American journal of human genetics最新文献

{"title":"The evolution of health data ecosystems: An international survey.","authors":"Jordan P Lerner-Ellis, E Magda Price, Shazia Subhani, Tiffany Boughtwood, Marie-Jo Brion, Augusto Rendon, Lene Cividanes, Jacob Gemmer, Danielle Ciofani, Nicolas Bertin, Seow Shih Wee, Stephen Robertson, Batoul Baz, Katrin Crameri, Sabine Österle, Valtteri Wirta, Per Sikora, Anna Lindstrand, Frédérique Nowak, Inês Amado, Nicola Jane Mulder, Andrea Ganna, Peter Goodhand, Lindsay D Smith, Christian R Marshall, Ma'n Zawati, Vincent Ferretti, Jacques L Michaud, Dennis Bulman, Francois Bernier, Kym M Boycott","doi":"10.1016/j.ajhg.2025.06.017","DOIUrl":"10.1016/j.ajhg.2025.06.017","url":null,"abstract":"<p><p>This paper reports the findings of an international survey of health data ecosystems (HDEs) in 12 countries plus the H3 Africa project using live, structured interviews with senior project team members under the auspices of Canada's All for One Precision Health Initiative. We note the high level of interest in HDEs around the world, as well as in Canada, despite the financial, jurisdictional, and other barriers that continue to hold back widespread data sharing. We present results detailing operational profiles for each of the 13 participants, including whether their healthcare systems are centralized (national) or decentralized (regional), project start date, funding, information technology (IT) infrastructure, and the extent to which participants have implemented a data-sharing mandate. We find no evidence to confirm common assumptions about features conferring an advantage on HDE development, such as early launch date or top-down government mandate. We also find no evidence of a reference model to explain what makes any HDE effective, valuable, or successful and conclude, on the basis of our interviews, that the diversity that makes each of these projects unique may undermine collective actions like data sharing. While participants provided useful cautions about pitfalls they encountered, more research on these issues is required, and we anticipate that advanced assessment tools like the maturity level model (MLM) developed by the European Union (EU) may help countries understand what stage of the HDE development process they have reached and what strategies will be most effective for them in later stages.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1769-1777"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688672","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":"Genomics-informed drug-repurposing strategy identifies two therapeutic targets for preventing liver disease associated with metabolic dysfunction.","authors":"Hannah M Seagle,Alexis T Akerele,Joseph A DeCorte,Jacklyn N Hellwege,Joseph H Breeyear,Jeewoo Kim,Michael G Levin,Samuel Khodursky,Adam Bress,Kyung Min Lee,Jens Meiler,Dipender Gill,Jennifer S Lee,Kent Heberer,Donald R Miller,Peter D Reaven,Kyong-Mi Chang,Julie A Lynch, ,Nikhil K Khankari,Megan M Shuey,Todd L Edwards,Marijana Vujkovic","doi":"10.1016/j.ajhg.2025.06.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.06.014","url":null,"abstract":"Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving the treatment of diseases. We employed a cross-disciplinary approach to identify potential therapeutics for the prevention of metabolic-dysfunction-associated steatotic liver disease (MASLD) in at-risk individuals by using humans as a model organism. We identified 212 putative candidate genes associated with MASLD by using data from a large multi-ancestry genetic association study, of which 158 (74.5%) were previously unreported. From this set, we identified 57 genes that encode for druggable protein targets and for which the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. We then used We then evaluated these potential targets for evidence of efficacy by using Mendelian randomization, pathway analysis, and protein structural modeling. Through these approaches, we present compelling evidence to suggest that the activation of FADS1 by icosapent ethyl, as well as S1PR2 by fingolimod, could be a promising therapeutic strategy for MASLD prevention.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"35 1","pages":"1778-1791"},"PeriodicalIF":9.8,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802504","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 genealogy-based approach for revealing ancestry-specific structures in admixed populations.","authors":"Ji Tang, Charleston W K Chiang","doi":"10.1016/j.ajhg.2025.06.016","DOIUrl":"10.1016/j.ajhg.2025.06.016","url":null,"abstract":"<p><p>Elucidating ancestry-specific structures in admixed populations is crucial for comprehending population history and mitigating confounding effects in genome-wide association studies. Existing methods to reveal the ancestry-specific structures generally rely on frequency-based estimates of genetic relationship matrix (GRM) among admixed individuals after masking segments from ancestry components not being targeted for investigation. However, these approaches disregard linkage information between markers, potentially limiting their resolution in revealing structure within an ancestry component. We introduce ancestry-specific expected GRM (as-eGRM), a novel framework for estimating the relatedness within ancestry components between admixed individuals. The key design of as-eGRM consists of defining ancestry-specific pairwise relatedness between individuals based on genealogical trees encoded in the ancestral recombination graph (ARG) and local ancestry calls and then computing the expectation of the ancestry-specific relatedness across the genome. Comprehensive evaluations using both simulated stepping-stone models of population structure and empirical datasets based on three-way admixed Latino cohorts showed that analysis based on as-eGRM robustly outperforms existing methods in revealing the structure in admixed populations with diverse demographic histories, which in turn improves the robustness against confounding due to population structure in association testing.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1906-1922"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688670","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":"An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.","authors":"Sanaa Choufani, Vanda McNiven, Cheryl Cytrynbaum, Maryam Jangjoo, Margaret P Adam, Hans T Bjornsson, Jacqueline Harris, David A Dyment, Gail E Graham, Marjan M Nezarati, Ritu B Aul, Claudia Castiglioni, Jeroen Breckpot, Koen Devriendt, Helen Stewart, Benito Banos-Pinero, Sarju Mehta, Richard Sandford, Carolyn Dunn, Remi Mathevet, Lionel van Maldergem, Juliette Piard, Elise Brischoux-Boucher, Antonio Vitobello, Laurence Faivre, Marie Bournez, Frederic Tran-Mau, Isabelle Maystadt, Alberto Fernández-Jaén, Sara Alvarez, Irene Díez García-Prieto, Fowzan S Alkuraya, Hessa S Alsaif, Zuhair Rahbeeni, Karen El-Akouri, Mariam Al-Mureikhi, Rebecca C Spillmann, Vandana Shashi, Pedro A Sanchez-Lara, John M Graham, Amy Roberts, Odelia Chorin, Gilad D Evrony, Minna Kraatari-Tiri, Tracy Dudding-Byth, Anamaria Richardson, David Hunt, Laura Hamilton, Sarah Dyack, Bryce A Mendelsohn, Nicolás Rodríguez, Rosario Sánchez-Martínez, Jair Tenorio-Castaño, Julián Nevado, Pablo Lapunzina, Pilar Tirado, Maria-Teresa Carminho Amaro Rodrigues, Lina Quteineh, A Micheil Innes, Antonie D Kline, P Y Billie Au, Rosanna Weksberg","doi":"10.1016/j.ajhg.2025.07.001","DOIUrl":"10.1016/j.ajhg.2025.07.001","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 8","pages":"1979"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803204","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":"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":"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":"1792-1804"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414659/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracting and calibrating evidence of variant pathogenicity from population biobank data.","authors":"Vineel Bhat, Tian Yu, Lara Brown, Vikas Pejaver, Matthew Lebo, Steven Harrison, Christopher A Cassa","doi":"10.1016/j.ajhg.2025.06.012","DOIUrl":"10.1016/j.ajhg.2025.06.012","url":null,"abstract":"<p><p>Genomic medicine requires a robust evidence base of variant phenotypic impacts, which remains incomplete even in extensively studied genes with monogenic disease associations. Here, we evaluated the broad potential of using population cohort data to identify evidence that can be used in variant assessment. Across 41 genes related to 18 clinically actionable monogenic phenotypes, we calculated variant-level odds ratios of disease enrichment using data from 469,803 UK Biobank participants. We found significant differences in odds ratio values between ClinVar-labeled pathogenic and benign variants in 11 phenotypes, spanning both common and rare disorders. To facilitate clinical translation, we calibrated the strength of evidence provided by variant-level odds ratios to align with American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) interpretation guidelines (PS4 criterion) and found that odds ratios may reach \"moderate,\" \"strong,\" or \"very strong\" evidence, varying by phenotype and gene. Overall, we found that 2.6% (N = 12,350) of participants harbor a rare variant of uncertain significance (VUS) with at least moderate evidence of pathogenicity-an indication of potentially unrecognized disease risk. Finally, by incorporating computational and functional data alongside population-based odds ratios, we identified variants that met the criteria for clinical reclassification. Notably, using this approach, we identified that 12.4% of rare VUSs in LDLR seen in participants meet diagnostic criteria to be classified as likely pathogenic, demonstrating its potential to scale the reclassification of VUSs.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1805-1817"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12401458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607165","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":"Efficient Mendelian randomization analysis with self-adaptive determination of sample structure and multiple pleiotropic effects.","authors":"Liye Zhang, Lu Liu, Jiadong Ji, Ran Yan, Ping Guo, Weiming Gong, Fuzhong Xue, Xiang Zhou, Zhongshang Yuan","doi":"10.1016/j.ajhg.2025.06.002","DOIUrl":"10.1016/j.ajhg.2025.06.002","url":null,"abstract":"<p><p>Mendelian randomization (MR) has emerged as a highly valuable tool for inferring the causal effects of exposures on outcomes in observational studies using genetic variants, typically single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs). Standard MR typically involves three steps: inputs of genome-wide association studies (GWASs) for both exposure and outcome, determination of IVs, and inference of causal effects. However, existing methods fail to simultaneously account for characteristics of GWAS data, uncertainty surrounding the validity of SNPs as IVs, and efficiency of estimating and testing the causal effect. Here, we developed MR method with self-adaptive determination of sample structure and multiple pleiotropic effects (MAPLE), a method for effective MR analysis. MAPLE utilizes correlated SNPs, self-adaptively accounts for the sample structure and the uncertainty that these correlated SNPs may exhibit multiple pleiotropic effects, and relies on a maximum-likelihood framework to infer the causal effects and obtain calibrated p values. We illustrate the advantage of MAPLE through comprehensively realistic simulations, where MAPLE, compared with another eight MR methods, shows calibrated type I error control and reduces false positives while being more powerful. In three types of lipid-trait-centric MR analyses in UK Biobank, MAPLE produces the most accurate causal-effect estimates in positive-control analyses evaluating the causal effect of each lipid trait on itself; reduces the false positives by 12.5% on average compared with existing methods in negative-control analyses investigating the causal effects of lipid traits on hair color and skin color; and highlights the causal effects of physical activity, alcohol, and smoking on lipid profiles in factor-screening analyses involving 412 trait pairs.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1962-1978"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615823","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":"Haplotype analysis reveals pleiotropic disease associations in the HLA region.","authors":"Courtney J Smith, Satu Strausz, Jeffrey P Spence, Hanna M Ollila, Jonathan K Pritchard","doi":"10.1016/j.ajhg.2025.06.011","DOIUrl":"10.1016/j.ajhg.2025.06.011","url":null,"abstract":"<p><p>The human leukocyte antigen (HLA) region plays an important role in human health through its involvement in immune cell recognition and maturation. While genetic variation in the HLA region is associated with many diseases, the pleiotropic patterns of these associations have not been systematically investigated. Here, we developed a haplotype approach to investigate disease associations phenome wide for 412,181 Finnish individuals and 2,459 diseases. Across the 1,035 diseases with a genome-wide association study association, we found a 17-fold average per-SNP enrichment of hits in the HLA region. Altogether, we identified 7,649 HLA associations across 647 diseases, including 1,750 associations uncovered by haplotype analysis. We found that some haplotypes show both risk-increasing and protective associations across different diseases, while others consistently increase risk across diseases, indicating a complex pleiotropic landscape involving a range of diseases. This study highlights the extensive impact of HLA variation on disease risk and underscores the importance of classical and non-classical genes as well as non-coding variation.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1833-1851"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615824","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":"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":"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":"1864-1876"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414684/pdf/","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":"OA","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":"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":"1892-1905"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12338089/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}