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| Open AccessValidation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes
Here the authors conduct a multi-ancestry meta-analysis of telomere length, used diverse approaches to identify genes underlying association signals, and experimentally validated POP5 and KBTBD6 as regulators of telomere length in human cells.
- Rebecca Keener
- , Surya B. Chhetri
- & Alexis Battle
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Article
| Open AccessDeep learning of left atrial structure and function provides link to atrial fibrillation risk
In this study, a deep learning-based model of left atrial size in UK Biobank enabled genome-wide association studies in 35,049 healthy participants. Several lines of evidence, including the PITX2 locus, linked left atrial dysfunction to atrial fibrillation risk.
- James P. Pirruccello
- , Paolo Di Achille
- & Patrick T. Ellinor
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| Open AccessMammographic density mediates the protective effect of early-life body size on breast cancer risk
Mammographic density is known to be linked to breast cancer risk. Here, the authors use Mendelian randomization to estimate the effects of childhood body size and age at menarche on density phenotypes and breast cancer risk.
- Marina Vabistsevits
- , George Davey Smith
- & Eleanor Sanderson
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Article
| Open AccessDeterminants of mosaic chromosomal alteration fitness
Here, the authors use passenger mutations to quantify expansion rate in ~6,000 people with mosaic chromosomal alterations in the NHLBI TOPMed cohort, finding associations between growth rate and blood counts along with germline genetic modulators of growth rate.
- Yash Pershad
- , Taralynn Mack
- & Alexander G. Bick
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Article
| Open AccessGenetic influence on within-person longitudinal change in anthropometric traits in the UK Biobank
The availability of longitudinal data in large biobanks is increasing. Here, using data from the UK Biobank, the authors develop and apply analytical approaches to quantify genetic contributions to change over time for traits like height and weight.
- Kathryn E. Kemper
- , Julia Sidorenko
- & Peter M. Visscher
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Article
| Open AccessDisentangling genetic effects on transcriptional and post-transcriptional gene regulation through integrating exon and intron expression QTLs
Expression quantitative trait loci (eQTL) studies typically only consider exon expression levels and discard intronic RNA sequencing reads. Here, the authors show that analyzing eQTLs together with QTLs for intron levels and exon-intron ratios expands the number and functional understanding of genetic effects on gene regulatory processes.
- Anneke Brümmer
- & Sven Bergmann
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| Open AccessGenetic association of inflammatory marker GlycA with lung function and respiratory diseases
Here, the authors observed significant genetic correlation of GlycA with lung function, asthma and COPD and identified ten shared loci revealing potential shared biological mechanisms involving ubiquitination and Wnt/β-catenin signaling.
- Yanjun Guo
- , Quanhong Liu
- & Weihong Chen
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Article
| Open AccessUsing genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes
Here, the authors integrate genomic and transcriptomic data obtained from African-ancestry female participants and identify six genes associated with breast cancer risk which provides biological insights into this common cancer in an underrepresented population.
- Jie Ping
- , Guochong Jia
- & Wei Zheng
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Article
| Open AccessThe impact of exercise on gene regulation in association with complex trait genetics
It is known that exercise influences many human traits, but not which tissues and genes are most important. This study connects transcriptome data collected across 15 tissues during exercise training in rats as part of the Molecular Transducers of Physical Activity Consortium with human data to identify traits with similar tissue specific gene expression signatures to exercise.
- Nikolai G. Vetr
- , Nicole R. Gay
- & Stephen B. Montgomery
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Article
| Open AccessLarge-scale cross-ancestry genome-wide meta-analysis of serum urate
This large-scale cross-ancestry genome-wide association study reveals the genetic architecture of serum urate across ancestries and identifies urate-associated diseases and potential targets of urate-lowering drugs.
- Chamlee Cho
- , Beomsu Kim
- & Hong-Hee Won
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Article
| Open AccessClinical associations with a polygenic predisposition to benign lower white blood cell counts
Here, the authors find that a benign polygenic predisposition to lower white blood cell counts is associated with multiple clinical endpoints, suggesting that predisposed individuals are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.
- Jonathan D. Mosley
- , John P. Shelley
- & Vivian K. Kawai
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Article
| Open AccessAn approach to identify gene-environment interactions and reveal new biological insight in complex traits
Here, the authors report 5 loci interacting with smoking/alcohol for serum lipids using a new method akin to Mendelian randomization. They unveil significant heritability through gene-environment interaction and mediation, enhancing understanding of complex trait genetics.
