American journal of human genetics最新文献

{"title":"Natural selection acting on complex traits hampers the predictive accuracy of polygenic scores in ancient samples.","authors":"Valeria Añorve-Garibay, Emilia Huerta-Sanchez, Mashaal Sohail, Diego Ortega-Del Vecchyo","doi":"10.1016/j.ajhg.2025.05.009","DOIUrl":"10.1016/j.ajhg.2025.05.009","url":null,"abstract":"<p><p>The prediction of phenotypes from ancient humans has gained interest due to its potential to investigate the evolution of complex traits. These predictions are commonly performed using polygenic scores computed with DNA information from ancient humans along with genome-wide association study (GWAS) data from present-day humans. However, numerous evolutionary processes could impact these phenotypic predictions. In this work, we investigate how natural selection shapes the temporal dynamics of variants with an effect on the trait and how these changes impact phenotypic predictions for ancient individuals using polygenic scores. We find that stabilizing selection accelerates the loss of large-effect alleles contributing to trait variation. Conversely, directional selection accelerates the loss of small- and large-effect alleles that drive individuals farther away from the optimal phenotypic value. These phenomena result in specific shared genetic variation patterns between ancient and modern populations that hamper the accuracy of polygenic scores to predict phenotypes. Our results assume perfectly estimated effect sizes at the causal loci of complex traits segregating in a GWAS performed in the present and, therefore, provide a putatively loose upper bound on the polygenic score portability to predict traits in the past. Furthermore, we show how natural selection could impact the predictive accuracy of ancient polygenic scores for two widely studied traits: height and body mass index. Our results emphasize the importance of considering decreases on the reliability of polygenic scores to perform phenotypic predictions in ancient individuals due to allele frequency changes driving the loss of alleles via natural selection.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1547-1561"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274017","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":"Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.","authors":"Hana Antonicka, Woranontee Weraarpachai, Katherine M Szigety, Robert Kopajtich, James B Gibson, Johan L K Van Hove, Marisa W Friederich, Piervito Lopriore, Christiane Neuhofer, Roxanne A Van Hove, Michel A Cole, Richard Reisdorph, James T Peterson, Katherine J Dempsey, Rebecca D Ganetzky, Michelangelo Mancuso, Holger Prokisch, Eric A Shoubridge","doi":"10.1016/j.ajhg.2025.05.007","DOIUrl":"10.1016/j.ajhg.2025.05.007","url":null,"abstract":"<p><p>Using exome sequencing, we identified compound heterozygous variants of unknown significance in FASTKD5, a gene that codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript, in three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia. Among the three subjects, we identified three missense variants and two frameshift variants leading to a premature stop codon. Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense mutations, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. Two of the three identified missense mutations resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability. These cases of mitochondrial disease associated with bi-allelic variants in FASTKD5 add to a growing list of primary genetic mutations causing Leigh syndrome associated with complex IV deficiency.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1699-1710"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274016","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":"Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities.","authors":"Claudie Gabillard-Lefort, Caroline Silveira Martinez, Naïg Gueguen, Valérie Desquiret-Dumas, Méline Wery, Louis Legoff, Anne Guimier, Sophie Rondeau, Giulia Barcia, Christine Barnerias, Benjamin Cogne, Thomas Besnard, Elsa Lorino, Jessica Douglas, Olaf Bodamer, Annalisa Vetro, Renzo Guerrini, Simona Balestrini, Valerio Conti, Laura Siri, Arnaud Chevrollier, Céline Bris, Estelle Colin, Vincent Procaccio, Delphine Prunier-Mirebeau, Guy Lenaers, Salim Khiati, Mathilde Nizon, Olivier R Baris","doi":"10.1016/j.ajhg.2025.05.004","DOIUrl":"10.1016/j.ajhg.2025.05.004","url":null,"abstract":"<p><p>We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. TM2D3 encodes a transmembrane protein present in many tissues, with a higher abundance in the central nervous system, but little is known about its function and cell localization. Here, by using chemical and genetically encoded probes in SNB75 cells, we show that TM2D3 is an endoplasmic reticulum (ER) protein. Further analysis on SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele revealed an impact of TM2D3 on ER-stress response, with dysregulated expression of