Featured
-
-
Article
| Open AccessHigh-throughput screening of prostate cancer risk loci by single nucleotide polymorphisms sequencing
Functional characterization of disease-causing variants at risk loci in cancer is challenging. Here, in prostate cancer the authors report a pipeline for high-throughput single-nucleotide polymorphisms sequencing (SNPs-seq) for large scale screening of functional SNPs at disease risk loci.
- Peng Zhang
- , Ji-Han Xia
- & Liang Wang
-
Article
| Open AccessCross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.
- Adriana I. Iglesias
- , Aniket Mishra
- & Stuart MacGregor
-
Article
| Open AccessCCDC102B confers risk of low vision and blindness in high myopia
Myopic maculopathy is a complication of myopia that often progresses to blindness. Here, in a genome-wide association study, Hosoda et al. find that rs11873439 intronic to CCDC102B is associated with myopic maculopathy, but not with myopia, thus representing a risk factor independent of myopia.
- Yoshikatsu Hosoda
- , Munemitsu Yoshikawa
- & Kenji Yamashiro
-
Article
| Open AccessIdentification of rare sequence variation underlying heritable pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2, ATP13A3, AQP1 and SOX17.
- Stefan Gräf
- , Matthias Haimel
- & Nicholas W. Morrell
-
Article
| Open AccessPlacenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum
Hyperemesis gravidarum (HG) is a severe form of nausea and vomiting associated with unfavourable outcomes during pregnancy. Here, Fejzo et al. perform genome-wide scans for HG and pregnancy nausea and vomiting and identify genetic associations at two loci implicating the genes GDF15 and IGFBP7.
- Marlena S. Fejzo
- , Olga V. Sazonova
- & Catherine H. Wilson
-
Article
| Open AccessHeritable DNA methylation marks associated with susceptibility to breast cancer
DNA methylation is associated with breast cancer risk. Here the authors measure DNA methylation in the blood of individuals from 25 Australian families with multiple cases of breast cancer but not known mutations associated with breast cancer risk to identify possible heritable methylation markers.
- Jihoon E. Joo
- , James G. Dowty
- & Yoland Antill
-
Article
| Open AccessComprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes
More than 100 risk loci for schizophrenia have been identified by genome-wide association studies. Here, the authors apply an integrative genomic approach to prioritize risk genes and validate GLT8D1 and CSNK2B as candidate causal genes by in vitro studies in neural stem cells.
- Cui-Ping Yang
- , Xiaoyan Li
- & Xiong-Jian Luo
-
Article
| Open AccessSomatic mutagenesis in satellite cells associates with human skeletal muscle aging
Aging skeletal muscle shows declining numbers and activity of satellite cells. Here, Franco et al. show that in satellite cells of the human leg muscle vastus lateralis, somatic mutations accumulate with age and that these mutations become enriched in exons and promoters of genes involved in muscle function.
- Irene Franco
- , Anna Johansson
- & Maria Eriksson
-
Review Article
| Open AccessFormalising recall by genotype as an efficient approach to detailed phenotyping and causal inference
Recall-by-Genotype (RbG) is an approach to recall participants from genetic studies based on their specific genotype for further, more extensive phenotyping. Here, the authors discuss examples of RbG as well as practical and ethical considerations and provide an online tool to aid in designing RbG studies.
- Laura J. Corbin
- , Vanessa Y. Tan
- & Nicholas J. Timpson
-
Article
| Open AccessBLM helicase suppresses recombination at G-quadruplex motifs in transcribed genes
Bloom syndrome is characterized by high levels of sister chromatid exchanges (SCEs). Here, the authors use single-cell DNA template strand-sequencing to map SCEs in patient cells, and propose that the BLM helicase protects the genome against unwanted recombination at sites of G-quadruplex structures.
- Niek van Wietmarschen
- , Sarra Merzouk
- & Peter M. Lansdorp
-
Article
| Open AccessGWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21
Childhood acute lymphoblastic leukemia is common in Latino Americans. Here, the authors conduct a genome-wide association study in a Californian cohort containing children of Latino heritage, and identify loci on 17q12 and 8q24 which may affect hematopoietic and growth-regulation pathways.
- Joseph L. Wiemels
- , Kyle M. Walsh
- & Xiaomei Ma
-
Article
| Open AccessGenome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels
Vitamin D deficiency is associated with multiple human pathologic conditions. In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.
- Xia Jiang
- , Paul F. O’Reilly
- & Douglas P. Kiel
-
Article
| Open AccessA PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients
Inborn errors of vitamin B12 metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.
