon H Wetton, Maciej Tomaszewski, Mark A Jobling, Celia A May

{"title":"Multiple origins and phenotypic implications of an extended human pseudoautosomal region shown by analysis of the UK Biobank.","authors":"Nitikorn Poriswanish, James Eales, Xiaoguang Xu, David Scannali, Rita Neumann, Jon H Wetton, Maciej Tomaszewski, Mark A Jobling, Celia A May","doi":"10.1016/j.ajhg.2025.01.026","DOIUrl":"10.1016/j.ajhg.2025.01.026","url":null,"abstract":"The 2.7-Mb major pseudoautosomal region (PAR1) on the short arms of the human X and Y chromosomes plays a critical role in meiotic sex chromosome segregation and male fertility and has been regarded as evolutionarily stable. However, some European Y chromosomes belonging to Y haplogroups (Y-Hgs) R1b and I2a carry an ∼115-kb extension (ePAR [extended PAR]) arising from X-Y non-allelic homologous recombination (NAHR). To investigate the diversity, history, and dynamics of ePAR formation, we screened for its presence, and that of the predicted reciprocal X chromosome deletion, among ∼218,300 46,XY males of the UK Biobank (UKB), a cohort associated with longitudinal clinical data. The UKB incidence of ePAR is ∼0.77%, and that of the deletion is ∼0.02%. We found that Y-Hg I2a sub-lineages accounted for nearly 90% of ePAR cases but, by Y haplotyping and breakpoint sequencing, determined that, in total, there have been at least 18 independent ePAR origins, associated with nine different Y-Hgs. We found examples of ePAR linked to Y-Hg K among men of self-declared Pakistani ancestry and Y-Hg E1, typical of men with African ancestry, showing that ePAR is not restricted to Europeans. ePAR formation is likely random, with high frequencies in some Y-Hgs arising through drift and male-mediated expansions. Sequencing recombination junction fragments identified likely reciprocal events, and the heterogeneity of ePAR and X-deletion junctions highlighted the recurrent nature of the NAHR events. A phenome-wide association study revealed an association between ePAR and elevated levels of circulating IGF-1 as well as musculoskeletal phenotypes.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"927-939"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472250","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}

引用次数: 0

Clinical validation of RNA sequencing for Mendelian disorder diagnostics.

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2025-04-03 Epub Date: 2025-03-04 DOI: 10.1016/j.ajhg.2025.02.006

Sen Zhao, Kristina Macakova, Jefferson C Sinson, Hongzheng Dai, Jill Rosenfeld, Gladys E Zapata, Shenglan Li, Patricia A Ward, Christiana Wang, Chunjing Qu, Becky Maywald, Brendan Lee, Christine Eng, Pengfei Liu

{"title":"Clinical validation of RNA sequencing for Mendelian disorder diagnostics.","authors":"Sen Zhao, Kristina Macakova, Jefferson C Sinson, Hongzheng Dai, Jill Rosenfeld, Gladys E Zapata, Shenglan Li, Patricia A Ward, Christiana Wang, Chunjing Qu, Becky Maywald, Brendan Lee, Christine Eng, Pengfei Liu","doi":"10.1016/j.ajhg.2025.02.006","DOIUrl":"10.1016/j.ajhg.2025.02.006","url":null,"abstract":"Despite rapid advancements in clinical sequencing, over half of diagnostic evaluations still lack definitive results. RNA sequencing (RNA-seq) has shown promise in research settings for bridging this gap by providing essential functional data for accurate interpretation of diagnostic sequencing results. However, despite advanced research pipelines, clinical translation of diagnostic RNA-seq has not yet been realized. We have developed and validated a clinical diagnostic RNA-seq test for individuals with suspected genetic disorders who have existing or concurrent comprehensive DNA diagnostic testing. This diagnostic RNA-seq test processes RNA samples from fibroblasts or blood and derives clinical interpretations based on the analytical detection of outliers in gene expressions and splicing patterns. The clinical validation involves 130 samples, including 90 negative and 40 positive samples. We developed provisional expression and splicing benchmarks using short-read and long-read RNA-seq data from the GM24385 lymphoblastoid sample produced by the Genome in a Bottle Consortium. For clinical validation, we first established reference ranges for each gene and junction based on expression distributions from our control data. We then evaluated the clinical performance of our outlier-based pipeline using 40 positive samples with previously identified diagnostic findings from the Undiagnosed Diseases Network project. Our study provides a paradigm and necessary resources for independent laboratories to validate a clinical RNA-seq test.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"779-792"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565790","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}

引用次数: 0

The contribution of coding variants to the heritability of multiple cancer types using UK Biobank whole-exome sequencing data.

