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| Open AccessGenome-wide rare variant score associates with morphological subtypes of autism spectrum disorder
Morphological subtypes of autism spectrum disorder (ASD) may differ in their genetic bases. Chan et al. develop a method for calculating a patient-level, genome-wide rare variant score and find significant differences in rare and common variant associations between dysmorphic and nondysmorphic ASD groups.
- Ada J. S. Chan
- , Worrawat Engchuan
- & Stephen W. Scherer
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Article
| Open AccessCharacterization of somatic structural variations in 528 Chinese individuals with Esophageal squamous cell carcinoma
The biological and clinical implications of high genome instability in esophageal squamous cell carcinoma (ESCC) remain to be explored. Here, the authors analyse 528 whole genomes and investigate the landscape and molecular mechanisms underlying structural variations in ESCC patients.
- Heyang Cui
- , Yong Zhou
- & Qimin Zhan
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Article
| Open AccessHost genetic factors related to innate immunity, environmental sensing and cellular functions are associated with human skin microbiota
Microbiome composition is influenced by genetics, although the specific host genetic factors responsible are not well known. Here, the authors performed a genome-wide meta-analysis to discover host genetic effects on skin microbiota and finding potential causal effects of microbiota composition on skin diseases.
- Lucas Moitinho-Silva
- , Frauke Degenhardt
- & Malte Christoph Rühlemann
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Article
| Open AccessGenetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells
The role of the immune system in the pathogenesis of psychiatric disorders is unclear. Here, the authors show that genetic risk variants for multiple psychiatric disorders are enriched in regions of the genome active in the brain and in lymphoid cells, especially stimulated T cells, but not in myeloid cells.
- Mary-Ellen Lynall
- , Blagoje Soskic
- & Ed Bullmore
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Article
| Open AccessBNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency
Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction that results in infertility. Here they show that BCN1 mutation results in premature ovarian follicle activation and atresia through dysregulation of ferroptosis.
- Feixia Wang
- , Yifeng Liu
- & Dan Zhang
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Article
| Open AccessThe CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma
Metastatic pancreatic ductal adenocarcinoma (mPDAC) has limited therapeutic options and is associated with a poor prognosis. Here the authors report the results of a randomized phase II trial showing that combining checkpoint inhibitors (durvalumab and tremelimumab) with chemotherapy (gemcitabine and nab-paclitaxel) does not improve survival compared to chemotherapy alone in patients with mPDAC.
- Daniel J. Renouf
- , Jonathan M. Loree
- & Chris J O’Callaghan
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Article
| Open AccessAn automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases
Rapid diagnosis and implementation of treatments is crucial in many genetic conditions. Here the authors describe Genome-to-Treatment, a virtual disease management system that can achieve a rapid diagnosis by expedited whole genome sequencing in 13.5 hours and provide guidance to clinicians for possible therapies.
- Mallory J. Owen
- , Sebastien Lefebvre
- & Stephen F. Kingsmore
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Article
| Open AccessDevelopment of a novel core genome MLST scheme for tracing multidrug resistant Staphylococcus capitis
Staphylococcus capitis is a common causative agent of bloodstream infections in neonatal intensive care units, with multidrug resistant isolates complicating treatment. Authors aimed to establish a core genome multilocus sequence typing (cgMLST) scheme to document the transmission and dissemination of multidrug-resistant S. capitis isolates.
- Zhengan Wang
- , Chao Gu
- & Yunsong Yu
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Article
| 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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Article
| Open AccessComprehensive genome-wide association study of different forms of hernia identifies more than 80 associated loci
Hernias involve protrusion of an organ or tissue through its surrounding cavity. Here the authors carry out GWAS for five types of hernia and find 81 variants, most of which are associated with inguinal hernia; downstream analysis suggests an important role for connective tissue morphology.
- João Fadista
- , Line Skotte
- & Frank Geller
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Article
| Open AccessUsing deep learning to predict abdominal age from liver and pancreas magnetic resonance images
Approaches to both determine abdominal age and identify risk factors for accelerated abdominal age will help delay the onset of several diseases. Here, the authors build an abdominal age predictor by training convolutional neural networks to predict abdominal age from liver and pancreas MRIs.
- Alan Le Goallec
- , Samuel Diai
- & Chirag J. Patel
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Article
| Open AccessMultidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers
Alterations in cis-regulatory elements (CREs) can contribute to pancreatic diseases. Here the authors combine chromatin profiling and interaction points with in vivo reporter assays in zebrafish to uncover functionally equivalent human CREs, helping to predict disease-relevant enhancers.
