Genome Medicine最新文献

{"title":"High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.","authors":"Ayesha Muhammad, Maria E Calandranis, Bian Li, Tao Yang, Daniel J Blackwell, M Lorena Harvey, Jeremy E Smith, Zerubabell A Daniel, Ashli E Chew, John A Capra, Kenneth A Matreyek, Douglas M Fowler, Dan M Roden, Andrew M Glazer","doi":"10.1186/s13073-024-01340-5","DOIUrl":"10.1186/s13073-024-01340-5","url":null,"abstract":"<p><strong>Background: </strong>KCNE1 encodes a 129-residue cardiac potassium channel (I_Ks) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility.</p><p><strong>Methods: </strong>In this study, we leveraged the power of variant effect mapping, which couples saturation mutagenesis with high-throughput sequencing, to ascertain the function of thousands of protein-coding KCNE1 variants.</p><p><strong>Results: </strong>We comprehensively assayed KCNE1 variant cell surface expression (2554/2709 possible single-amino-acid variants) and function (2534 variants). Our study identified 470 loss- or partial loss-of-surface expression and 574 loss- or partial loss-of-function variants. Of the 574 loss- or partial loss-of-function variants, 152 (26.5%) had reduced cell surface expression, indicating that most functionally deleterious variants affect channel gating. Nonsense variants at residues 56-104 generally had WT-like trafficking scores but decreased functional scores, indicating that the latter half of the protein is dispensable for protein trafficking but essential for channel function. 22 of the 30 KCNE1 residues (73%) highly intolerant of variation (with > 70% loss-of-function variants) were in predicted close contact with binding partners KCNQ1 or calmodulin. Our functional assay data were consistent with gold standard electrophysiological data (ρ =  - 0.64), population and patient cohorts (32/38 presumed benign or pathogenic variants with consistent scores), and computational predictors (ρ =  - 0.62). Our data provide moderate-strength evidence for the American College of Medical Genetics/Association of Molecular Pathology functional criteria for benign and pathogenic variants.</p><p><strong>Conclusions: </strong>Comprehensive variant effect maps of KCNE1 can both provide insight into I _Ks channel biology and help reclassify variants of uncertain significance.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11138074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179495","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":"Metabolome-wide Mendelian randomization for age at menarche and age at natural menopause.","authors":"Mojgan Yazdanpanah, Nahid Yazdanpanah, Isabel Gamache, Ken Ong, John R B Perry, Despoina Manousaki","doi":"10.1186/s13073-024-01322-7","DOIUrl":"10.1186/s13073-024-01322-7","url":null,"abstract":"<p><strong>Background: </strong>The role of metabolism in the variation of age at menarche (AAM) and age at natural menopause (ANM) in the female population is not entirely known. We aimed to investigate the causal role of circulating metabolites in AAM and ANM using Mendelian randomization (MR).</p><p><strong>Methods: </strong>We combined MR with genetic colocalization to investigate potential causal associations between 658 metabolites and AAM and between 684 metabolites and ANM. We extracted genetic instruments for our exposures from four genome-wide association studies (GWAS) on circulating metabolites and queried the effects of these variants on the outcomes in two large GWAS from the ReproGen consortium. Additionally, we assessed the mediating role of the body mass index (BMI) in these associations, identified metabolic pathways implicated in AAM and ANM, and sought validation for selected metabolites in the Avon Longitudinal Study of Parents and Children (ALSPAC).</p><p><strong>Results: </strong>Our analysis identified 10 candidate metabolites for AAM, but none of them colocalized with AAM. For ANM, 76 metabolites were prioritized (FDR-adjusted MR P-value ≤ 0.05), with 17 colocalizing, primarily in the glycerophosphocholines class, including the omega-3 fatty acid and phosphatidylcholine (PC) categories. Pathway analyses and validation in ALSPAC mothers also highlighted the role of omega and polyunsaturated fatty acids levels in delaying age at menopause.