- Jean-Louis Guéant
- , Céline Chéry
- & David S. Rosenblatt
-
Article
| Open AccessObligatory and facilitative allelic variation in the DNA methylome within common disease-associated loci
Genomic polymorphisms affect the epigenome, which in turn influences how epigenome- and genome-wide analysis are interpreted. Here, the authors characterise allelic differences in DNA methylation driven by obligatory or facilitative genetic effects, which may affect disease-related loci.
- Christopher G. Bell
- , Fei Gao
- & Timothy D. Spector
-
Article
| Open AccessA large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure
Intraocular pressure (IOP) is a major risk factor for glaucoma. Here, Choquet and co-authors perform a multi-ethnic genome-wide association study of repeat IOP measurements in 69,756 individuals and identify 40 novel loci, 36 of which show directionally consistent effects in glaucoma.
- Hélène Choquet
- , Khanh K. Thai
- & Eric Jorgenson
-
Article
| Open AccessTwo missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis
Growth retardation is most commonly caused by genetic defects in the growth hormone pathway. Here, in families with growth retardation and gingival fibromatosis, the authors identify mutations in the potassium channel gene KCNQ1 that cause electrophysiological aberrations and altered ACTH secretion in vitro.
- Johanna Tommiska
- , Johanna Känsäkoski
- & Taneli Raivio
-
Article
| Open AccessPan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors
Homozygous deletions are rare in cancers and often target tumour suppressor genes. Here, the authors conduct pan-cancer analyses and apply statistical modelling to identify 27 candidate tumour suppressors, including MAFTRR, KIAA1551, and IGF2BP2.
- Jiqiu Cheng
- , Jonas Demeulemeester
- & Peter Van Loo
-
Article
| Open AccessVariation in a range of mTOR-related genes associates with intracranial volume and intellectual disability
The mTOR pathway is a key regulator of normal brain development. Here, the authors identify de novo mutations in RHEB, an mTOR activator protein, in patients with intellectual disability associated with megalencephaly and find a role for RHEB in regulating neuronal soma size and migration in vitro and in vivo.
- M. R. F. Reijnders
- , M. Kousi
- & H. G. Brunner
-
Article
| Open AccessGenome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity
Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
- Peter K. Joshi
- , Nicola Pirastu
- & James F. Wilson
-
Article
| Open AccessGenome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections
Susceptibility to infectious diseases is, among others, influenced by the genetic landscape of the host. Here, Tian and colleagues perform genome-wide association studies for 23 common infections and find 59 risk loci for 17 of these, both within the HLA region and non-HLA loci.
- Chao Tian
- , Bethann S. Hromatka
- & David A. Hinds
-
Article
| Open AccessTransancestral mapping and genetic load in systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong ethnic and gender bias. In a transancestral genetic association study, Langefeldet al. identify 24 novel regions associated with risk to lupus and propose a cumulative hits hypothesis for loci conferring risk to SLE.
- Carl D. Langefeld
- , Hannah C. Ainsworth
- & Timothy J. Vyse
-
Article
| Open AccessLarge-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness
Hand grip strength as a proxy of muscular fitness is a clinical predictor of mortality and morbidity. In a large-scale GWA study, the authors find 16 robustly associated genetic loci that highlight roles in muscle fibre structure and function, neuronal maintenance and nervous system signal transduction.
- Sara M. Willems
- , Daniel J. Wright
- & Robert A. Scott
-
Article
| Open AccessA defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome
During embryogenesis, the cytoplasmic protein Myomarker (MYMK) mediates muscle fibre formation by fusion of myoblasts. Here, the authors identify autosomal recessive mutations in MYMK that cause Carey-Fineman-Ziter syndrome in humans, and model the disease variants in zebrafish.
- Silvio Alessandro Di Gioia
- , Samantha Connors
- & Elizabeth C. Engle
-
Article
| Open AccessGenetic diagnosis of Mendelian disorders via RNA sequencing
Genome sequencing alone fails to provide a genetic diagnosis for many Mendelian disorder patients. Here, the authors utilize RNA sequencing to complement genotyping of patients with a rare mitochondrial disease by detecting aberrant RNA expression, splicing and allele-specific expression.
- Laura S. Kremer
- , Daniel M. Bader
- & Holger Prokisch
-
Article
| Open AccessSequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis
A hallmark of diverticular disease is pouches in the bowel wall which can become infected and inflamed, causing the more severe diverticulitis. Here, the authors report the first genome-wide association study on these interconnected conditions and identifyARHGAP15, COLQ and FAM155Aas novel risk loci.
- Snaevar Sigurdsson
- , Kristjan F. Alexandersson
- & Kari Stefansson
-
Article
| Open AccessMeta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism
Endometriosis is a major cause of infertility. Molecular mechanisms underlying the disease involve genetic and environmental risk factors. In a meta-analysis of eleven GWA studies, Sapkota and colleagues identify five novel risk loci, implicating steroid sex hormone pathways in the pathogenesis.
