Featured
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Article
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Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
Here, the authors perform a large-scale meta-analysis of genome-wide association studies and cis-MR proteomics to identify protein biomarkers and drug targets for heart failure.
- Danielle Rasooly
- , Gina M. Peloso
- & Juan P. Casas
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Article
| Open Access
Joint analysis of phenotype-effect-generation identifies loci associated with grain quality traits in rice hybrids
Genetic dissection of hybrids is more difficult than inbreds as nonadditive effects are involved. Here, the authors report a pipeline for joint analysis of phenotypes, effects, and generations and demonstrate its usefulness in identification of loci associated with quality traits and improving predict accuracy in genomic selection of hybrid rice.
- Lanzhi Li
- , Xingfei Zheng
- & Zhongli Hu
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Article
| Open Access
UBAP2 plays a role in bone homeostasis through the regulation of osteoblastogenesis and osteoclastogenesis
The authors identify UBAP2 as a novel osteoporosis susceptibility gene by performing association studies focusing on coding regions of the genome, and report that it plays a role in bone homeostasis through the regulation of bone remodelling.
- Jeonghyun Kim
- , Bo-Young Kim
- & Seon-Yong Jeong
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Article
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Pan-cancer and cross-population genome-wide association studies dissect shared genetic backgrounds underlying carcinogenesis
Investigating genetically correlated cancers can enhance our understanding of carcinogenesis. Here, the authors perform Pan-cancer and cross-population GWAS meta-analysis to identify novel cancer risk loci and highlight shared heritability between breast and prostate cancer.
- Go Sato
- , Yuya Shirai
- & Yukinori Okada
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Comment
| Open Access
Unravelling the genetic architecture of human complex traits through whole genome sequencing
Whole genome sequencing has enabled new insights into the genetic architecture of complex traits, especially through access to low-frequency and rare variation. This Comment highlights the key contributions from this technology and discusses considerations for its use and future perspectives.
- Ozvan Bocher
- , Cristen J. Willer
- & Eleftheria Zeggini
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Article
| Open Access
Rare genetic variants impact muscle strength
Here, the authors provide an exome study of hand grip strength, a proxy of generalized muscle strength. They identify six exome-wide significant genes, with links to disease, and additivity of rare and common genetic variant effects on muscle strength.
- Yunfeng Huang
- , Dora Bodnar
- & Heiko Runz
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Article
| Open Access
Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups
Here, the authors assess performance and limitations to polygenic risk scores in different race/ethnic groups. They find that polygenic risk score performance improves with diverse training data, and a better understanding of varying genetic backgrounds, social and environmental factors, and gene-environment interactions, is needed to enhance PRS performance for all groups.
- Nuzulul Kurniansyah
- , Matthew O. Goodman
- & Tamar Sofer
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Article
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Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations
Here, the authors perform a whole-genome sequencing association analysis of genetic variants in ≤11,840 multi-ethnic participants with ≤1666 circulating metabolites, discovering 1985 novel variant-metabolite associations and insights into human disease.
- Elena V. Feofanova
- , Michael R. Brown
- & Bing Yu
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Article
| Open Access
Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population
Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of lung adenocarcinoma but known susceptibility variants explain only a small fraction of the familial risk. Here, the authors perform a two-stage GWAS and report 12 novel genetic loci associated with lung adenocarcinoma in East Asians.
- Jianxin Shi
- , Kouya Shiraishi
- & Qing Lan
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Article
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Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement.
- Hanna M. Ollila
- , Eilon Sharon
- & Emmanuel J. Mignot
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Article
| Open Access
Cross-disorder genetic analysis of immune diseases reveals distinct gene associations that converge on common pathways
Immune related diseases have been found to have overlapping genetic susceptibility loci. Here the authors perform cross-disorder genetic analysis to uncover three genetic groups of immune diseases that converge on the same immune cells and pathways.
- Pietro Demela
- , Nicola Pirastu
- & Blagoje Soskic
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Article
| Open Access
Genetics implicates overactive osteogenesis in the development of diffuse idiopathic skeletal hyperostosis
The genetic contribution to risk of Diffuse Idiopathic Skeletal Hyperostosis has been unclear. Here, the authors find genetic variation associated with Diffuse Idiopathic Skeletal Hyperostosis, finding phenotypic and genetic association with increased bone mass throughout the skeletal system.
- Anurag Sethi
- , J. Graham Ruby
- & Eugene Melamud
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Article
| Open Access
Cross-modal autoencoder framework learns holistic representations of cardiovascular state
A challenge in diagnostics is integrating different data modalities to characterize physiological state. Here, the authors show, using the heart as a model system, that cross-modal autoencoders can integrate and translate modalities to improve diagnostics and identify associated genetic variants.