ATF4, HSPA5, and DDIT3. Transmission electron microscopy highlighted ER swelling as well as unexpected secondary mitochondrial alterations including increased length, cristae width, and ER-mitochondria distance. To gain further insights into the pathomechanisms at play, we performed RNA sequencing from the fibroblasts of the three individuals harboring the p.Gly168Asp variant and four available parents and disclosed 21 differentially expressed genes, including genes coding for extracellular matrix components involved in the migration of neuronal precursors. Altogether, these clinical and experimental data show that bi-allelic TM2D3 variants underlie a severe syndromic neurodevelopmental disorder linked to exacerbated ER-stress sensitivity, secondary mitochondrial alterations, and altered extracellular matrix gene expression.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1711-1721"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191293","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":"Complexity within simplicity: Exploring the multifactorial nature of sickle cell disease.","authors":"Athena Starlard-Davenport","doi":"10.1016/j.ajhg.2025.05.008","DOIUrl":"10.1016/j.ajhg.2025.05.008","url":null,"abstract":"<p><p>Sickle cell disease, though monogenic, exhibits complex clinical variability driven by genetic, epigenetic, and environmental factors. This commentary highlights advances in precision therapies and underscores the urgent need for equitable access, global collaboration, and personalized approaches to address the significant health disparities impacting individuals with sickle cell disease worldwide.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1499-1503"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245916","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":"Cross-omics risk scores of inflammation markers are associated with all-cause mortality: The Canadian Longitudinal Study on Aging.","authors":"Anat Yaskolka Meir, Huan Yun, Jie Hu, Jun Li, Jiaxuan Liu, Alaina Bever, Andrew Ratanatharathorn, Mingyang Song, A Heather Eliassen, Lori Chibnik, Karestan Koenen, Guillaume Pare, Meir J Stampfer, Liming Liang","doi":"10.1016/j.ajhg.2025.06.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.06.009","url":null,"abstract":"<p><p>Inflammation is a critical component of chronic diseases, aging progression, and lifespan. Omics signatures may characterize inflammation status beyond blood biomarkers. We leveraged genetics (polygenic risk score [PRS]), metabolomics (metabolomic risk score [MRS]), and epigenetics (epigenetic risk score [ERS]) to build multi-omics-multi-marker risk scores for inflammation status represented by the level of circulating C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α). We found that multi-omics risk scores generally outperformed single-omics risk scores in predicting all-cause mortality in the Canadian Longitudinal Study on Aging. Compared with circulating inflammation biomarkers, some multi-omics risk scores had a higher hazard ratio (HR) for all-cause mortality when including both score and circulating IL-6 in the same model (1-SD IL-6 MRS-ERS: HR = 2.20 [1.55-3.13] vs. 1-SD circulating IL-6 HR = 0.94 [0.67,1.32]. 1-SD IL-6 PRS-MRS: HR = 1.47 [1.35,1.59] vs. 1-SD circulating IL-6 HR = 1.33 [1.18, 1.51]. 1-SD PRS-MRS-ERS: HR = 1.95 [1.40, 2.70] vs. 1-SD circulating IL-6: HR = 0.99 [0.71, 1.39]). In the Nurses' Health Study (NHS), NHS II, and Health Professional Follow-up Study with available omics, 1 SD of IL-6 PRS and 1-SD IL-6 PRS-MRS had HR = 1.12 [1.00,1.26] and HR = 1.13 [1.01,1.26] among individuals >65 years old without mutual adjustment of the score and circulating IL-6. Our study demonstrates that some multi-omics scores for inflammation markers may characterize important inflammation burden for an individual beyond those represented by blood biomarkers and improve our prediction capability for the aging process and lifespan.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599147","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":"Mapping chromatin interactions at melanoma susceptibility loci uncovers distant cis-regulatory gene targets.","authors":"Rohit Thakur, Mai Xu, Hayley Sowards, Joshuah Yon, Lea Jessop, Timothy Myers, Tongwu Zhang, Raj Chari, Erping Long, Thomas Rehling, Rebecca Hennessey, Karen Funderburk, Jinhu Yin, Mitchell J Machiela, Matthew E Johnson, Andrew D Wells, Alessandra Chesi, Struan F A Grant, Mark M Iles, Maria Teresa Landi, Matthew H Law, Jiyeon Choi, Kevin M Brown","doi":"10.1016/j.ajhg.2025.04.015","DOIUrl":"10.1016/j.ajhg.2025.04.015","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) of melanoma risk have identified 68 independent signals at 54 loci. For most loci, specific functional variants and their respective target genes remain to be established. Capture-HiC is an assay that links fine-mapped risk variants to candidate target genes by comprehensively mapping chromatin interactions. We