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| Open AccessClinical utility of polygenic scores for cardiometabolic disease in Arabs
Arabs account for 5% of the world population and have a high burden of cardiometabolic disease. Here, the authors optimize polygenic scores for 10 cardiometabolic traits in 5399 Arabs, achieving a performance on par with that among European-ancestry individuals.
- Injeong Shim
- , Hiroyuki Kuwahara
- & Akl C. Fahed
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| Open AccessFine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease
The mechanisms underlying many genetic variants associated with human traits are often unknown. Here, the authors identify the developmental stage-, organ-, tissue- and cell type-specific associations between genetic variation and gene expression in cardiac tissues, and describe how these associations affect complex cardiac traits and disease.
- Matteo D’Antonio
- , Jennifer P. Nguyen
- & Kelly A. Frazer
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| Open AccessAnalysis of clinically relevant variants from ancestrally diverse Asian genomes
Clinically significant genetic variation in Asian populations is under-characterized. Here, the authors show the diversity in prevalence and spectrum of human disease and pharmacogenetic variants in a multi-ethnic Asian population.
- Sock Hoai Chan
- , Yasmin Bylstra
- & Weng Khong Lim
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| Open AccessMulti-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
The molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) remains poorly characterised. Here, the authors perform multi-omics analysis for 84 ALL patients and suggest 5 distinct subgroups for risk stratification and personalised treatment.’
- Tomoya Isobe
- , Masatoshi Takagi
- & Junko Takita
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| Open AccessMultiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes
Fat distribution is associated with cardiometabolic disease, although it has been less well studied than overall obesity. In a multiancestry exome-sequencing study, the authors identified predicted loss-of-function mutations in INHBE associated with favorable fat distribution and protection from type 2 diabetes.
- Parsa Akbari
- , Olukayode A. Sosina
- & Luca A. Lotta
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| Open AccessLarge-scale genomic analyses reveal insights into pleiotropy across circulatory system diseases and nervous system disorders
Circulatory system diseases and nervous system disorders often co-occur in patients. Here the authors use eMERGE and UK BioBank data to identify genomic regions associated with both phenotypes, providing insight into the relationship between these conditions.
- Xinyuan Zhang
- , Anastasia M. Lucas
- & Marylyn D. Ritchie
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| Open AccessThe potential of polygenic scores to improve cost and efficiency of clinical trials
Polygenic scores can identify individuals with high disease risk based on inborn DNA variation. We explore their potential to enrich clinical trials by identifying individuals based on higher risk of disease (‘prognostic enrichment’), or increased probability of benefit (‘predictive enrichment’).
- Akl C. Fahed
- , Anthony A. Philippakis
- & Amit V. Khera
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Article
| Open AccessDirect genome-wide identification of G-quadruplex structures by whole-genome resequencing
Current methods to identify G-quadruplex structures in DNA require specialized protocols and multiple rounds of sequencing. Here, the authors develop a method to detect G-quadruplex structures in DNA based on fluctuations in sequencing quality in a standard sequencing experiment.
- Jing Tu
- , Mengqin Duan
- & Zuhong Lu
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Article
| Open AccessRobust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing
Preservation of cancer biopsies by FFPE introduces DNA fragmentation, hindering analysis of rearrangements. Here the authors introduce FFPE Targeted Locus Capture for identification of translocations in preserved samples.
- Amin Allahyar
- , Mark Pieterse
- & Wouter de Laat
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Article
| Open AccessMicrofluidic platform accelerates tissue processing into single cells for molecular analysis and primary culture models
Existing methods for tissue dissociation are inefficient and lead to variable outcomes and biases. Here, the authors present a microfluidic platform that combines digestion, disaggregation and filtration of tissue to allow single cell analysis and RNA sequencing.
- Jeremy A. Lombardo
- , Marzieh Aliaghaei
- & Jered B. Haun
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Article
| Open AccessConstruction and integration of three de novo Japanese human genome assemblies toward a population-specific reference
Human reference genomes are typically constructed from few individuals, and are biased towards European and African genomes. Here, the authors assemble three Japanese genomes to create a population-specific reference genome. They then demonstrate improved variant calling from exome sequencing with this reference genome.
- Jun Takayama
- , Shu Tadaka
- & Gen Tamiya
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Article
| Open AccessNOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation
BRCA1 mutation carriers have higher chances of developing triple-negative breast cancer (TNBC). Here, the authors use the Sleeping Beauty mutagenesis system in Brca1 deficient mice and identify 169 putative driver genes, of which NOTCH1 accelerates TNBC formation through promoting epithelial-mesenchymal transition and cell cycle progression.