- Renata Bordeira-Carriço
- , Joana Teixeira
- & José Bessa
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Article
| Open AccessDNA methylation in newborns conceived by assisted reproductive technology
Timing of assisted reproduction technology (ART) procedures coincides with extensive epigenetic remodeling early after conception. Here the authors identify 176 DNA methylation differences in cord blood of newborns conceived with ART. including genes related to growth, neurodevelopment, and cancer.
- Siri E. Håberg
- , Christian M. Page
- & Robert Lyle
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Article
| Open AccessIdentification of host–pathogen-disease relationships using a scalable multiplex serology platform in UK Biobank
Here, the authors design a multiplex serology platform to quantitatively measure antibodies against 20 infectious agents in UK Biobank participants and confirm associations of antibody responses with sociodemographic characteristics, HLA genetic variants, and disease outcomes.
- Alexander J. Mentzer
- , Nicole Brenner
- & Tim Waterboer
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Article
| Open AccessEmpirical prediction of variant-activated cryptic splice donors using population-based RNA-Seq data
Genetic variants affecting the consensus splicing motifs can alter binding of spliceosomal components and induce mis-splicing. Here, the authors develop a method, showing that ranking the most common recurring mis-splicing events in public RNA-Seq data can predict the activation of cryptic-donors.
- Ruebena Dawes
- , Himanshu Joshi
- & Sandra T. Cooper
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Article
| Open AccessMechanism of action and therapeutic route for a muscular dystrophy caused by a genetic defect in lipid metabolism
Mutations in the CHKB gene cause muscular dystrophy. Here, the authors show that in mouse models of the disease changes in lipid metabolism are associated with decreased PPAR signaling, and show PPAR agonists can rescue expression of injury markers in myocytes in vitro.
- Mahtab Tavasoli
- , Sarah Lahire
- & Christopher R. McMaster
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Article
| Open AccessSmall RNA pathways in the nematode Ascaris in the absence of piRNAs
The parasitic nematode Ascaris lacks piRNAs. Here the authors compare Argonaute proteins and small RNAs from C. elegans and Ascaris, expanding our understanding of the conservation, divergence, and flexibility of Argonautes and small RNA pathways in nematodes.
- Maxim V. Zagoskin
- , Jianbin Wang
- & Richard E. Davis
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Article
| Open AccessA platform for oncogenomic reporting and interpretation
The interpretation of somatic variants in cancer is challenging due to the scale and complexity of sequencing data. Here, the authors present PORI, an open-source framework for interpreting somatic variants in cancer using graph knowledge base tools, automated reporting, and manual curation.
- Caralyn Reisle
- , Laura M. Williamson
- & Steven J. M. Jones
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Article
| Open AccessGenome-wide association meta-analysis identifies 29 new acne susceptibility loci
Better understanding of the genetic basis of acne can pave the way to more effective treatments. Here, the authors perform a genome-wide association study meta-analysis of >20,000 cases and identify 29 new acne susceptibility loci, uncovering genetic links to Mendelian hair and skin disorders and other complex traits.
- Brittany L. Mitchell
- , Jake R. Saklatvala
- & Michael A. Simpson
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Article
| Open AccessPopulation-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene
While the consequences of homozygous loss of function variants have been studied, the effect of missense variants is less understood. Here, the authors identify pathogenic genotypes through an observed deficit of homozygous carriers of missense variants in a population, elucidating previously unexplained recessive disease and miscarriage.
- Gudny A. Arnadottir
- , Asmundur Oddsson
- & Kari Stefansson
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Article
| Open AccessA robust method for collider bias correction in conditional genome-wide association studies
Genetic associations can be biased by conditioning on a phenotype. This study presents ‘Slope-Hunter’, a method which uses model-based clustering to correct this bias, even in the presence of genetic correlation, assuming the class of SNPs affecting only the collider explains more variation in the collider than any other class of SNPs.
- Osama Mahmoud
- , Frank Dudbridge
- & Kate Tilling
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Article
| Open AccessDeepNull models non-linear covariate effects to improve phenotypic prediction and association power
GWAS often assume a linear phenotype-covariate relationship which may not hold in practice. Here the authors present DeepNull, in which they apply deep learning to identify and adjust for complex non-linear relationships, improving phenotypic prediction and GWAS power.
- Zachary R. McCaw
- , Thomas Colthurst
- & Farhad Hormozdiari
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Article
| Open AccessFunctional dissection of inherited non-coding variation influencing multiple myeloma risk
The causality and functional roles of disease-associated variants revealed by genome-wide association studies (GWAS) are mostly unexplored. Here the authors identify putative causal variants in multiple myeloma and find their association with gene expression and chromatin accessibility.