performed a melanoma GWAS region-focused capture-HiC assay in human primary melanocytes to identify physical interactions between fine-mapped risk variants and potential causal melanoma-susceptibility genes. Overall, chromatin-interaction data alone nominated potential causal genes for 61 of the 68 melanoma risk signals, identifying many candidates beyond those reported by previous studies. We further integrated these data with epigenomic (chromatin state, accessibility), gene expression (expression quantitative trait locus [eQTL]/transcriptome-wide association study [TWAS]), DNA methylation (methylation QTL [meQTL]/methylome-wide association study [MWAS]), and massively parallel reporter assay (MPRA) data generated from melanoma-relevant cell types to prioritize potentially cis-regulatory variants and their respective candidate gene targets. From the set of fine-mapped variants across these loci, we identified 140 prioritized credible causal variants linked to 195 candidate genes at 42 risk signals. In addition, we developed an integrative scoring system to facilitate candidate gene prioritization, integrating melanocyte and melanoma datasets. Notably, at several GWAS risk signals, we observed long-range chromatin connections (500 kb to >1 Mb) with distant candidate target genes. We validated several such cis-regulatory interactions using CRISPR inhibition, providing evidence for known cancer driver genes MDM4 and CBL, as well as the SRY-box transcription factor SOX4, as likely melanoma risk genes.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1625-1648"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132107","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":"Extremely early genomic events and temporal order of esophageal squamous cell carcinogenesis: Longitudinal self-comparison of progressors and non-progressors.","authors":"Ying Liu, Mengfei Liu, Yang Yang, Lihua Cao, Wei He, Zhen Liu, Chuanhai Guo, Yaqi Pan, Fangfang Liu, Zhe Hu, Huanyu Chen, Hong Cai, Zhonghu He, Jianmin Wu, Yang Ke","doi":"10.1016/j.ajhg.2025.06.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.06.008","url":null,"abstract":"<p><p>The current surveillance guideline of esophageal squamous cell carcinoma (ESCC) runs the risk of underestimation of early Lugol-unstained lesions (LULs), and extremely early genomic events in the carcinogenesis and their temporal order of occurrence remain unclear. Here, we performed whole-exome sequencing analyses of 148 biopsy samples obtained at different time points (with a median 4.6-year interval) from the same esophageal lesions of 74 asymptomatic subjects with LULs detected at community-based screening, of whom 33 individuals showed progression at the follow-up chromoendoscopy, while the other 41 did not. We found that progressors showed higher tumor mutational burden, chromosomal instability level, whole-genome doubling (WGD) events, and apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) activity at both index and follow-up compared to non-progressors. Sustained TP53 two-hit events, absence of NOTCH1 mutation, presence of CDKN2A mutation/deletion, and WGD were detected both before and after LUL progression in 64% (9/14) of progressors and none (0/19) of non-progressors with non-dysplastic LULs (ND-LULs). CCND1, FGFs, and MIR548K amplification in chromosome 11q13.3 only occurred in progressors with high-grade intraepithelial neoplasia or above lesions. TP53 two-hit events, absence of NOTCH1 mutation, and presence of CDKN2A mutation/deletion were positively correlated with WGD and successfully distinguished all 5 progressed individuals from the 24 subjects at so-called \"low risk\" of progression (ND-LULs with a size of ≤5 mm) under current surveillance criteria. Collectively, TP53 two-hit events, absence of NOTCH1 mutation, and presence of CDKN2A mutation/deletion are extremely early events in the carcinogenesis of ESCC, providing early warning markers for the surveillance of high-risk precursor lesions of ESCC.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590269","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":"Exclusion-based exome sequencing in critically ill adults 18-40 years old has a 24% diagnostic rate and finds racial disparities in access to genetic testing.","authors":"Jessica I Gold, Colleen M Kripke, Theodore G Drivas","doi":"10.1016/j.ajhg.2025.06.