</p><p><strong>Conclusions: </strong>Our study suggests that metabolites from the glycerophosphocholine and fatty acid families play a causal role in the timing of both menarche and menopause. This underscores the significance of specific metabolic pathways in the biology of female reproductive longevity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157480","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":"Analysis of admixed Greenlandic siblings shows that the mean genotypic values for metabolic phenotypes differ between Inuit and Europeans.","authors":"Long Lin, Mette K Andersen, Frederik Filip Stæger, Zilong Li, Kristian Hanghøj, Allan Linneberg, Niels Grarup, Marit Eika Jørgensen, Torben Hansen, Ida Moltke, Anders Albrechtsen","doi":"10.1186/s13073-024-01326-3","DOIUrl":"10.1186/s13073-024-01326-3","url":null,"abstract":"<p><strong>Background: </strong>Disease prevalence and mean phenotype values differ between many populations, including Inuit and Europeans. Whether these differences are partly explained by genetic differences or solely due to differences in environmental exposures is still unknown, because estimates of the genetic contribution to these means, which we will here refer to as mean genotypic values, are easily confounded, and because studies across genetically diverse populations are lacking.</p><p><strong>Methods: </strong>Leveraging the unique genetic properties of the small, admixed and historically isolated Greenlandic population, we estimated the differences in mean genotypic value between Inuit and European genetic ancestry using an admixed sibling design. Analyses were performed across 26 metabolic phenotypes, in 1474 admixed sibling pairs present in a cohort of 5996 Greenlanders.</p><p><strong>Results: </strong>After FDR correction for multiple testing, we found significantly lower mean genotypic values in Inuit genetic ancestry compared to European genetic ancestry for body weight (effect size per percentage of Inuit genetic ancestry (se), -0.51 (0.16) kg/%), body mass index (-0.20 (0.06) kg/m²/%), fat percentage (-0.38 (0.13) %/%), waist circumference (-0.42 (0.16) cm/%), hip circumference (-0.38 (0.11) cm/%) and fasting serum insulin levels (-1.07 (0.51) pmol/l/%). The direction of the effects was consistent with the observed mean phenotype differences between Inuit and European genetic ancestry. No difference in mean genotypic value was observed for height, markers of glucose homeostasis, or circulating lipid levels.</p><p><strong>Conclusions: </strong>We show that mean genotypic values for some metabolic phenotypes differ between two human populations using a method not easily confounded by possible differences in environmental exposures. Our study illustrates the importance of performing genetic studies in diverse populations.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081218","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":"Analysis of 3760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes.","authors":"Xueqi Cao, Sandra Huber, Ata Jadid Ahari, Franziska R Traube, Marc Seifert, Christopher C Oakes, Polina Secheyko, Sergey Vilov, Ines F Scheller, Nils Wagner, Vicente A Yépez, Piers Blombery, Torsten Haferlach, Matthias Heinig, Leonhard Wachutka, Stephan Hutter, Julien Gagneur","doi":"10.1186/s13073-024-01331-6","DOIUrl":"10.1186/s13073-024-01331-6","url":null,"abstract":"<p><strong>Background: </strong>Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging.</p><p><strong>Methods: </strong>To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes.</p><p><strong>Results: </strong>We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities.</p><p><strong>Conclusions: </strong>Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11103968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070780","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":"The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson's disease comorbidity.","authors":"Meltem Ece Kars, Yiming Wu, Peter D Stenson, David N Cooper, Johan Burisch, Inga Peter, Yuval Itan","doi":"10.1186/s13073-024-01335-2","DOIUrl":"10.1186/s13073-024-01335-2","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory bowel disease (IBD) and Parkinson's disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity.</p><p><strong>Methods: </strong>We analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD.</p><p><strong>Results: </strong>The analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein-protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD.</p><p><strong>Conclusions: </strong>Our study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11092054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916017","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":"Correction: Genome Med 15, 115 & Genome Med 16, 3.","authors":"Ning Shen","doi":"10.1186/s13073-024-01343-2","DOIUrl":"10.1186/s13073-024-01343-2","url":null,"abstract":"","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11092180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921863","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":"Longitudinal analysis within one hospital in sub-Saharan Africa over 20 years reveals repeated replacements of dominant clones of Klebsiella pneumoniae and stresses the importance to include temporal patterns for vaccine design considerations.","authors":"Eva Heinz, Oliver Pearse, Allan Zuza, Sithembile Bilima, Chisomo Msefula, Patrick Musicha, Patriciah Siyabu, Edith Tewesa, Fabrice E Graf, Rebecca Lester, Samantha Lissauer, Jennifer Cornick, Joseph M Lewis, Kondwani Kawaza, Nicholas R Thomson, Nicholas A Feasey","doi":"10.1186/s13073-024-01342-3","DOIUrl":"10.1186/s13073-024-01342-3","url":null,"abstract":"<p><strong>Background: </strong>Infections caused by multidrug-resistant gram-negative bacteria present a severe threat to global public health. The WHO defines drug-resistant Klebsiella pneumoniae as a priority pathogen for which alternative treatments are needed given the limited treatment options and the rapid acquisition of novel resistance mechanisms by this species. Longitudinal descriptions of genomic epidemiology of Klebsiella pneumoniae can inform management strategies but data from sub-Saharan Africa are lacking.</p><p><strong>Methods: </strong>We present a longitudinal analysis of all invasive K. pneumoniae isolates from a single hospital in Blantyre, Malawi, southern Africa, from 1998 to 2020, combining clinical data with genome sequence analysis of the isolates.</p><p><strong>Results: </strong>We show that after a dramatic increase in the number of infections from 2016 K. pneumoniae becomes hyperendemic, driven by an increase in neonatal infections. Genomic data show repeated waves of clonal expansion of different, often ward-restricted, lineages, suggestive of hospital-associated transmission. We describe temporal trends in resistance and surface antigens, of relevance for vaccine development.</p><p><strong>Conclusions: </strong>Our data highlight a clear need for new interventions to prevent rather than treat K. pneumoniae infections in our setting. Whilst one option may be a vaccine, the majority of cases could be avoided by an increased focus on and investment in infection prevention and control measures, which would reduce all healthcare-associated infections and not just one.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11073982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853755","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":"imply: improving cell-type deconvolution accuracy using personalized reference profiles","authors":"Guanqun Meng, Yue Pan, Wen Tang, Lijun Zhang, Ying Cui, Fredrick R. Schumacher, Ming Wang, Rui Wang, Sijia He, Jeffrey Krischer, Qian Li, Hao Feng","doi":"10.1186/s13073-024-01338-z","DOIUrl":"https://doi.org/10.1186/s13073-024-01338-z","url":null,"abstract":"Using computational tools, bulk transcriptomics can be deconvoluted to estimate the abundance of constituent cell types. However, existing deconvolution methods are conditioned on the assumption that the whole study population is served by a single reference panel, ignoring person-to-person heterogeneity. Here, we present imply, a novel algorithm to deconvolute cell type proportions using personalized reference panels. Simulation studies demonstrate reduced bias compared with existing methods. Real data analyses on longitudinal consortia show disparities in cell type proportions are associated with several disease phenotypes in Type 1 diabetes and Parkinson’s disease. imply is available through the R/Bioconductor package ISLET at https://bioconductor.org/packages/ISLET/ .","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":12.3,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140812588","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":"Clustering of predicted loss-of-function variants in genes linked with monogenic disease can explain incomplete penetrance","authors":"Robin N. Beaumont, Gareth Hawkes, Adam C. Gunning, Caroline