IF 8.1 1区生物学

American journal of human genetics Pub Date : 2025-04-03 Epub Date: 2025-03-11 DOI: 10.1016/j.ajhg.2025.02.013

Naomi Wilcox, Jonathan P Tyrer, Joe Dennis, Xin Yang, John R B Perry, Eugene J Gardner, Douglas F Easton

{"title":"The contribution of coding variants to the heritability of multiple cancer types using UK Biobank whole-exome sequencing data.","authors":"Naomi Wilcox, Jonathan P Tyrer, Joe Dennis, Xin Yang, John R B Perry, Eugene J Gardner, Douglas F Easton","doi":"10.1016/j.ajhg.2025.02.013","DOIUrl":"10.1016/j.ajhg.2025.02.013","url":null,"abstract":"Genome-wide association studies have been highly successful at identifying common variants associated with cancer; however, they do not explain all the inherited risks of cancer. Family-based studies, targeted sequencing, and, more recently, exome-wide association studies have identified rare coding variants in some genes associated with cancer risk, but the overall contribution of these variants to the heritability of cancer is less clear. Here, we describe a method to estimate the genome-wide contribution of rare coding variants to heritability that fits models to the burden effect sizes using an empirical Bayesian approach. We apply this method to the burden of protein-truncating variants in over 15,000 genes for 11 cancers in the UK Biobank using whole-exome sequencing data on over 400,000 individuals. We extend the method to consider the overlap of genes contributing to pairs of cancers. We found ovarian cancer to have the greatest proportion of heritability attributable to protein-truncating variants in genes (46%). The joint cancer models highlight significant clustering of cancer types, including a near-complete overlap in susceptibility genes for breast, ovarian, prostate, and pancreatic cancer. Our results provide insights into the contribution of rare coding variants to the heritability of cancer and identify additional genes with strong evidence of susceptibility to multiple cancer types.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"903-912"},"PeriodicalIF":8.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613023","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}

引用次数: 0

EndoPRS: Incorporating endophenotype information to improve polygenic risk scores for clinical endpoints-A study in asthma.

IF 9.8 1区生物学

American journal of human genetics Pub Date : 2025-04-03 DOI: 10.1016/j.ajhg.2025.03.008

Elena V Kharitonova,Quan Sun,Franklin Ockerman,Brian Chen,Laura Y Zhou,Micah R Hysong,Bjoernar Tuftin,Hongyuan Cao,Rasika A Mathias,Paul L Auer,Carole Ober,Laura M Raffield,Alexander P Reiner,Nancy J Cox,Samir N P Kelada,Ran Tao,Yun Li

{"title":"EndoPRS: Incorporating endophenotype information to improve polygenic risk scores for clinical endpoints-A study in asthma.","authors":"Elena V Kharitonova,Quan Sun,Franklin Ockerman,Brian Chen,Laura Y Zhou,Micah R Hysong,Bjoernar Tuftin,Hongyuan Cao,Rasika A Mathias,Paul L Auer,Carole Ober,Laura M Raffield,Alexander P Reiner,Nancy J Cox,Samir N P Kelada,Ran Tao,Yun Li","doi":"10.1016/j.ajhg.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.03.008","url":null,"abstract":"Polygenic risk score (PRS) prediction of complex diseases can be improved by leveraging related phenotypes. This has motivated the development of several multi-trait PRS methods that jointly model genetically correlated traits. However, these methods do not account for vertical pleiotropy, where one trait acts as a mediator for another. Here, we introduce endoPRS, a weighted lasso model that incorporates information from relevant endophenotypes to improve disease risk prediction without making assumptions about the genetic architecture underlying the endophenotype-disease relationship. Through extensive simulation analysis, we demonstrate the robustness of endoPRS in a variety of complex genetic frameworks. We also apply endoPRS to predict the risk of childhood-onset asthma in UK Biobank and All of Us by leveraging a paired genome-wide association study of eosinophil count, a relevant endophenotype. We find that endoPRS significantly improves prediction and transferability compared to many existing PRS methods, including multi-trait PRS methods MTAG and wMT-BLUP, which suggests advantages of endoPRS in real-life clinical settings.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"39 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819159","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}

引用次数: 0