- Adityanarayanan Radhakrishnan
- , Sam F. Friedman
- & Caroline Uhler
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Article
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A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression
Primary biliary cholangitis is a rare, chronic immune-mediated liver disease triggered by environmental exposures in genetically susceptible individuals. Here, the authors investigate the functional mechanism underlying the association of 19p13.3 variants with primary biliary cholangitis.
- You Li
- , Zhiqiang Li
- & Xiong Ma
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Article
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Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease
The spatial and frontal QRS-T angles are electrocardiographic (ECG) predictors for arrhythmia. This work used genetic analyses to identify associated loci and pathways, and explore their relationships with other ECG traits and cardiovascular disease.
- William J. Young
- , Jeffrey Haessler
- & Patricia B. Munroe
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Article
| Open Access
Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank
An exome wide association study of UK Biobank data revealed 158 variants and 105 genes significantly associated with kidney function traits and disease. The findings are supported by functional evidence for a previously unreported mutation in CLDN10.
- Matthias Wuttke
- , Eva König
- & Christian Fuchsberger
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Article
| Open Access
OTTERS: a powerful TWAS framework leveraging summary-level reference data
Here, the authors present a TWAS framework OTTERS that adapts multiple polygenic risk score methods to estimate eQTL weights from summary-level eQTL data. Both simulation and real studies show OTTERS is powerful across a wide range of genetic architectures.
- Qile Dai
- , Geyu Zhou
- & Jingjing Yang
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Article
| Open Access
Reciprocal causation mixture model for robust Mendelian randomization analysis using genome-scale summary data
Mendelian randomization methods are prone to produce false positive results when assumptions are violated. Here, the authors propose a statistical model that offers good power to detect causation between traits while controlling the false positive rate.
- Zipeng Liu
- , Yiming Qin
- & Pak Chung Sham
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Article
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Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis
The genetic basis of primary sclerosing cholangitis has only been partially uncovered. Here, the authors perform a multitrait genome-wide association study to provide insight into the genetic etiology of primary sclerosing cholangitis risk and possible therapeutic drug targets.
- Younghun Han
- , Jinyoung Byun
- & Christopher I. Amos
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Article
| Open Access
Genome-wide genotype-serum proteome mapping provides insights into the cross-ancestry differences in cardiometabolic disease susceptibility
Integrating genetic information with circulating proteomics can help understand mechanisms of disease. Here, the authors conduct genome-wide association analyses of the serum proteome in 2,958 Han Chinese individuals, uncovering proteins which may contribute to ancestry differences in cardiometabolic disease susceptibility.
- Fengzhe Xu
- , Evan Yi-Wen Yu
- & Ju-Sheng Zheng
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Article
| Open Access
Quantifying portable genetic effects and improving cross-ancestry genetic prediction with GWAS summary statistics
Polygenic risk scores are used to improve risk prediction for common diseases but typically have reduced accuracy for individuals of non-European ancestry. Here, the authors present an approach that improves polygenic risk score performance in ancestrally diverse populations.
- Jiacheng Miao
- , Hanmin Guo
- & Qiongshi Lu
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Article
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A method for an unbiased estimate of cross-ancestry genetic correlation using individual-level data
Cross-ancestry genetic correlation can reveal differences in the genetic basis of traits between populations, but methods can be biased by ancestry-specific genetic architecture. Here, the authors present a method to for estimating cross-ancestry genetic correlations, accounting for ancestry-specific genetic architecture.
- Md. Moksedul Momin
- , Jisu Shin
- & S. Hong Lee
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Article
| Open Access
Multi-ancestry and multi-trait genome-wide association meta-analyses inform clinical risk prediction for systemic lupus erythematosus
The genetic basis of systemic lupus erythematosus is not completely understood. Here, the authors perform multi-ancestry and multi-trait meta-analyses to identify 16 novel genetic loci and demonstrate the utility of polygenic risk score in clinical risk prediction when used with conventional lab tests.
- Chachrit Khunsriraksakul
- , Qinmengge Li
- & Dajiang J. Liu
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Article
| Open Access
Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
Many genetic factors that contribute to uterine leiomyomata (UL) - the most common tumours of the female genital tract - remain to be discovered. Here, the authors conduct a UL meta-genome-wide association study, and find loci related to altered muscle tissue biology that are associated with UL.
- Eeva Sliz
- , Jaakko S. Tyrmi
- & Johannes Kettunen
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Article
| Open Access
Estimation and implications of the genetic architecture of fasting and non-fasting blood glucose
Most genetic studies of glucose levels have been done on fasting samples, which can be difficult to obtain. Here, the authors identify 156 genetic loci controlling the physiological variation of glucose levels in healthy non-fasting individuals, demonstrating that the results non-fasting samples can be used to predict fasting glucose levels.