F. Wright","doi":"10.1186/s13073-024-01333-4","DOIUrl":"https://doi.org/10.1186/s13073-024-01333-4","url":null,"abstract":"Genetic variants that severely alter protein products (e.g. nonsense, frameshift) are often associated with disease. For some genes, these predicted loss-of-function variants (pLoFs) are observed throughout the gene, whilst in others, they occur only at specific locations. We hypothesised that, for genes linked with monogenic diseases that display incomplete penetrance, pLoF variants present in apparently unaffected individuals may be limited to regions where pLoFs are tolerated. To test this, we investigated whether pLoF location could explain instances of incomplete penetrance of variants expected to be pathogenic for Mendelian conditions. We used exome sequence data in 454,773 individuals in the UK Biobank (UKB) to investigate the locations of pLoFs in a population cohort. We counted numbers of unique pLoF, missense, and synonymous variants in UKB in each quintile of the coding sequence (CDS) of all protein-coding genes and clustered the variants using Gaussian mixture models. We limited the analyses to genes with ≥ 5 variants of each type (16,473 genes). We compared the locations of pLoFs in UKB with all theoretically possible pLoFs in a transcript, and pathogenic pLoFs from ClinVar, and performed simulations to estimate the false-positive rate of non-uniformly distributed variants. For most genes, all variant classes fell into clusters representing broadly uniform variant distributions, but genes in which haploinsufficiency causes developmental disorders were less likely to have uniform pLoF distribution than other genes (P < 2.2 × 10−6). We identified a number of genes, including ARID1B and GATA6, where pLoF variants in the first quarter of the CDS were rescued by the presence of an alternative translation start site and should not be reported as pathogenic. For other genes, such as ODC1, pLoFs were located approximately uniformly across the gene, but pathogenic pLoFs were clustered only at the end, consistent with a gain-of-function disease mechanism. Our results suggest the potential benefits of localised constraint metrics and that the location of pLoF variants should be considered when interpreting variants.","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":12.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140804993","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":"Polygenic scores for longitudinal prediction of incident type 2 diabetes in an ancestrally and medically diverse primary care physician network: a patient cohort study","authors":"Ravi Mandla, Philip Schroeder, Bianca Porneala, Jose C. Florez, James B. Meigs, Josep M. Mercader, Aaron Leong","doi":"10.1186/s13073-024-01337-0","DOIUrl":"https://doi.org/10.1186/s13073-024-01337-0","url":null,"abstract":"The clinical utility of genetic information for type 2 diabetes (T2D) prediction with polygenic scores (PGS) in ancestrally diverse, real-world US healthcare systems is unclear, especially for those at low clinical phenotypic risk for T2D. We tested the association of PGS with T2D incidence in patients followed within a primary care practice network over 16 years in four hypothetical scenarios that varied by clinical data availability (N = 14,712): (1) age and sex; (2) age, sex, body mass index (BMI), systolic blood pressure, and family history of T2D; (3) all variables in (2) and random glucose; and (4) all variables in (3), HDL, total cholesterol, and triglycerides, combined in a clinical risk score (CRS). To determine whether genetic effects differed by baseline clinical risk, we tested for interaction with the CRS. PGS was associated with incident T2D in all models. Adjusting for age and sex only, the Hazard Ratio (HR) per PGS standard deviation (SD) was 1.76 (95% CI 1.68, 1.84) and the HR of top 5% of PGS vs interquartile range (IQR) was 2.80 (2.39, 3.28). Adjusting for the CRS, the HR per SD was 1.48 (1.40, 1.57) and HR of the top 5% of PGS vs IQR was 2.09 (1.72, 2.55). Genetic effects differed by baseline clinical risk ((PGS-CRS interaction p = 0.05; CRS below the median: HR 1.60 (1.43, 1.79); CRS above the median: HR 1.45 (1.35, 1.55)). Genetic information can help identify high-risk patients even among those perceived to be low risk in a clinical evaluation.","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":12.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140804965","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}