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| Open AccessCombining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
Most genetic studies have been done on European cohorts, which affects the efficacy of polygenic risk scores in non-European populations. Here, the authors demonstrate that a colorectal cancer PRS including Asian and European ancestries has improved performance over the European-centric PRS across racial and ethnic groups.
- Minta Thomas
- , Yu-Ru Su
- & Li Hsu
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Article
| Open AccessGenome-wide association studies and cross-population meta-analyses investigating short and long sleep duration
Here, the authors investigate the genetic basis of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration, identifying 84 independent significant risk loci for short sleep and 1 locus for long sleep, and causal associations between sleep and psychiatric traits.
- Isabelle Austin-Zimmerman
- , Daniel F. Levey
- & Joel Gelernter
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Article
| Open AccessAnalysis of 72,469 UK Biobank exomes links rare variants to male-pattern hair loss
Here, the authors perform an association study on 72,469 exomes to identify significant associations between male-pattern hair loss and rare genetic variants in EDA2R, WNT10A, HEPH, CEPT1, and EIF3F, finding an enrichment of implicated genes in monogenic trichosis genes.
- Sabrina Katrin Henne
- , Rana Aldisi
- & Stefanie Heilmann-Heimbach
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Article
| Open AccessContribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes
A deep understanding of the genetic signatures of neovascular age-related macular degeneration subtypes in Asian patients remains a significant gap. Here the authors pinpoint contributing common and rare variants using GWAS and exome sequencing approaches.
- Qiao Fan
- , Hengtong Li
- & Ching-Yu Cheng
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Article
| Open AccessProjecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms
PhenoPLIER integrates genetic studies with gene modules expressed in specific contexts. This aids in extracting mechanistic insight from statistical associations to enhance our understanding of complex diseases and their therapeutic modalities.
- Milton Pividori
- , Sumei Lu
- & Casey S. Greene
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Article
| Open AccessADuLT: An efficient and robust time-to-event GWAS
Robust genome-wide association study (GWAS) methods that can utilise time-to-event information such as age-of-onset will help increase power in analyses for common health outcomes. Here, the authors propose a computationally efficient time-to-event model for GWAS.
- Emil M. Pedersen
- , Esben Agerbo
- & Bjarni J. Vilhjálmsson
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Article
| Open AccessMulti-trait discovery and fine-mapping of lipid loci in 125,000 individuals of African ancestry
There have been few genome-wide association studies that analyze multiple lipid traits simultaneously, especially in individuals of African ancestry. To address this, the authors performed a multi-trait analysis of GWAS along with fine-mapping to find new genetic loci associated with lipid traits in individuals of African ancestry.
- Abram Bunya Kamiza
- , Sounkou M. Touré
- & Segun Fatumo
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Article
| Open AccessDemonstrating paths for unlocking the value of cloud genomics through cross cohort analysis
The emergence of large-scale genomics projects has led to genetic studies across cohorts. Here, the authors conduct genome-wide association studies meta-analyzing in trusted research environments or pooling together and find similar, but not identical results.
- Nicole Deflaux
- , Margaret Sunitha Selvaraj
- & Alexander G. Bick
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Article
| Open AccessAccurate haplotype construction and detection of selection signatures enabled by high quality pig genome sequences
Accurate haplotypes with abundant genomic variations benefit genetic research. Here, the authors accurately construct 1,874 pig haplotypes and demonstrate their applications in genome-wide association studies, prediction of breeding values and analyses of evolutionary selection.
- Xinkai Tong
- , Dong Chen
- & Lusheng Huang
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Article
| Open AccessEnvironmental and genetic predictors of human cardiovascular ageing
Cardiovascular ageing is characterised by a progressive decline in function, which contributes to multi-morbidity. Here, the authors use machine learning to predict biological age and identify key genetic risk factors.
- Mit Shah
- , Marco H. de A. Inácio
- & Declan P. O’Regan
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Article
| Open AccessSingle-cell genomics improves the discovery of risk variants and genes of atrial fibrillation
Here the authors combine an experimental and analytical approach that integrates single cell epigenomics with GWAS to prioritize risk variants and genes to provide a comprehensive map of Atrial Fibrillation risk variants and genes.
- Alan Selewa
- , Kaixuan Luo
- & Sebastian Pott
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Article
| Open AccessGenome-wide association studies reveal novel loci associated with pyrethroid and organophosphate resistance in Anopheles gambiae and Anopheles coluzzii
Insecticide resistance in mosquitoes threatens the success of malaria control programmes. This study found that in different populations of a malaria mosquito species in West Africa, resistance is associated with different genes or different mutations in the same set of genes.
- Eric R. Lucas
- , Sanjay C. Nagi
- & David Weetman
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Article
| Open AccessGenetic insights into resting heart rate and its role in cardiovascular disease
The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.
- Yordi J. van de Vegte
- , Ruben N. Eppinga
- & Pim van der Harst
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Article
| Open AccessGenome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals
Here, the authors perform a meta-analysis in 26,699 people with seizures and 492,324 controls to identify 25 genome-wide significant copy-number variants. The discovered loci point to known disease genes and associations with clinical annotations.
- Ludovica Montanucci
- , David Lewis-Smith
- & Dennis Lal
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Article
| Open AccessGenome-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 AccessJoint 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 AccessUBAP2 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
| Open AccessPan-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 AccessUnravelling 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 AccessRare 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 AccessEvaluating 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
| Open AccessWhole-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 AccessGenome-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
| Open AccessNarcolepsy 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 AccessCross-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 AccessGenetics 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 AccessCross-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
| Open AccessA 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
| Open AccessGenetic 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 AccessImputation-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 AccessOTTERS: 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 AccessReciprocal 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
| Open AccessMultitrait 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 AccessGenome-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 AccessQuantifying 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
| Open AccessA 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 AccessMulti-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 AccessEvidence 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 AccessEstimation 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 AccessLarge 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 AccessInflammatory 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 AccessGraph-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 AccessCombining 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
| Open AccessA 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 AccessGenetic 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 AccessPhenome-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 AccessA 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 AccessWhole 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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Article
| Open AccessGenome-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