- Yadav Sapkota
- , Valgerdur Steinthorsdottir
- & Dale R. Nyholt
-
Article
| Open AccessZinc is a potent and specific inhibitor of IFN-λ3 signalling
Lambda interferons (IFNL) are involved in the immune response to viral infection. Here the authors show that zinc can interfere with IFNL signalling, and that in HCV patients the rs12979860 polymorphism regulates blood zinc levels and, subsequently, the hepatic immune response.
- Scott A. Read
- , Kate S. O’Connor
- & Golo Ahlenstiel
-
Article
| Open AccessCirculating tumour DNA sequence analysis as an alternative to multiple myeloma bone marrow aspirates
Genetic profiling of multiple myeloma requires painful bone marrow biopsies. Here, the authors develop an alternative non-invasive method for sequencing of five oncogenes in circulating cell-free DNA from myeloma patients, demonstrating 96% concordance with bone marrow tumour profiling results.
- Olena Kis
- , Rayan Kaedbey
- & Trevor J. Pugh
-
Article
| Open AccessGenome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.
- Anne E. Justice
- , Thomas W. Winkler
- & L Adrienne Cupples
-
Article
| Open AccessGenome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy
Fuchs endothelial corneal dystrophy (FECD) is one of the most common reasons for corneal transplantation, and is known to cluster in families. Here, the authors discover new genetic loci associated with FECD with sex-specific effects and implications for disease mechanism.
- Natalie A. Afshari
- , Robert P. Igo Jr
- & Sudha K. Iyengar
-
Article
| Open AccessGenetic correlation between amyotrophic lateral sclerosis and schizophrenia
Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.
- Russell L. McLaughlin
- , Dick Schijven
- & Michael C. O’Donovan
-
Article
| Open AccessGenomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia
Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.
- Zhaohui Gu
- , Michelle Churchman
- & Charles G. Mullighan
-
Article
| Open AccessGenome-wide association study for acute otitis media in children identifies FNDC1 as disease contributing gene
Acute otitis media (AOM) is an acute infection of middle ear mucosa and among the most common pediatric diseases. Here, the authors performed a genome-wide association study to link a variant in the FNDC1 locus on 6q25.3 and differential methylation status of the FNDC1gene with predisposition to AOM.
- Gijs van Ingen
- , Jin Li
- & Hakon Hakonarson
-
Article
| Open AccessMBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C
Chronic Hepatitis C infection is associated with a broad spectrum of liver pathologies, ranging from inflammation to fibrosis and liver cancer. Here Thabet et al. identified a polymorphism in the gene MBOAT7 that is associated with increased hepatic inflammation and higher risk of fibrosis development and progression.
- Khaled Thabet
- , Anastasia Asimakopoulos
- & Rosanna Santaro
-
Article
| Open AccessMutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis
Neonatal cholestasis is a result of elevated bile acid levels, and is associated with mutations in genes regulating bile acid homeostasis. Here the authors identify mutations in the bile acid sensing farnesoid X receptor in four individuals with neonatal cholestasis from two unrelated families.
- Natalia Gomez-Ospina
- , Carol J. Potter
- & David D. Moore
-
Article
| Open AccessA new tool called DISSECT for analysing large genomic data sets using a Big Data approach
Availability of computing power can limit computational analysis of large genetic and genomic datasets. Here, Canela-Xandri, et al. describe a software called DISSECT that is capable of analyzing large-scale genetic data by distributing the work across thousands of networked computers.
- Oriol Canela-Xandri
- , Andy Law
- & Albert Tenesa
-
Article
| Open AccessC. elegans maximum velocity correlates with healthspan and is maintained in worms with an insulin receptor mutation
Increases in lifespan do not necessarily translate into prolonged healthspan. Here, the authors devise a simple metric, maximum velocity, to study ageing in C. elegansand, using this metric, show that reduced insulin signalling improves physical healthspan as well as worm lifespan.
- Jeong-Hoon Hahm
- , Sunhee Kim
- & Hong Gil Nam
-
Article |
PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis
Platelet-derived growth factor (PDGF) signaling in vascular smooth muscle cells (VSMCs) promotes atherogenesis. Here, the authors show that mutant mice with increased PDGF activity in VSMCs have augmented STAT1-dependent chemokine signals resulting in artery wall inflammation and formation of advanced plaque morphologies clinically relevant in humans.
- Chaoyong He
- , Shayna C. Medley
- & Lorin E. Olson
-
Article
| Open AccessStereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes
The gut epithelium is damaged in inflammatory bowel disease, but capturing such lesions by histology can be difficult. Here, the authors use stereomicroscopy to visualize different 3D inflammatory structures and associated microbes in humans and in 16 genetic mouse models relevant to intestinal inflammation.
- Alex Rodriguez-Palacios
- , Tomohiro Kodani
- & Fabio Cominelli
-
Article
| Open AccessPrediction model for aneuploidy in early human embryo development revealed by single-cell analysis
Aneuploidy may be fatal for the embryo, hence predicting its occurrence is important for successfulin vitrofertilization. Here the authors monitor development of human preimplantation embryos in real-time and correlate the blastomere ploidy with cleavage dynamics and gene expression, identifying 12-transcript signature that determines ploidy.
- Maria Vera-Rodriguez
- , Shawn L. Chavez
- & Carlos Simon
-
Article
| Open AccessObesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance
The hormone adiponectin is produced by fat cells and has positive metabolic effects. Here, Kim et al.show that DNA methyltransferase 1 (DNMT1) represses adiponectin expression through hypermethylation of its promoter, and that inflammatory cytokines enhance DNMT1 activity in obese mice and humans.
- A. Young Kim
- , Yoon Jeong Park
- & Jae Bum Kim
-
Article |
Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin
Adult expression of fetal haemoglobin is beneficial and thus desirable in patients with haemoglobin disorders. Here the authors introduce a naturally occurring mutation in the γ-globinpromoter and show that it causes binding of an activator TAL1, chromosome looping and revival of fetal haemoglobin expression in erythroid cells.
- Beeke Wienert
- , Alister P. W. Funnell
- & Merlin Crossley
-
Article
| Open AccessCorrection of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy
Phospholamban (PLN) is a regulator of heart contractility. Here the authors show that cardiomyocytes derived from induced pluripotent stem cells of a cardiomyopathy patient with mutant PLN exhibit functional defects consistent with the disease, and that this mutation can be functionally corrected by genome editing and gene therapy.
- Ioannis Karakikes
- , Francesca Stillitano
- & Roger J. Hajjar
-
Article
| Open AccessCapturing the cloud of diversity reveals complexity and heterogeneity of MRSA carriage, infection and transmission
Populations of bacterial pathogens can be diverse within colonized individuals. Here, the authors sequence the genomes of methicillin-resistant Staphylococcus aureusisolated from staff and animal patients at a veterinary hospital and show considerable within-host diversity that can rise and fall over time.
- Gavin K. Paterson
- , Ewan M. Harrison
- & Mark A. Holmes
-
Article
| Open AccessDefective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy
Diabetic kidney disease is associated with ER stress in podocytes. Here the authors use various genetically modified mouse models to study ER-stress-related signalling pathways and propose a mechanistic framework that links insulin signalling with ER stress in podocytes of diabetic mice.
- Thati Madhusudhan
- , Hongjie Wang
- & Berend Isermann
-
Article |
Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension
Transcription factor Nr2f2 is linked to high blood pressure in humans and animals. Using hypertensive rats that have been genetically modified to express a mutant Nr2f2 that binds stronger to transcription factor Fog2, the authors show that the interaction between these two proteins is critical for blood pressure regulation.
- Sivarajan Kumarasamy
- , Harshal Waghulde
- & Bina Joe
-
Article
| Open AccessGenetic targeting of sprouting angiogenesis using Apln-CreER
Apelin expression is robust in embryonic but not in adult endothelial cells (ECs), where it can be reactivated by hypoxia. Liu et al. show that apelin-driven expression of Cre recombinase in mice can be used for labelling of, or gene ablation in, sprouting but not quiescent ECs in pathologies characterized by hypoxia.
- Qiaozhen Liu
- , Tianyuan Hu
- & Bin Zhou
-
Article
| Open AccessDrawing a high-resolution functional map of adeno-associated virus capsid by massively parallel sequencing
Adeno-associated viruses (AAV) are promising gene transfer vectors for human gene therapy. Here, the authors report a high-throughput, sequencing-based method for characterizing amino acid function in AAV capsids and highlight the potential of this method for improving capsid design.
- Kei Adachi
- , Tatsuji Enoki
- & Hiroyuki Nakai
-
Article |
A common functional promoter variant links CNR1 gene expression to HDL cholesterol level
Haplotypes in CNR1, the gene encoding the cannabinoid receptor CB1, are known to influence HDL cholesterol levels. Here Feng and colleagues identify rs806371 as a novel regulatory element reducing CNR1 gene expression and as the causal allele driving the association between CNR1 and HDL cholesterol levels in humans.
- Q. Feng
- , K.C. Vickers
- & R.A. Wilke