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| Open AccessMutations in COMP cause familial carpal tunnel syndrome
Familial carpal tunnel syndrome (CTS) is common, but causal genes are not characterized. Here the authors report two CTS-related mutations in two large families that impair secretion of COMP in tenocytes, leading to ER stress-induced unfolded protein response, inflammation and fibrosis in patients and mouse models.
- Chunyu Li
- , Ni Wang
- & Bo Gao
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Article
| Open AccessDisruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype
The molecular basis of the clinically important MAM blood group antigen present in most humans is unknown. We identify EMP3 as its encoding gene, establishing MAM as a new blood group system, and demonstrate the role of EMP3 in erythropoiesis through its interaction with the signalling molecule CD44.
- Nicole Thornton
- , Vanja Karamatic Crew
- & David J. Anstee
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Article
| Open AccessAvoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses
Family-based study designs have been applied to resolve confounding by population stratification, dynastic effects and assortative mating in genetic association analyses. Here, Brumpton et al. describe theory and simulations for overcoming such biases in Mendelian randomization through within-family studies.
- Ben Brumpton
- , Eleanor Sanderson
- & Neil M. Davies
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Article
| Open AccessCharacterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.
- Nicola Whiffin
- , Konrad J. Karczewski
- & James S. Ware
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Article
| Open AccessMulti-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction
Mutations in PTEN have been associated with various human disease, including autism spectrum disorder (ASD) and cancer. Here, the authors assess the function of 106 PTEN variants in yeast, invertebrate models and cell culture and report that PTEN variants generally decrease protein stability.
- Kathryn L. Post
- , Manuel Belmadani
- & Kurt Haas
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Article
| Open AccessExome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes
Around half of the heritability underpinning familial high-grade serous ovarian carcinoma remains unidentified. Here, the authors show that extremely rare protein encoding loss-of-function variants, with a high degree of genetic heterogeneity, may account for some of this missing heritability.
- Deepak N. Subramanian
- , Magnus Zethoven
- & Ian G. Campbell
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Article
| Open AccessGenomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan
Age at voice-breaking is used to determine puberty timing in men, recall of which is considered less accurate than age at first menarche in women. Here, the authors perform multi-trait GWAS for male puberty timing by including both age at voice breaking and age of first facial hair for improved phenotype definition and power.
- Ben Hollis
- , Felix R. Day
- & John R. B. Perry
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Article
| Open Access8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer
Inherited alterations of the 8q24 genomic locus are linked to cancer etiology. Here, the authors investigate hereditary prostate cancer to reveal ancestral risk-altering haplotypes, the sentinel genetic variants optimally predicting risk, and causal mutation candidates.
- William D. Dupont
- , Joan P. Breyer
- & Jeffrey R. Smith
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Article
| Open AccessExploiting horizontal pleiotropy to search for causal pathways within a Mendelian randomization framework
In Mendelian randomization (MR) studies, one typically selects SNPs as instrumental variables that do not directly affect the outcome to avoid violation of MR assumptions. Here, Cho et al. present a framework, MR-TRYX, that leverages knowledge of such outliers of horizontal pleiotropy to identify putative causal relationships between exposure and outcome.
- Yoonsu Cho
- , Philip C. Haycock
- & Gibran Hemani
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Article
| Open AccessExceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study
APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.
- Eric M. Reiman
- , Joseph F. Arboleda-Velasquez
- & Yi Zhao
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Article
| Open AccessHuman and mouse essentiality screens as a resource for disease gene discovery
Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.
- Pilar Cacheiro
- , Violeta Muñoz-Fuentes
- & Coleen Kane
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Article
| Open AccessGenome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts
Population-based association analyses of rare genetic variants with complex traits are limited by the availability of data from sufficiently large cohorts. Here, Cirulli et al. report gene-based collapsing analysis of exomes from 49,960 participants of the UK Biobank and 21,866 participants of the Healthy Nevada Project over a total of 4377 traits.
- Elizabeth T. Cirulli
- , Simon White
- & Nicole L. Washington
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Article
| Open AccessThe Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.
- Mark Pinese
- , Paul Lacaze
- & David M. Thomas
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Article
| Open AccessImmune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility
The role of impaired lung function in lung cancer etiology is complex due to the relation of cigarette smoking to both conditions. Here, supported by Mendelian randomization analysis the authors find a link between pulmonary function impairment and lung cancer risk beyond smoking, implicating immune-related pathways
- Linda Kachuri
- , Mattias Johansson
- & Rayjean J. Hung
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Article
| Open AccessCaSpER identifies and visualizes CNV events by integrative analysis of single-cell or bulk RNA-sequencing data
RNA-sequencing is mostly used to assess gene expression; however, it can also give information about genetic variants. Here, the authors present CaSpER, a statistical framework that utilises RNA-sequencing reads to identify and visualise CNV events by integrating transcriptome-wide expression and allelic shift profiles.
- Akdes Serin Harmanci
- , Arif O. Harmanci
- & Xiaobo Zhou
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Article
| Open AccessThe genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact
Detecting genomic abnormalities in metastatic castration-resistant prostate cancer (mCRPC) may impact clinical treatment. Here, the authors present whole-genome sequencing of metastatic biopsies from 197 mCRPC patients, highlighting the landscape of microsatellite stability, homologous repair deficiency, and other genomic subgroups.
- Lisanne F. van Dessel
- , Job van Riet
- & Martijn P. Lolkema
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Article
| Open AccessRanking of non-coding pathogenic variants and putative essential regions of the human genome
Whole genome sequencing (WGS) holds promise to solve a subset of Mendelian disease cases for which exome sequencing did not provide a genetic diagnosis. Here, Wells et al. report a supervised machine learning model trained on functional, mutational and structural features for rank-scoring and interpreting variants in non-coding regions from WGS.
- Alex Wells
- , David Heckerman
- & Julia di Iulio
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Article
| Open AccessQuantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders
Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals. Here, Oetjens et al. systematically study the contribution of common genetic variation to variable expressivity of RGDs and find it is frequently influenced by polygenic factors identified in genome-wide association studies of relevant traits.
- M. T. Oetjens
- , M. A. Kelly
- & D. H. Ledbetter
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Article
| Open AccessGene-diet interactions associated with complex trait variation in an advanced intercross outbred mouse line
Complex traits associate with genetic variation and environment and their interaction. Here, the authors study the influence of different diets on trait variability in 1154 outbred mice from an advanced intercross line and find gene-diet interactions associated with spontaneous autoimmunity development in these animals.
- Artem Vorobyev
- , Yask Gupta
- & Ralf J. Ludwig
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Article
| Open AccessVariants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration
Gestational duration depends on both maternal and fetal genetic influences. Here, the authors perform a fetal genome-wide association meta-analysis and find that a locus on 2q13 is associated with pregnancy duration and further show that the lead SNP rs7594852 changes the binding properties of transcriptional repressor HIC1.
- Xueping Liu
- , Dorte Helenius
- & Bjarke Feenstra
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Article
| Open AccessLoci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies
Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.
- Rajkumar Dorajoo
- , Xuling Chang
- & Chew-Kiat Heng
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Article
| Open AccessPancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk
Risk loci for type 2 diabetes (T2D) reside in pancreatic islet enhancers. Here, the authors generate high-resolution maps of islet chromatin conformation using Hi-C which they combine with ATAC-seq and ChIP-seq data to annotate candidate target genes of enhancers and validate IGF2BP2 activity in mouse islets.
- William W. Greenwald
- , Joshua Chiou
- & Kyle J. Gaulton
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Article
| Open AccessSequencing of human genomes with nanopore technology
Nanopore sequencing technology generates longer reads than current technologies, but with more errors. Here, the authors develop new analytical tools to improve accuracy and evaluate the potential of nanopore sequencing for clinical human genomics.
- Rory Bowden
- , Robert W. Davies
- & Peter Donnelly
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Article
| Open AccessGenome-wide association study of medication-use and associated disease in the UK Biobank
An understanding of the genetic variants associated with medication use may shed light on the underlying biological pathways of disease, and aid in drug development. Here, Wu and colleagues conduct a GWAS for self-reported medication-use in the UK Biobank, finding more than 500 independent variants and many promising leads for future work.
- Yeda Wu
- , Enda M. Byrne
- & Naomi R. Wray
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Article
| Open AccessAdjustment for index event bias in genome-wide association studies of subsequent events
Different from GWAS for susceptibility to disease, GWAS for prognosis or survival may be vulnerable to selection bias. Here, Dudbridge et al present an approach to reduce index event bias in simulated and realistic situations, and apply it to GWAS of survival with idiopathic pulmonary fibrosis and Crohn’s disease prognosis.
- Frank Dudbridge
- , Richard J. Allen
- & Riyaz S. Patel
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Article
| Open AccessProteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia
High hyperploidy is a common feature in childhood B-cell precursor acute lymphoblastic leukemia. Here, the authors perform proteogenomic and Hi-C analyses of this leukemia and the ETV6/RUNX1 subtype and show that CTCF and cohesin expression are low in hyperdiploid cases and transcriptional dysregulation in relation to topologically associating domain borders in some of these cases.
- Minjun Yang
- , Mattias Vesterlund
- & Kajsa Paulsson
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Article
| Open AccessGenome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations
The genetic underpinnings of alcohol use disorder and consumption are incompletely understood. Here, the authors perform GWAS for Alcohol Use Disorder (AUD) Identification Test-Consumption scores and AUD diagnosis from electronic health records of 274,424 individuals and identify a total of 18 associated loci.
- Henry R. Kranzler
- , Hang Zhou
- & Joel Gelernter
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Article
| Open AccessMyoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions
Myoglobin is a hemeprotein that reversibly binds oxygen and gives muscle its red color. Here, the authors report a genetic variant in the MB gene that associates with myoglobinopathy, an autosomal dominant progressive myopathy, and altered oxygen binding properties of the mutant protein.
- Montse Olivé
- , Martin Engvall
- & Nigel G. Laing
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Article
| Open AccessAssessing the causal association of glycine with risk of cardio-metabolic diseases
Epidemiological studies have associated circulating levels of the amino acid glycine with cardiometabolic outcomes. Here, in a genome-wide meta-analysis of 80,003 individuals, Wittemans et al. identify 22 novel genetic loci for glycine and find a causal relationship with coronary heart disease using MR.
- Laura B. L. Wittemans
- , Luca A. Lotta
- & Claudia Langenberg
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Article
| Open AccessQuantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection
Negative selection removes deleterious genetic variation, and can influence genetic architectures and evolution of complex traits. Here, the authors analyze data from 25 UK Biobank diseases and complex traits, and quantify frequency-dependent genetic architectures which suggests actions of negative selection.
- Armin P. Schoech
- , Daniel M. Jordan
- & Alkes L. Price
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Article
| Open AccessGenome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
Epilepsies are common brain disorders and are classified based on clinical phenotyping, imaging and genetics. Here, the authors perform genome-wide association studies for 3 broad and 7 subtypes of epilepsy and identify 16 loci - 11 novel - that are further annotated by eQTL and partitioned heritability analyses.
- Bassel Abou-Khalil
- , Pauls Auce
- & Fritz Zimprich
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Article
| Open AccessChromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities
Multimorbidities of common diseases often have shared underlying predisposing factors. Here Fadason et al. study the pleiotropy of SNPs and their effects on target genes by integrating chromatin interaction and expression quantitative trait loci data to identify target genes shared between phenotypes.
- Tayaza Fadason
- , William Schierding
- & Justin M. O’Sullivan
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Article
| Open AccessMolecular insights into genome-wide association studies of chronic kidney disease-defining traits
The molecular mechanisms that underlie associations in GWAS, incl. chronic kidney disease (CKD), are largely unknown. Here, the authors perform an integrative analysis of genetic, transcriptomic and epigenomic data from human kidney to pinpoint plausible molecular pathways of CKD genetic associations.
- Xiaoguang Xu
- , James M. Eales
- & Maciej Tomaszewski
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Article
| Open AccessPhenome-wide association studies across large population cohorts support drug target validation
Testing the association between genetic variants and a range of phenotypes can assist drug development. Here, in a phenome-wide association study in up to 697,815 individuals, Diogo et al. identify genotype–phenotype associations predicting efficacy, alternative indications or adverse drug effects.
- Dorothée Diogo
- , Chao Tian
- & Heiko Runz
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Article
| Open AccessA comprehensive overview of genomic imprinting in breast and its deregulation in cancer
In growth and development genomic imprinting is important in regulating gene expression. Here, the authors study loss of imprinting (LOI) in cancer, developing a mixture model to detect monoallelically expressed loci without genotyping data - applying this novel methodology to TCGA breast cancer data they find massive deregulation of imprinting.
- Tine Goovaerts
- , Sandra Steyaert
- & Tim De Meyer
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Article
| Open AccessPathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
Mitochondrial protein synthesis requires charging a mitochondrial tRNA with its amino acid. Here, the authors describe pathogenic variants in the GatCAB protein complex genes required for the generation of glutaminyl-mt-tRNAGln, that impairs mitochondrial translation and presents with cardiomyopathy.
- Marisa W. Friederich
- , Sharita Timal
- & Johan L. K. Van Hove
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Article
| Open AccessFine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity
The basis for associations between lung cancer and major histocompatibility complex genes is not completely understood. Here the authors further consider genetic variation within the MHC region in lung cancer patients and identify independent associations within HLA genes that explain MHC lung cancer associations in Europeans and Asian populations.
- Aida Ferreiro-Iglesias
- , Corina Lesseur
- & Paul Brennan
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Article
| Open AccessRecurrent WNT pathway alterations are frequent in relapsed small cell lung cancer
Small cell lung cancer (SCLC) patients frequently relapse and become resistant to chemotherapy. Here, the authors analyse the genomic and transcriptomic landscape of primary and relapsed SCLC patients as well as in vitro models, and discover that activation of WNT signalling can drive chemotherapy resistance.
- Alex H. Wagner
- , Siddhartha Devarakonda
- & Ramaswamy Govindan
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Article
| Open AccessVariants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits
Uterine leiomyomas are common benign tumors. Here, a meta-analysis of two European leiomyoma GWAS uncovers 21 leiomyoma risk variants at 16 loci, providing evidence of genetic overlap between leiomyoma and various benign and malignant tumors and highlighting the role of estrogen in tumor growth.
- Thorunn Rafnar
- , Bjarni Gunnarsson
- & Kari Stefansson
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Comment
| Open AccessA critical view on transgenerational epigenetic inheritance in humans
- Bernhard Horsthemke
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Article
| Open AccessMultiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function
Pulmonary function is influenced by environmental factors, lifestyle, and genetics. Here, in a multiethnic GWAS meta-analysis for pulmonary function traits, the authors identify over 50 additional genetic loci, a subset of which are specific for European, African, Asian, or Hispanic/Latino ancestry.
- Annah B. Wyss
- , Tamar Sofer
- & Stephanie J. London
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Perspective
| Open AccessA framework for enhancing ethical genomic research with Indigenous communities
Indigenous peoples are still underrepresented in genetic research. Here, the authors propose an ethical framework consisting of six major principles that encourages researchers and Indigenous communities to build strong and equal partnerships to increase trust, engagement and diversity in genomic studies.
- Katrina G. Claw
- , Matthew Z. Anderson
- & Joseph M. Yracheta
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Article
| Open AccessIBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
Most of the more than 200 known genetic risk loci for inflammatory bowel disease (IBD) reside in regulatory regions. Here, the authors provide eQTL datasets for six circulating immune cell types and ileal, colonic and rectal biopsies to map regulatory modules and identify potential causative genes for IBD.
- Yukihide Momozawa
- , Julia Dmitrieva
- & Michel Georges
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Article
| Open AccessGenetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.
- Viktoria Gusarova
- , Colm O’Dushlaine
- & Jesper Gromada
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Article
| Open AccessFine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants
Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.
- Tokhir Dadaev
- , Edward J. Saunders
- & Zsofia Kote-Jarai
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Article
| Open AccessA multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci
Primary open-angle glaucoma (POAG) leads to progressive vision loss. Here, Choquet et al. perform genome-wide association analysis for POAG in a multi-ethnic cohort, identify a total of nine novel genetic loci and show relevant function of FMNL2 and LMX1B using cell line and mouse experiments.
- Hélène Choquet
- , Seyyedhassan Paylakhi
- & Eric Jorgenson
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Article
| Open AccessDominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation
Severe growth hormone insensitivity syndrome (GHIS) with immunodeficiency is caused by autosomal recessive mutations in STAT5B. Here the authors report heterozygous STAT5B mutations with dominant-negative effects, causing mild GHIS without immune defects.
- Jürgen Klammt
- , David Neumann
- & Vivian Hwa
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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
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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