- Xiaofeng Zhu
- , Yihe Yang
- & Hugues Aschard
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Article
| Open AccessAn ensemble penalized regression method for multi-ancestry polygenic risk prediction
Great efforts are being made to develop advanced polygenic risk scores (PRS) to improve the prediction of complex traits and diseases. However most existing PRS are primarily trained on European ancestry populations, limiting their transferability to non-European populations. Here the authors propose a new multi-ancestry PRS method, PROSPER, to reduce disparity of PRS performance across ancestry groups.
- Jingning Zhang
- , Jianan Zhan
- & Nilanjan Chatterjee
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| Open AccessIntegration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment
Risk prediction for prognosis in colorectal cancer is an important tool. Here, the authors utilise GWAS from 5 cohorts of colorectal cancer patients, and show a healthy lifestyle is associated with a 7.6% improvement in overall survival among patients with high pathologic and genetic risk.
- Junyi Xin
- , Dongying Gu
- & Meilin Wang
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Article
| Open AccessGenetic associations of protein-coding variants in venous thromboembolism
Here, the authors perform a large exome-wide study for venous thromboembolism and identify 18 potential risk genes, including 4 new genes, revealing a significant role of rare coding variants, and offering insights into genetic risk factors.
- Xiao-Yu He
- , Bang-Sheng Wu
- & Jin-Tai Yu
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Article
| Open AccessGenetic control of DNA methylation is largely shared across European and East Asian populations
Most functional genomic resources have been based on individuals with European ancestry. Here, the authors perform DNA methylation quantitative trait locus (mQTL) analyses in 3,701 European and 2,099 East Asian individuals to identify thousands of genetic variants, a large degree of which are shared between the two populations.
- Alesha A. Hatton
- , Fei-Fei Cheng
- & Allan F. McRae
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Article
| Open AccessAbundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study
The authors uncover extensive genetic overlap across brain structure, functional connectivity, and brain tissue composition using multivariate methods. Insights gained enhance understanding of brain biology and prediction of psychiatric conditions.
- E. P. Tissink
- , A. A. Shadrin
- & O. A. Andreassen
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Article
| Open AccessUsing rare genetic mutations to revisit structural brain asymmetry
Asymmetry is a key organising principle of the brain. Here the authors leveraged rare genetic mutations to revisit structural brain asymmetry showing the planum temporale is susceptible to deletions & duplications of specific gene sets.
- Jakub Kopal
- , Kuldeep Kumar
- & Danilo Bzdok
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Article
| Open AccessGenetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets
Genetic mechanisms of blood pressure regulation remain poorly defined. Here, the authors perform a kidney multi-omics study to identify 399 kidney effector genes, 11 miRNAs and 97 proteins for blood pressure and hypertension.
- Xiaoguang Xu
- , Chachrit Khunsriraksakul
- & Maciej Tomaszewski
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Article
| Open AccessIntegrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation
Here the authors report 20 novel genomic risk loci for calcific aortic valve stenosis, the most common heart valve disorder. Using RNA sequencing in 500 human aortic valves, they prioritize candidate causal genes including TWIST1, a gene involved in endothelial-mesenchymal transition.
- Sébastien Thériault
- , Zhonglin Li
- & Yohan Bossé
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| Open AccessGenetic architecture of the structural connectome
The structural connectome is the complete set of anatomical connections between brain cells. Here, the authors perform a genome-wide association study of white-matter structural connectivity in the human brain, finding 30 variants influencing the density of myelinated connections between brain regions.
- Michael Wainberg
- , Natalie J. Forde
- & Shreejoy J. Tripathy
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Article
| Open AccessQuantitative pathogenicity and host adaptation in a fungal plant pathogen revealed by whole-genome sequencing
The understanding of pathogenicity in quantitative plant pathosystems remains limited. This study reveals the genetic architecture of quantitative pathogenicity traits in a significant fungal plant pathogen, shedding light on potential evolutionary mechanisms involved in host adaptation.
- Reda Amezrou
- , Aurélie Ducasse
- & Thierry C. Marcel
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Article
| Open AccessWhole-exome sequencing in UK Biobank reveals rare genetic architecture for depression
Despite many common genetic variants being linked to depression, the impact of rare coding variants on depression remains largely unknown. Here, the authors perform a whole-exome sequencing study of depression, providing insights into the rare genetic architecture of depression.
- Ruoyu Tian
- , Tian Ge
- & Chia-Yen Chen
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| Open AccessGenetic influences on circulating retinol and its relationship to human health
Retinol, a form of vitamin A, plays an essential role in many biological processes throughout the human lifespan. Here the authors identify genetic variants that influence the level of circulating retinol and use this information to better understand how retinol impacts human health.