- Ram Ajore
- , Abhishek Niroula
- & Björn Nilsson
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Article
| Open AccessGenome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis
Physterols are cholesterol homologs derived from plants, which are found in humans through consumption of plant products. Here the authors have performed a genome-wide meta-analysis of 32 serum phytosterol traits, with evidence suggesting causality between sitosterol and coronary artery disease.
- Markus Scholz
- , Katrin Horn
- & Uta Ceglarek
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Article
| Open AccessFinding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.
- Catherine S. Storm
- , Demis A. Kia
- & Nicholas W. Wood
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Article
| Open AccessThe telomere length landscape of prostate cancer
Despite the known role of telomere length in cancer, its association with genomic features remains unclear. Here, the authors integrate telomere length, genomics, transcriptomics and proteomics in localized prostate cancer and reveal links between telomere maintenance, disease drivers and clinical outcomes.
- Julie Livingstone
- , Yu-Jia Shiah
- & Paul C. Boutros
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Article
| Open AccessAssociations between patterns in comorbid diagnostic trajectories of individuals with schizophrenia and etiological factors
Schizophrenia is a complex disorder where individuals experience different symptoms and outcomes that can be captured by patterns in other diagnoses. Here the authors use computational approaches to summarize these patterns and suggest they are associated with genetic and environmental exposure.
- Morten Dybdahl Krebs
- , Gonçalo Espregueira Themudo
- & Wesley K. Thompson
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Article
| Open AccessNetwork analysis reveals rare disease signatures across multiple levels of biological organization
Despite the clear causal relationship between genotype and phenotype in rare diseases, identifying the pathobiological mechanisms at various levels of biological organization remains a practical and conceptual challenge. Here, the authors introduce a network approach for evaluating the impact of rare gene defects across biological scales.
- Pisanu Buphamalai
- , Tomislav Kokotovic
- & Jörg Menche
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Article
| Open AccessThe history and geographic distribution of a KCNQ1 atrial fibrillation risk allele
Many rare high-impact variants have been associated with disease, but the origins and functional impact are not always explored. Here, the authors trace the ancestry of a rare high impact atrial fibrillation allele in KCNQ1, and use iPSC-derived cardiomyocytes to characterize the effect of the allele.
- Shannon Hateley
- , Angelica Lopez-Izquierdo
- & Martin Tristani-Firouzi
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Article
| Open AccessEstimating disease prevalence in large datasets using genetic risk scores
Estimating disease prevalence in biobanks is prone to error, especially for self-reported traits. Here, the authors propose a method to estimate the prevalence of a disease within a cohort based on genetic risk scores.
- Benjamin D. Evans
- , Piotr Słowiński
- & Nicholas J. Thomas
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Article
| Open AccessGenetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases
Fibromuscular dysplasia is a cardiovascular disease affecting mostly women with a mostly unknown genetic basis. Here the authors have performed a genome-wide association meta-analysis of Fibromuscular dysplasia to identify genetic loci, some of which are shared with common cardiovascular disease and traits.
- Adrien Georges
- , Min-Lee Yang
- & Nabila Bouatia-Naji
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Article
| Open AccessGenomic sequencing of SARS-CoV-2 in Rwanda reveals the importance of incoming travelers on lineage diversity
Genomic surveillance of SARS-CoV-2 can inform regional transmission dynamics and inform public health interventions. Here, the authors sequence ~200 samples from Rwanda, identify shifts in predominating strains from May 2020 to February 2021, and infer geographic origins.
- Yvan Butera
- , Enatha Mukantwari
- & Nadine Rujeni
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Article
| Open AccessIdentical twins carry a persistent epigenetic signature of early genome programming
The mechanisms underlying how monozygotic (or identical) twins arise are yet to be determined. Here, the authors investigate this in an epigenome-wide association study, showing that monozygotic twinning has a characteristic DNA methylation signature in adult somatic tissues.
- Jenny van Dongen
- , Scott D. Gordon
- & Dorret I. Boomsma
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Article
| Open AccessInvestigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases
An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well-established, but a genetic link is unclear. Here, the authors investigate the shared genetic architecture between MS and IBD to shed light on the biological basis of comorbidity.
- Yuanhao Yang
- , Hannah Musco
- & Yuan Zhou
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| Open AccessAnalyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach
Huang and colleagues used machine-learning estimators to analyse a broad range of parameters in a prospective cohort consisting ART and spontaneously conceived children. Small differences in stature and growth could not be explained by parental or perinatal environment factors, nor differences in fetal DNA methylation. No strong differences in metabolic parameters were seen.
- Jonathan Yinhao Huang
- , Shirong Cai
- & Shiao-Yng Chan
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Article
| Open AccessDiscovery and prioritization of variants and genes for kidney function in >1.2 million individuals
Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.