- Zhen Qiao
- , Julia Sidorenko
- & Loic Yengo
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Article
| Open Access
Large scale phenotype imputation and in vivo functional validation implicate ADAMTS14 as an adiposity gene
Our understanding of the genetic contribution to human adiposity is incomplete, as few studies measure adiposity directly. Here, the authors impute whole-body imaging adiposity phenotypes in large biobanks, enhancing their power to discover genes driving human adiposity, and further investigate one such gene using a mouse model.
- Katherine A. Kentistou
- , Jian’an Luan
- & Nicholas M. Morton
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Article
| Open Access
Inflammatory and infectious upper respiratory diseases associate with 41 genomic loci and type 2 inflammation
The shared genetics between upper respiratory diseases have not been well studied. Here, the authors find shared and distinct genetic loci for pharyngeal and sinonasal inflammatory conditions, which show shared heritability with autoimmune conditions and immune deficiency, highlighting the TNFR2 pathway.
- Elmo C. Saarentaus
- , Juha Karjalainen
- & Aarno Palotie
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Article
| Open Access
Graph-based pangenomics maximizes genotyping density and reveals structural impacts on fungal resistance in melon
The power of pangenomic graphs to improve genetic mapping is still unclear. Here, the authors demonstrate its value in identification of genetic variants associated with disease resistance traits in melon using PanPipes, a pangenome construction and low-coverage genotype-by-sequencing pipeline.
- Justin N. Vaughn
- , Sandra E. Branham
- & William P. Wechter
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Article
| Open Access
Combining genome-wide association studies highlight novel loci involved in human facial variation
Combining multiple related traits can increase power in genetic association studies. Here, the authors develop a method to integrate GWAS statistics for multiple traits and apply it to find genetic loci affecting human facial variation.
- Ziyi Xiong
- , Xingjian Gao
- & Fan Liu
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Article
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A comparison of the genes and genesets identified by GWAS and EWAS of fifteen complex traits
Genome-wide and epigenome-wide association studies both link genomic regions to human traits, but here the authors demonstrate that these study types are capturing different genes and biological aspects of complex traits.
- Thomas Battram
- , Tom R. Gaunt
- & Gibran Hemani
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Article
| Open Access
Genetic architecture of heart failure with preserved versus reduced ejection fraction
While the genetic basis of heart failure has been explored by genetic studies, the differences between subtypes are not well understood. Here, the authors performed genetic analyses on the two major subtypes of heart failure in a large biobank with genetic and health record data, finding unique genetic architecture for each subtype.
- Jacob Joseph
- , Chang Liu
- & Yan V. Sun
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Article
| Open Access
Phenome-wide association study of loci harboring de novo tandem repeat mutations in UK Biobank exomes
In UK Biobank exomes, the authors identified de novo mutations in tandem repeat loci. On the population level, these tandem repeats confer large effects on several trait domains including biomarkers, anthropometrics, and tissue microstructures.
- Frank R. Wendt
- , Gita A. Pathak
- & Renato Polimanti
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Article
| Open Access
A multi-phenotype analysis reveals 19 susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common skin cancers and have genetic overlap. Here, the authors use a multi-trait genetic and phenotypic analysis to reveal susceptibility loci for BCC and SCC, and report an optimised polygenic risk score for risk stratification.
- Mathias Seviiri
- , Matthew H. Law
- & Stuart MacGregor
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Article
| Open Access
Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program
Most genetic association studies have been done on single nucleotide polymorphisms and small indels, while other types of variants have been less studied. Here, the authors use whole genome sequencing in a diverse population to identify and provide experimental evidence for associations between structural variants and blood-cell traits.
- Marsha M. Wheeler
- , Adrienne M. Stilp
- & Alex P. Reiner
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| Open Access
Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects
REM-sleep behavior disorder often precedes Parkinson’s disease or dementia. Here, the authors perform a genome-wide association study for REM-sleep behavior disorder, and discover how it potentially affects gene expression in the brain.
- Lynne Krohn
- , Karl Heilbron
- & Ziv Gan-Or
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Article
| Open Access
Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma
Elevated intraocular pressure is a risk factor for glaucoma. Here, the authors performed an exome-wide association study for intraocular pressure, demonstrating the power of rare variants in gene discovery and uncovering potential therapeutic targets for glaucoma.
- Xiaoyi Raymond Gao
- , Marion Chiariglione
- & Alexander J. Arch
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Article
| Open Access
GhostKnockoff inference empowers identification of putative causal variants in genome-wide association studies
The authors present GhostKnockoff, a method for genome-wide association studies which can be applied to enhance existing and future studies to identify functional variants with weaker statistical effects that might be missed by conventional association tests.