- William R. Reay
- , Dylan J. Kiltschewskij
- & Murray J. Cairns
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Article
| Open AccessChildren born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight
Assisted reproduction increases low birthweight risk in children. This study finds a mitochondrial DNA genotype that is more common in ART children, associates to birthweight and that is linked to maternal ageing and to ovarian stimulation.
- Joke Mertens
- , Florence Belva
- & Claudia Spits
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Article
| Open AccessGWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region
Here, the authors identify six risk SNPs for systemic sclerosis by performing GWAS on Japanese patients and meta-analyzing Japanese and European GWAS datasets. Downstream analyses indicate that B cells contribute to pathogenesis.
- Yuki Ishikawa
- , Nao Tanaka
- & Chikashi Terao
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Article
| Open AccessMulti-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications
Thyroid dysfunction is involved in many diseases. Here, the authors provide insights into the genetics and biological pathways influencing important thyroid function parameters, showing potential causal effects on many clinical outcomes.
- Rosalie B. T. M. Sterenborg
- , Inga Steinbrenner
- & Marco Medici
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Article
| Open AccessGenetic architecture distinguishes tinnitus from hearing loss
The genetic basis of tinnitus and how it relates to hearing loss genetics is unknown. In a large GWAS for tinnitus, the authors discover tinnitus’ distinct genetic architecture from hearing loss and its correlation with a spectrum of psychiatric disorders.
- Royce E. Clifford
- , Adam X. Maihofer
- & Caroline M. Nievergelt
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| Open AccessX-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements
X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases such as chronic kidney disease (CKD). Here, the authors perform a sex-stratified, cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits, with results including identification of four novel loci associated with the CKD-defining trait eGFR.
- Markus Scholz
- , Katrin Horn
- & Cristian Pattaro
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Article
| Open AccessA genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren’s disease
In this meta-analysis of the fibrotic hand disorder Dupuytren’s disease, the authors identify genetic risk variants, study them for their functional consequences and implicate two signaling pathways involved in the disease mechanism of this debilitating disorder.
- Sophie A. Riesmeijer
- , Zoha Kamali
- & Ilja M. Nolte
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| Open AccessMicrobiome homeostasis on rice leaves is regulated by a precursor molecule of lignin biosynthesis
The underlying mechanisms of host-driven assembly of phyllosphere microbiota remain largely unknown. Here, 4-hydroxycinnamic acid synthesized by the rice plant’s PAL02 in the phenylpropanoid biosynthesis pathway is shown to be the main driver for enrichment of Pseudomonadales bacteria.
- Pin Su
- , Houxiang Kang
- & Yong Liu
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Article
| Open AccessUnraveling the causal genes and transcriptomic determinants of human telomere length
Variation in human telomere length has been well studied, but most previous studies have used adult telomere length. Here, the authors explore the genetic basis of telomere length in the placenta and find suggestive causal genes modulating human telomere length.
- Ying Chang
- , Yao Zhou
- & Dandan Huang
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Article
| Open AccessGenome-wide association study meta-analysis of blood pressure traits and hypertension in sub-Saharan African populations: an AWI-Gen study
Hypertension is a major risk factor for cardiovascular disease prevalent in Africa. Here the authors report a genome-wide study providing insights into the genetics and physiology of blood pressure variation in African populations.
- Surina Singh
- , Ananyo Choudhury
- & Michèle Ramsay
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Article
| Open AccessPrediction and stratification of longitudinal risk for chronic obstructive pulmonary disease across smoking behaviors
Many people who never smoke develop COPD. Here, the authors derive and validate the Socioeconomic and Environmental Risk Score (SERS) which captures cumulative exposure risks beyond tobacco smoking to predict and stratify risk of COPD.
- Yixuan He
- , David C. Qian
- & Chirag J. Patel
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Article
| Open AccessBinge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease
Deaths from alcohol-related liver disease have sharply increased following the Covid-19 pandemic. Here, the authors show that binge-pattern alcohol consumption, genetic factors and the presence of diabetes mellitus confer the greatest risk, allowing targeted interventions for high-risk individuals.
- Chengyi Ding
- , Linda Ng Fat
- & Gautam Mehta
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Article
| Open AccessAccurate and efficient estimation of local heritability using summary statistics and the linkage disequilibrium matrix
The authors propose “HEELS”, a new method for precise local heritability estimation. It significantly reduces the variances of summary-statistics-based heritability estimators, offering an REML-like estimator without requiring individual-level data.
- Hui Li
- , Rahul Mazumder
- & Xihong Lin
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Article
| Open AccessEvaluation of circulating plasma proteins in breast cancer using Mendelian randomisation
Proteomics of blood samples is a promising avenue for cancer diagnosis. Here, the authors conduct Mendelian randomisation analysis of protein levels across multiple cohorts, and identify 5 proteins that show promise as biomarkers for the long-term risk of breast cancer, and as potential drug targets.
