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meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans
Here, the authors performed a large-scale in-depth cis-meQTL mapping study in 961 African Americans from the GENOA study, investigating the co-regulation of methylation and gene expression in African Americans.
- Lulu Shang
- , Wei Zhao
- & Xiang Zhou
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Article
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Analysis of transcriptional changes in the immune system associated with pubertal development in a longitudinal cohort of children with asthma
Puberty is an important developmental period marked by hormonal, metabolic and immunological changes. Here the authors report gene expression changes in immune cells associated with age and puberty, and that may be relevant for sex differences in susceptibility to asthma, in a longitudinal cohort of 251 children with asthma.
- Justyna A. Resztak
- , Jane Choe
- & Francesca Luca
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SUMMIT: An integrative approach for better transcriptomic data imputation improves causal gene identification
Genes with moderate-low expression heritability cannot be sufficiently captured with conventional TWAS. This study introduces a new method, Summary-level Unified Method for Modeling Integrated Transcriptome (SUMMIT), to improve the expression prediction of TWAS by using eQTL summary-level data.
- Zichen Zhang
- , Ye Eun Bae
- & Chong Wu
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Multi-context genetic modeling of transcriptional regulation resolves novel disease loci
Transcriptome-wide association studies (TWAS) often ignore the specificity and sharing of effects across contexts (e.g., tissues). Here, the authors describe a method to split genetic effects into context-shared and context-specific terms. They apply their method to tissue and single-cell RNA-seq and show improved power in TWAS.
- Mike Thompson
- , Mary Grace Gordon
- & Noah Zaitlen
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
Genetic mechanisms influencing COVID-19 susceptibility are not well understood. Here, the authors analyzed whole blood RNA-seq data of 465 Japanese individuals with COVID-19, highlighting thousands of fine-mapped variants affecting expression and splicing of genes, as well as the presence of COVID-19 severity-interaction eQTLs.
- Qingbo S. Wang
- , Ryuya Edahiro
- & Yukinori Okada
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Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers
Understanding how our genes interact with the environment is critical to improving health. Using a large-scale discovery pipeline, here the authors investigate synergies between genetic variants and a broad range of environmental factors impacting cardiometabolic health.
- Kenneth E. Westerman
- , Timothy D. Majarian
- & Joanne B. Cole
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Disentangling the genetic basis of rhizosphere microbiome assembly in tomato
Genetics factors involved in rhizosphere microbiomes assembly remain largely elusive. Here, the authors integrate microbiomics and quantitative plant genetics to reveal genetic loci associated with specific microbes and rhizobacterial traits underlying microbiome assembly in tomato.
- Ben O. Oyserman
- , Stalin Sarango Flores
- & Jos M. Raaijmakers
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Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci
The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms.
- Xianyong Yin
- , Lap Sum Chan
- & Michael Boehnke
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The interplay of additivity, dominance, and epistasis on fitness in a diploid yeast cross
Heritable traits can be affected by additive, dominance, and epistatic effects at genetic loci. Here, the authors use chromosomally-encoded barcodes to perform linkage mapping in diploid cross progeny in budding yeast, finding that epistasis in diploids frequently modifies both additivity and dominance.
- Takeshi Matsui
- , Martin N. Mullis
- & Ian M. Ehrenreich
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Functional 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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Synergistic insights into human health from aptamer- and antibody-based proteomic profiling
Broad-capture affinity-based proteomic technologies inform how the readout of our genes affects human health. Here, the authors integrate aptamer- and antibody-based profiling to understand the mechanisms underlying gene-protein-disease associations.
- Maik Pietzner
- , Eleanor Wheeler
- & Claudia Langenberg
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Genome sequencing unveils a regulatory landscape of platelet reactivity
Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.
- Ali R. Keramati
- , Ming-Huei Chen
- & Andrew D. Johnson
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Population-scale study of eRNA transcription reveals bipartite functional enhancer architecture
Enhancer RNAs are transcribed bidirectionally from core transcription initiation regions. Here, by employing nascent RNA sequencing, the authors identify quantitative trait loci (QTLs) associated with enhancer RNA level and directionality, revealing the bipartite architecture of enhancers.
- Katla Kristjánsdóttir
- , Alexis Dziubek
- & Hojoong Kwak
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Multivariate genomic scan implicates novel loci and haem metabolism in human ageing
Ageing phenotypes are of great interest but are difficult to study genetically, partly due to the sample sizes required. Here, the authors present a multivariate framework to combine GWAS summary statistics and increase statistical power, identifying additional loci enriched for aging.
- Paul R. H. J. Timmers
- , James F. Wilson
- & Joris Deelen
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Properties of structural variants and short tandem repeats associated with gene expression and complex traits
Genetic variation associated with gene expression changes has mostly been studied in the context of single nucleotide variants. Here, Jakubosky et al. report eQTL analysis of structural variants and short tandem repeats and find properties, such as length of variation, that affect the association.
- David Jakubosky
- , Matteo D’Antonio
- & Kelly A. Frazer
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Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data
Promoter-anchored chromatin interaction (PAI) is a mechanism by which gene expression is regulated, but methods to measure PAIs are costly and currently not scalable. Here, the authors develop an approach by which PAIs can be predicted using summary-level data from methylation QTL studies.
- Yang Wu
- , Ting Qi
- & Jian Yang
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Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression
Studying the genetic effects on early stages of human development is challenging due to a scarcity of biological material. Here, the authors utilise induced pluripotent stem cells from 125 donors to track gene expression changes and expression quantitative trait loci at single cell resolution during in vitro endoderm differentiation.
- Anna S. E. Cuomo
- , Daniel D. Seaton
- & Oliver Stegle
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Heritability estimates for 361 blood metabolites across 40 genome-wide association studies
Blood metabolite levels are under the influence of environmental and genetic factors. Here, Hagenbeek et al. perform heritability estimations for metabolite measures and determine the contribution of known metabolite loci to metabolite levels using data from 40 genome-wide association studies.
- Fiona A. Hagenbeek
- , René Pool
- & Dorret I. Boomsma
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Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease
Differentially methylated CpGs can inform on disease mechanisms and be useful as biomarkers. Here, the authors perform GWAS for DNA methylation in whole blood, cis- and trans-meQTL mapping, followed by Mendelian randomization analysis that links meQTLs with cardiovascular diseases.
- Tianxiao Huan
- , Roby Joehanes
- & Daniel Levy
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Gene-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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Functional genetic variants can mediate their regulatory effects through alteration of transcription factor binding
Functional variants have been proposed to alter transcription factor binding. Here, the authors provide direct evidence that functional variants within the TBC1D4 gene, encoding an NFκB binding site, can alter transcription factor binding, and use CRISPR-Cas9 to reveal localization of the transcription factor to be the regulator of chromatin accessibility and p65 binding and ultimately TBC1D4 expression.
- Andrew D. Johnston
- , Claudia A. Simões-Pires
- & John M. Greally
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Facial recognition from DNA using face-to-DNA classifiers
Prediction of face from DNA followed by matching to facial images has been proposed for forensic applications. Here, Sero et al. present a different approach that can establish facial identity from DNA without directly predicting the face but is based on classifying given faces by individual DNA-encoded traits.
- Dzemila Sero
- , Arslan Zaidi
- & Peter Claes
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Article
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Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis
Estimated glomerular filtration rate (eGFR) is a measure of kidney function and used to characterize chronic kidney disease. Here, Graham et al. identify 53 novel loci for eGFR in a GWAS meta-analysis, a subset of which are associated with other common diseases, such as diabetes and hypertension, based on PheWAS.
- Sarah E. Graham
- , Jonas B. Nielsen
- & Cristen J. Willer
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Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance
Latin Americans trace their ancestry to the admixture of Native Americans, Europeans and Sub-Saharan Africans. Here, the authors develop a novel haplotype-based approach and analyse over 6,500 Latin Americans to infer the geographically-detailed genetic structure of this population.
- Juan-Camilo Chacón-Duque
- , Kaustubh Adhikari
- & Andrés Ruiz-Linares
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Carotid intima-media thickness (cIMT) and plaque are associated with subclinical atherosclerosis and coronary heart disease (CHD). Here, the authors identify and prioritize genetic loci for cIMT and plaque by GWAS and colocalization approaches and further demonstrate genetic correlation with CHD and stroke.
- Nora Franceschini
- , Claudia Giambartolomei
- & Christopher J. O’Donnell
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Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes
GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.
- Angli Xue
- , Yang Wu
- & Jian Yang
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Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks
Disease risk variants can exert their influence on phenotypes by altering epigenome function. Here, Pelikan et al. show that variants inducing allelic imbalance in histone marks in lymphoblastoid cell lines from lupus patients are enriched in autoimmune disease haplotypes and influence gene expression.
- Richard C. Pelikan
- , Jennifer A. Kelly
- & Patrick M. Gaffney
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Large-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
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Multiple novel gene-by-environment interactions modify the effect of FTO variants on body mass index
Common variants in the fat mass and obesity associated (FTO) gene are linked to body mass index (BMI). Using the latest UK Biobank data, this study shows novel gene x environment interactions between FTOand lifestyle factors, including frequency of alcohol consumption, sleep, and added dietary salt.
- Alexander I. Young
- , Fabian Wauthier
- & Peter Donnelly
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Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci
Coronary heart disease is the leading cause of death worldwide with multiple environmental and genetic risk factors. Here the authors integrate genomic, epigenomic and transcriptomic mapping to elucidate causal variation and mechanisms of known genetic associations.
- Clint L. Miller
- , Milos Pjanic
- & Thomas Quertermous
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Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41
A common susceptibility haplotype for renal cell carcinoma is located on chromosome 12p12.1. Here, the authors show that the variant rs7132434 alters binding of the AP-1 transcription factor, which increases the expression of BHLHE41in renal cells.
- Pierre Bigot
- , Leandro M. Colli
- & Stephen J. Chanock
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Article
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Genome-wide association and high-resolution phenotyping link Oryza sativa panicle traits to numerous trait-specific QTL clusters
Panicle architecture is an important determinant of crop yield and a target of selection by plant breeders. Here, Crowell et al.combine image-based phenotyping with high-density array-based genotyping to perform a genome-wide association study revealing a number of candidate genes linked to panicle variation in rice.
- Samuel Crowell
- , Pavel Korniliev
- & Susan McCouch
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Genetic interactions contribute less than additive effects to quantitative trait variation in yeast
This study uses a large number of crosses between a common lab strain and vineyard-isolated strain of yeast, and estimates the phenotypic variance for various quantitative traits. Using this data set, the authors show additive quantitative trait loci (QTL) and QTL–QTL interactions to be on average 43% and 9%, respectively.
- Joshua S. Bloom
- , Iulia Kotenko
- & Leonid Kruglyak
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Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
Genome-wide association studies have identified regions which confer risk of high-grade serous epithelial ovarian cancer. Here the authors use expression quantitative train locus analysis to identify candidate genes and functionally characterise them, identifying a role for HOXD9 in ovarian cancer.
- Kate Lawrenson
- , Qiyuan Li
- & Matthew L. Freedman
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Genetic mapping uncovers cis-regulatory landscape of RNA editing
Adenosine-to-inosine (A-to-I) RNA editing plays an important role in neurological functions. Here, by a quantitative trait loci (QTL) mapping approach in 131 Drosophila melanogasterstrains, the authors identify 545 QTLs associated with differences in RNA editing.
- Gokul Ramaswami
- , Patricia Deng
- & Jin Billy Li
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Article
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Genome-wide analysis of the genetic regulation of gene expression in human neutrophils
Neutrophils are abundant immune cells important for antimicrobial defence and in autoimmunity. Here, by mapping expression quantitative trait loci (eQTL) in neutrophils of Chinese ethnicity from Singapore, Andiappan et al.provide a resource for understanding immune-related trait associated genetic variants.
- Anand Kumar Andiappan
- , Rossella Melchiotti
- & Olaf Rotzschke
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Genomic modulators of gene expression in human neutrophils
Neutrophils are the most abundant subset of leukocyte and central to many diseases. Here by mapping expression quantitative trait loci (eQTL) in the context of epigenetic marks in neutrophils and monocytes of 101 healthy European adults, the authors provide a resource to advance understanding of immune-related trait-associated genetic variants.
- Vivek Naranbhai
- , Benjamin P. Fairfax
- & Julian C. Knight
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Genome-wide identification of microRNA expression quantitative trait loci
As important post-transcriptional regulators of gene expression, microRNAs play a key role in the generation of complex phenotypes. Here, Huan et al.identify miR-eQTLs in whole blood samples to create a roadmap linking regulation of microRNA expression to complex diseases.
- Tianxiao Huan
- , Jian Rong
- & Jane E. Freedman
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Epigenetic variation in the Egfr gene generates quantitative variation in a complex trait in ants
Variation in complex traits is generated by the interaction of genetic and environmental factors. Here, the authors show that genome-wide DNA methylation indirectly regulates quantitative methylation of the Egfrgene to generate continuous size variation of larvae workers in the carpenter ant.
- Sebastian Alvarado
- , Rajendhran Rajakumar
- & Moshe Szyf
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Long-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci
There is a functional link between SNPs and epigenetic variations when they are in close range, but the long-range effect is unclear. Here, by analysing methylation quantitative trait loci, the authors demonstrate that methylation levels at CpG sites in lymphocytes are correlated with distal SNPs.
- Mathieu Lemire
- , Syed H.E. Zaidi
- & Thomas J. Hudson
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OsAAP6 functions as an important regulator of grain protein content and nutritional quality in rice
Grain protein content (GPC) contributes to the nutritional quality of cereals. Here, the authors show that the OsAAP6 quantitative trait locus in rice controls GPC by regulating the synthesis and accumulation of several grain storage proteins and starch.
- Bo Peng
- , Huili Kong
- & Yuqing He
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Natural variation in arsenate tolerance identifies an arsenate reductase in Arabidopsis thaliana
Arsenic tolerance in plants is critical for their adaptation to some soils and has therefore played an important role in plant distribution. Here, the authors identify a quantitative trait locus encoding an arsenate reductase enzyme that confers arsenic tolerance in plants.
- Eduardo Sánchez-Bermejo
- , Gabriel Castrillo
- & Antonio Leyva
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| Open Access
Identification of a novel salt tolerance gene in wild soybean by whole-genome sequencing
The identification of genes that control economically important traits is an essential step towards crop improvement. Here the authors sequence the genome of the wild soybean and, through a combined genetic and functional approach, identify a new gene affecting salt tolerance in soybean.
- Xinpeng Qi
- , Man-Wah Li
- & Hon-Ming Lam
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Article
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New approach for rice improvement using a pleiotropic QTL gene for lodging resistance and yield
Much effort has been devoted to the generation of rice plants with short stature to improve grain yield and increased resistance to lodging. Through quantitative trait analysis, these authors identify a gene—STRONG CULM2—that confers increased grain yield, culm strength and spikelet number in rice.
- Taiichiro Ookawa
- , Tokunori Hobo
- & Makoto Matsuoka
A landscape of gene expression regulation for synovium in arthritis