- Kai Miao
- , Josh Haipeng Lei
- & Chu-Xia Deng
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Article
| Open AccessGenetic drug target validation using Mendelian randomisation
Mendelian randomisation (MR) analysis of drug targets has potential to aid drug development. Here, the authors introduce a mathematical framework to elucidate this specific application of MR.
- Amand F. Schmidt
- , Chris Finan
- & Aroon D. Hingorani
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| Open AccessGenomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke
Stroke risk is influenced by genetic and lifestyle factors and previously a genomic risk score (GRS) for stroke was proposed, albeit with limited predictive power. Here, Abraham et al. develop a metaGRS that is composed of several stroke-related GRSs and demonstrate improved predictive power compared with individual GRS or classic risk factors.
- Gad Abraham
- , Rainer Malik
- & Martin Dichgans
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| Open AccessPhenotyping ciliary dynamics and coordination in response to CFTR-modulators in Cystic Fibrosis respiratory epithelial cells
Personalized approaches to diagnosis and treatment monitoring could improve the management of cystic fibrosis patients. Here the authors show that multiscale differential dynamic microscopy can assess changes in cilia beating dynamics and coordination in patient-derived airway epithelial cells, in response to different CFTR-modulating drugs, in a patient-specific manner.
- M. Chioccioli
- , L. Feriani
- & P. Cicuta
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| Open AccessMulti-platform discovery of haplotype-resolved structural variation in human genomes
Structural variants (SVs) in human genomes contribute diversity and diseases. Here, the authors use a multi-platform strategy to generate haplotype-resolved SVs for three human parent–child trios.
- Mark J. P. Chaisson
- , Ashley D. Sanders
- & Charles Lee
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Article
| Open AccessHaplosaurus computes protein haplotypes for use in precision drug design
Proteoforms arise as protein isoforms or as protein haplotypes, which are the result of genetic variation. Here, the authors develop Haplosaurus, a database that computes protein haplotypes genome-wide from existing genotype data and analyse protein haplotype variability in the 1000 Genomes dataset.
- William Spooner
- , William McLaren
- & Catherine Chaillan Huntington
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Article
| Open AccessAPOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism
Oral squamous cell carcinoma is a prevalent malignancy in Taiwan. Here, the authors show that OSCC in Taiwanese show a frequent deletion polymorphism in the cytidine deaminases gene cluster APOBEC3 resulting in increased expression of A3A, which is shown to be of clinical prognostic relevance.
- Ting-Wen Chen
- , Chi-Ching Lee
- & Yu-Sun Chang
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| Open AccessAnnotating pathogenic non-coding variants in genic regions
While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.
- Sahar Gelfman
- , Quanli Wang
- & David B. Goldstein
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| Open AccessPredicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity
Efficacy of anticancer treatments vary across patients, imposing a need for personalized approaches. Here the authors show that responsiveness to chemotherapy can be predicted using tumour explant cultures in a patient-matched microenvironment, coupled with a machine-learning algorithm.
- Biswanath Majumder
- , Ulaganathan Baraneedharan
- & Pradip K. Majumder
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Article |
A smart and versatile theranostic nanomedicine platform based on nanoporphyrin
Nanoparticles can be used for therapeutic and diagnostic purposes. Here, the authors report that nanoparticles made of a single chemical building block, called nanoporphyrins, incorporate eight different functionalities, including various types of imaging, drug delivery and cancer therapy.
- Yuanpei Li
- , Tzu-yin Lin
- & Kit S. Lam
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| Open AccessStrong effects of genetic and lifestyle factors on biomarker variation and use of personalized cutoffs
Protein biomarkers could play an important role in the diagnosis and management of diseases. Here the authors investigate the impact of genetic, clinical and lifestyle factors on 92 protein biomarkers for cancer and inflammation and suggest that personalized biomarker thresholds should be used in cancer management.
- Stefan Enroth
- , Åsa Johansson
- & Ulf Gyllensten
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| Open AccessA designer cell-based histamine-specific human allergy profiler
The advancement of sensitive, accurate and non-invasive methods to identify the allergen that drives allergic disease in an individual remains a challenge. Here, the authors develop a synthetic biology approach using human designer cells to profile allergic reactions against an array of allergens measuring histamine release from whole blood.
- David Ausländer
- , Benjamin Eggerschwiler
- & Martin Fussenegger