- Anders Mälarstig
- , Felix Grassmann
- & Åsa K. Hedman
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Article
| Open AccessGlobal pathogenomic analysis identifies known and candidate genetic antimicrobial resistance determinants in twelve species
A global analysis of antimicrobial resistance (AMR) across 27,155 genomes and 69 drugs reveals patterns in AMR gene transfer between species and identifies 142 AMR gene candidates, two of which were tested and confirmed as contributing to AMR.
- Jason C. Hyun
- , Jonathan M. Monk
- & Bernhard O. Palsson
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Article
| Open AccessIntegrative genome-wide analyses identify novel loci associated with kidney stones and provide insights into its genetic architecture
Kidney stone disease is a complex disorder with high heritability and prevalence. Here, the authors perform a large genome-wide association study meta-analysis, identifying 28 new loci and genes potentially involved in disease etiology.
- Xingjie Hao
- , Zhonghe Shao
- & Chaolong Wang
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Article
| Open AccessJoint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape
The genetic architecture of normal-range cranial vault shape in humans is poorly understood. Here, the authors extract cranial vault shape from MRI and conduct a multi-ancestry GWAS, identifying 30 independently associated genomic loci of which 29 are novel.
- Seppe Goovaerts
- , Hanne Hoskens
- & Peter Claes
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Article
| Open AccessA large meta-analysis identifies genes associated with anterior uveitis
Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.
- Sahar Gelfman
- , Arden Moscati
- & Giovanni Coppola
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Article
| Open AccessLeveraging information between multiple population groups and traits improves fine-mapping resolution
Statistical fine-mapping helps to pinpoint likely causal variants underlying genetic association signals, and can be enhanced by using multi-ancestry datasets. Here, the authors introduce MGflashfm, a fine-mapping method for pinpointing likely causal variants amongst multiple traits and population groups.
- Feng Zhou
- , Opeyemi Soremekun
- & Jennifer L. Asimit
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| Open AccessSpeos: an ensemble graph representation learning framework to predict core gene candidates for complex diseases
Understanding phenotype-genotype relationships is a grand challenge of current biological research. Here, the authors use graph representation learning to identify human genes which display key characteristics of core genes for five complex diseases.
- Florin Ratajczak
- , Mitchell Joblin
- & Matthias Heinig
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| Open AccessUnappreciated subcontinental admixture in Europeans and European Americans and implications for genetic epidemiology studies
European ancestry individuals are not typically treated as admixed in genetic studies. Here, the authors detect higher than expected admixture in European populations, which could potentially affect the results of genetic studies if it is not accounted for.
- Mateus H. Gouveia
- , Amy R. Bentley
- & Daniel Shriner
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Article
| Open AccessGenome-wide association analysis of plasma lipidome identifies 495 genetic associations
The human plasma lipidome captures risk for cardiometabolic diseases. Here, the authors perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals, revealing genetic links between diseases and lipid species beyond the standard lipids HDL-Cholesterol, LDL-Cholesterol, Triglycerides, and total Cholesterol.
- Linda Ottensmann
- , Rubina Tabassum
- & Matti Pirinen
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| Open AccessXMAP: Cross-population fine-mapping by leveraging genetic diversity and accounting for confounding bias
Fine-mapping prioritizes risk variants identified by genome-wide association studies to uncover biological mechanisms underlying complex traits. Here, the authors develop a reliable fine-mapping method (XMAP) by leveraging genetic diversity and accounting for confounding bias.
- Mingxuan Cai
- , Zhiwei Wang
- & Can Yang
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Article
| Open AccessGenome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease
Thyroid hormones play a critical role in regulation of multiple physiological functions. Here the authors via meta-analyses and detailed variant-to-gene mapping strategies implicate novel genes, pathways and associations for thyroid function and disease.
- Alexander T. Williams
- , Jing Chen
- & Catherine John
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Article
| Open AccessA deep population reference panel of tandem repeat variation
Tandem repeats (TRs) comprise some of the most polymorphic regions of the human genome but are difficult to study. Here, the authors develop an ensemble-based genotyping method and characterize 1.7 million TRs across 3,550 humans from diverse populations.
- Helyaneh Ziaei Jam
- , Yang Li
- & Melissa Gymrek
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| Open AccessEuropean and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation
The genetic basis of atopic dermatitis is not fully understood. Here, the authors find 91 genetic loci associated with atopic dermatitis in a GWAS of >1million individuals, which highlight the importance of systemic immune regulation.
- Ashley Budu-Aggrey
- , Anna Kilanowski
- & Lavinia Paternoster