- Kira J. Stanzick
- , Yong Li
- & Thomas W. Winkler
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Article
| Open AccessGenome-wide association study identifies five risk loci for pernicious anemia
Pernicious anemia shows co-incidence with autoimmune disorders, yet the genetic basis for this condition is understudied. Here, the authors perform a genome-wide association study meta-analysis on pernicious anemia, identifying five susceptibility loci that map to genes with known roles in autoimmune disease.
- Triin Laisk
- , Maarja Lepamets
- & Reedik Mägi
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Article
| Open AccessVariant-specific inflation factors for assessing population stratification at the phenotypic variance level
Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.
- Tamar Sofer
- , Xiuwen Zheng
- & Kenneth M. Rice
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Article
| Open AccessThe genetic architecture of the human thalamus and its overlap with ten common brain disorders
Differences in thalamic structure have been observed in several psychiatric disorders, but the genetic overlap has not been explored. Here, the authors perform a genome-wide association study on thalamic nuclei volume and find genetic loci in common between thalamic volumes and brain disorders.
- Torbjørn Elvsåshagen
- , Alexey Shadrin
- & Tobias Kaufmann
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Article
| Open AccessThe transcriptional landscape of Shh medulloblastoma
Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.
- Patryk Skowron
- , Hamza Farooq
- & Michael D. Taylor
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Article
| Open AccessSingle cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain
The contribution of distinct types of dorsal root ganglion neurons to chronic pain is unclear. Here, the authors molecularly profile non-human primate sensory neurons and show that genome-wide associations converge on two neuronal types with different genetic susceptibilities for chronic pain.
- Jussi Kupari
- , Dmitry Usoskin
- & Patrik Ernfors
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Article
| Open AccessRevealing the role of the human blood plasma proteome in obesity using genetic drivers
Blood circulating proteins reflect biological processes, thus providing insight into complex traits. Here the authors study the relationship between 1000 plasma proteins and body mass index (BMI), highlighting widespread proteome changes and causal relationships between BMI and specific proteins.
- Shaza B. Zaghlool
- , Sapna Sharma
- & Karsten Suhre
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Article
| Open AccessWhole genome sequencing in the Middle Eastern Qatari population identifies genetic associations with 45 clinically relevant traits
The genetic basis for traits can vary between populations. Here the authors report a genome wide association study with 45 clinically-relevant traits in individuals from Qatar, replicating many known loci and identifying new Qatari-predominant signals.
- Gaurav Thareja
- , Yasser Al-Sarraj
- & Omar M. E. Albagha
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Article
| Open AccessInflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease
Inflammatory bowel diseases are heterogeneous, and little is known about how underlying genetic variation can affect their development. Here, the authors report that intestinal inflammation modulates the effect of host genetics on the gut mucosal expression of 190 genes in the context of inflammatory bowel diseases.
- Shixian Hu
- , Werna T. Uniken Venema
- & Rinse K. Weersma
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Article
| Open AccessGenome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.
- Garan Jones
- , Katerina Trajanoska
- & Luke C. Pilling
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Article
| Open AccessMendelian randomization study of maternal influences on birthweight and future cardiometabolic risk in the HUNT cohort
Observationally, lower birthweight is a risk factor for cardiometabolic disease. Using Mendelian Randomization, the authors investigate whether maternal genetic factors that lower offspring birthweight also increase offspring cardiometabolic risk and show that the observational correlation is unlikely to be due to the intrauterine environment.
- Gunn-Helen Moen
- , Ben Brumpton
- & David M. Evans
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Article
| Open AccessA shared genetic contribution to breast cancer and schizophrenia
Schizophrenia has been associated with increased risk of breast cancer, yet the risk of schizophrenia following breast cancer is unclear. Here, the authors show a bidirectional association between breast cancer and schizophrenia in Sweden and a shared genetic contribution to both diseases.
- Donghao Lu
- , Jie Song
- & Unnur A. Valdimarsdóttir
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Article
| Open AccessAn investigation of causal relationships between prediabetes and vascular complications
Prediabetes has been associated with diabetes complications, but these relationships may be confounded. Here the authors show, using genetic data in causal inference analyses, that prediabetes raises risk of coronary heart disease, but not other diabetes complications.
- Pascal M. Mutie
- , Hugo Pomares-Millan
- & Paul W. Franks
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Article
| Open AccessLoss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology
Mandibuloacral dysplasias (MADs) are rare progeroid syndromes characterized by nuclear morphological and functional abnormalities. Here the authors report that loss of mitochondrial membrane protein MTX2 causes a progeroid MAD sharing clinical features with lamin-associated progeroid syndromes.
- Sahar Elouej
- , Karim Harhouri
- & Annachiara De Sandre-Giovannoli