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.06.007","url":null,"abstract":"<p><p>Despite the well-documented benefits of genome sequencing in critically ill pediatric patients, genomic testing is rarely utilized in critically ill adults, and data on its diagnostic yield and clinical implications in this population are lacking. We retrospectively analyzed whole-exome sequencing (WES) data from 365 adults ages 18-40 years with intensive care unit (ICU) admissions at the University of Pennsylvania Health System. For each participant, two medical genetics- and internal medicine-trained clinicians reviewed WES reports and patient charts for variant classification, result interpretation, and identification of genetic diagnoses related to their critical illness. We identified a diagnostic genetic variant in 24.4% of patients, with nearly half of these being unknown to patients and their care teams at the time of ICU admission. Of these genetic diagnoses, 76.6% conferred specific care-altering medical management recommendations. Importantly, diagnostic yield did not decrease with increasing patient age, and patients with undocumented diagnoses trended toward higher mortality rates compared to either patients with known diagnoses or patients with negative exomes. Significant disparities were seen by electronic health record-reported race, with genetic diagnoses known/documented for 63.1% of White patients at the time of ICU admission but only for 22.7% of Black patients. Altogether, the results of this study of broad, exclusion-based genetic testing in the critically ill adult population suggest that the broad implementation of genetic testing in critically ill adults has the potential to improve patient care and dismantle disparities in healthcare delivery.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590268","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":"Exploring depression treatment response by using polygenic risk scoring across diverse populations","authors":"Sandra Lapinska, Aditya Pimplaskar, Zhuozheng Shi, Yi Ding, Clara Frydman-Gani, Kangcheng Hou, Vidhya Venkateswaran, Kristin Boulier, Loes M. Olde Loohuis, Bogdan Pasaniuc","doi":"10.1016/j.ajhg.2025.06.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.06.003","url":null,"abstract":"Treatment-resistant depression (TRD), usually defined as limited or no response to at least two antidepressants, occurs in approximately one-third of individuals diagnosed with major depressive disorder (MDD). Studies of individuals of European ancestry highlight a genetic overlap between TRD and MDD. We analyzed two large and diverse biobanks, the UCLA ATLAS Community Health Study (ATLAS) and the All of Us Research Program (AoU), to test for associations between a polygenic score for major depression (MDD-PGS) and TRD. Compared to treatment responders, TRD individuals have higher MDD-PGS across all ancestries. MDD-PGS was significantly associated with response to selective serotonin reuptake inhibitors in individuals of European and Hispanic/Latin American genetic ancestries in both biobanks. In AoU, a decreased MDD-PGS was observed in response to tricyclics or serotonin modulators in individuals of European American ancestry and in response to serotonin and norepinephrine reuptake inhibitors in individuals of African American ancestry. ATLAS found that MDD-PGS showed lower odds of responding to atypical agents than did TRD in MDD-affected individuals belonging to the Hispanic/Latin American group, MDD-PGS was associated with atypical agents. Overall, by leveraging larger sample sizes from two diverse biobanks, we provide new insights into antidepressant response and treatment specificity for MDD in individuals of diverse genetic ancestries.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"274 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504023","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":"TransferTWAS: A transfer learning framework for cross-tissue transcriptome-wide association study.","authors":"Daoyuan Lai, Han Wang, Tian Gu, Siqi Wu, Dajiang J Liu, Pak Chung Sham, Yan Dora Zhang","doi":"10.1016/j.ajhg.2025.06.006","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.06.006","url":null,"abstract":"<p><p>Transcriptome-wide association studies (TWASs) utilize gene-expression data to explore the genetic basis of complex traits. A key challenge in TWASs is developing robust imputation models for tissues with limited sample sizes. This paper introduces transfer learning-assisted TWAS (TransferTWAS), a framework that adaptively transfers information from multiple tissues to improve gene-expression prediction in the target tissue. TransferTWAS employs a data-driven strategy that assigns higher weights to genetically similar external tissues. It outperforms other multi-tissue TWAS methods, such as the Unified Test for Molecular Signatures (UTMOST), which neglects tissue similarity, and Joint-Tissue Imputation (JTI), which relies on functional annotations to represent tissue similarity. Simulation studies demonstrate that TransferTWAS achieves the highest imputation accuracy, and analyses using the ROS/MAP and GEUVADIS datasets show a substantial power gain while maintaining control over type-I errors. Furthermore, analysis of the low-density lipoprotein cholesterol GWAS dataset and other complex traits demonstrates that TransferTWAS effectively identifies more associations compared with existing methods.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537779","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}