- Zihuai He
- , Linxi Liu
- & Iuliana Ionita-Laza
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Article
| Open Access
Integrating transcription factor occupancy with transcriptome-wide association analysis identifies susceptibility genes in human cancers
Transcriptome-wide association studies can uncover genes involved in disease. Here, the authors extend the framework with a transcriptome-wide association study approach which incorporates transcription factor occupancy, adding tissue-specific mechanistic support to associations.
- Jingni He
- , Wanqing Wen
- & Xingyi Guo
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Article
| Open Access
Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure
Heart failure is a major cause of cardiovascular morbidity and mortality. Here, the authors report results of a genome-wide association study meta-analysis, characterizing the role of common genetic variants in heart failure, finding overlap with common cardiovascular risk factors and imaging measures of cardiac structure/function.
- Michael G. Levin
- , Noah L. Tsao
- & Scott M. Damrauer
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Article
| Open Access
Pleiotropic genetic architecture and novel loci for C-reactive protein levels
Chronic inflammation and lipometabolism share many causal genes and possibly pathways. Here, the authors use a multi-trait GWAS approach to study shared genetic determinants of low-grade inflammation, measured by C-reactive protein (CRP), and closely linked lipid and metabolic pathways.
- Fotios Koskeridis
- , Evangelos Evangelou
- & Ioanna Tzoulaki
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Article
| Open Access
Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology
Cognitive impairments are a key feature of psychopathology. Here, authors exploit the genetic overlap between cognitive dimensions and psychopathology to parse the biology of psychiatric illness and identify “meta-loci” genome segments characterized by specific patterns of overlap.
- Max Lam
- , Chia-Yen Chen
- & Todd Lencz
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Article
| Open Access
Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
Immunoglobulin A protects against infectious disease and contributes to autoimmune and inflammatory disorders. Here, the authors perform a genome-wide association study for serum IgA levels, identifying 20 genome-wide significant loci, providing new insights into the genetic regulation of IgA levels.
- Lili Liu
- , Atlas Khan
- & Krzysztof Kiryluk
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Article
| Open Access
Parent-of-Origin inference for biobanks
Studies on parent-of-origin effects have been limited in terms of sample size due to lack of parental genomes or known genealogies. Here, the authors develop a method to infer the parent-of-origin of an individual alleles in biobank-scale datasets, without requiring parental genomes or prior knowledge of genealogy, allowing discovery of parent-of-origin effects with an unprecedented sample size.
- Robin J. Hofmeister
- , Simone Rubinacci
- & Olivier Delaneau
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Article
| Open Access
The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians
Metabolic traits are heritable intermediate phenotypes widely used in assessing the risk of various diseases. By conducting a genome-wide meta-analysis for metabolic traits in 288,137 East Asians, the authors highlight the interplay of common and rare variants on inherited risk of metabolic traits.
- Young Jin Kim
- , Sanghoon Moon
- & Bong-Jo Kim
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Article
| Open Access
Shared genetic risk factors and causal association between psoriasis and coronary artery disease
Coronary artery disease (CAD) and psoriasis are established comorbidities, however their molecular relationship remains unclear. Here, the authors performed trans-disease meta-analysis, highlighting four genetic loci with evidence of colocalization, and prioritized genes based on multiomic data integration.
- Matthew T. Patrick
- , Qinmengge Li
- & Lam C. Tsoi
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Article
| Open Access
Mendelian randomization accounting for complex correlated horizontal pleiotropy while elucidating shared genetic etiology
Mendelian randomization uses genetic variation to study the causal effect of exposure on outcome, but results can be biased by confounders, such as horizontal pleiotropy. Here, the authors present MR-CUE, a method to determine causal effects by accounting for correlated and uncorrelated horizontal pleiotropic effects.
- Qing Cheng
- , Xiao Zhang
- & Jin Liu
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Article
| Open Access
Whole genome sequence analysis of blood lipid levels in >66,000 individuals
Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.
- Margaret Sunitha Selvaraj
- , Xihao Li
- & Pradeep Natarajan
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Article
| Open Access
Variation in the fruit development gene POINTED TIP regulates protuberance of tomato fruit tip
While auxin has been implicated in the development of tomato fruit with pointed tips, the mechanism are largely unknown. Here, the authors report variation of a C2H2-type zinc finger transcription factor affects transcription of FUL2, which consequently regulates auxin transport and distribution to determine tomato fruit shape.
- Jianwen Song
- , Lele Shang
- & Junhong Zhang
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Article
| Open Access
GWAS, MWAS and mGWAS provide insights into precision agriculture based on genotype-dependent microbial effects in foxtail millet
Plant genotype alone appears to be insufficient to explain trait variations. This study integrates GWAS, MWAS and mGWAS in 827 foxtail millet cultivars, revealing that root-associated microbiota affect plant phenotypes in a host genotype-dependent manner.
- Yayu Wang
- , Xiaolin Wang
- & Huan Liu
Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals