Featured
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| Open AccessTotal genetic contribution assessment across the human genome
Quantifying the effects of individual loci on the human phenome is a challenging task. Here, the authors introduce a modelling technique, TGCA, that assesses total genetic contribution per locus and apply this to UK Biobank phenotype domains, revealing top loci and links to tissue-specific gene expression.
- Ting Li
- , Zheng Ning
- & Xia Shen
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Article
| Open AccessEpigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption
While coffee and tea consumption has been associated with risk of diseases, their mechanisms of action remain elusive. Here the authors present a large EWAS on coffee and tea consumption in cohorts of European and African-American ancestries, finding that coffee consumption is associated with differential DNA methylation levels at multiple CpGs.
- Irma Karabegović
- , Eliana Portilla-Fernandez
- & Mohsen Ghanbari
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Article
| Open AccessModeling regulatory network topology improves genome-wide analyses of complex human traits
Gene regulatory networks are a useful means of inferring functional interactions from large-scale genomic data. Here, the authors develop a Bayesian framework integrating GWAS summary statistics with gene regulatory networks to identify genetic enrichments and associations simultaneously.
- Xiang Zhu
- , Zhana Duren
- & Wing Hung Wong
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Article
| Open AccessGenetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes
Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases.
- Raha Pazoki
- , Marijana Vujkovic
- & Rachel B. Ramoni
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Article
| Open AccessThe impact of non-additive genetic associations on age-related complex diseases
Most genome-wide association studies assume an additive model, exclude the X chromosome, and use one reference panel. Here, the authors implement a strategy including non-additive models and find that the number of loci for age-related traits increases as compared to the additive model alone.
- Marta Guindo-Martínez
- , Ramon Amela
- & David Torrents
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| Open AccessGenomic architecture and prediction of censored time-to-event phenotypes with a Bayesian genome-wide analysis
Few genome-wide association studies have explored the genetic architecture of age-of-onset for traits and diseases. Here, the authors develop a Bayesian approach to improve prediction in timing-related phenotypes and perform age-of-onset analyses across complex traits in the UK Biobank.
- Sven E. Ojavee
- , Athanasios Kousathanas
- & Matthew R. Robinson
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Article
| Open AccessChromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices
The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.
- Pradeep Natarajan
- , Akhil Pampana
- & Gina M. Peloso
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Article
| Open AccessSmc5/6 functions with Sgs1-Top3-Rmi1 to complete chromosome replication at natural pause sites
Smc5/6, part of the structural maintenance of chromosomes (SMC) family, plays roles in genome structural integrity. Here the authors reveal that Smc5/6 acts jointly with Top3 within the STR complex to mediate DNA replication completion at genomic natural pausing sites (NPSs).
- Sumedha Agashe
- , Chinnu Rose Joseph
- & Dana Branzei
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Article
| Open AccessGenetic substructure and complex demographic history of South African Bantu speakers
Despite linguistic and geographic diversity in South Eastern Bantu-speaking (SEB) groups of South Africa, genetic variation in these groups has not been investigated in depth. Here, the authors analyse genome-wide data from 5056 individuals, providing insights into demographic history across SEB groups.
- Dhriti Sengupta
- , Ananyo Choudhury
- & Michèle Ramsay
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Article
| Open AccessDetecting local genetic correlations with scan statistics
Genetic correlation analyses give insight on complex disease, yet are limited by oversimplification. Here, the authors present LOGODetect, a method using summary statistics from genome-wide association studies to identify genomic regions with correlation signals across multiple phenotypes.
- Hanmin Guo
- , James J. Li
- & Lin Hou
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Article
| Open AccessModel-based assessment of replicability for genome-wide association meta-analysis
In genome-wide association meta-analysis, it is often difficult to find an independent dataset of sufficient size to replicate associations. Here, the authors have developed MAMBA to calculate the probability of replicability based on consistency between datasets within the meta-analysis.
- Daniel McGuire
- , Yu Jiang
- & Dajiang J. Liu
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Article
| Open AccessA deep learning method for HLA imputation and trans-ethnic MHC fine-mapping of type 1 diabetes
Human leukocyte antigen (HLA) genes contribute to risk of many complex traits, yet understanding inter-ethnic heterogeneity is computationally challenging. Here, the authors develop DEEP*HLA for imputation of HLA genotypes and show its ability to disentangle HLA variant risk effects in diverse populations.
- Tatsuhiko Naito
- , Ken Suzuki
- & Yukinori Okada
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Article
| Open AccessA molecular quantitative trait locus map for osteoarthritis
Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments.
- Julia Steinberg
- , Lorraine Southam
- & Eleftheria Zeggini
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Article
| Open AccessGenome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries
Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.
- Puya Gharahkhani
- , Eric Jorgenson
- & Janey L. Wiggs
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Article
| Open AccessWhole genome sequencing in the Middle Eastern Qatari population identifies genetic associations with 45 clinically relevant traits
The genetic basis for traits can vary between populations. Here the authors report a genome wide association study with 45 clinically-relevant traits in individuals from Qatar, replicating many known loci and identifying new Qatari-predominant signals.
- Gaurav Thareja
- , Yasser Al-Sarraj
- & Omar M. E. Albagha
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| Open AccessGWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression
Genetic factors contribute to peptic ulcer disease (PUD). Here, the authors perform a genome-wide association analysis on PUD in the UK Biobank, highlighting shared architecture with other gastrointestinal disorders and possible causal links with depression.
- Yeda Wu
- , Graham K. Murray
- & Naomi R. Wray
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Article
| Open AccessWidespread signatures of natural selection across human complex traits and functional genomic categories
Methods to study how natural selection shapes genetic architecture of complex traits rely on individual level genome-wide association study (GWAS) data. Here, the authors present a Bayesian method using GWAS summary statistics to study genetic architecture and apply this to 155 complex traits.
- Jian Zeng
- , Angli Xue
- & Jian Yang
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Article
| Open AccessGenome-wide association studies provide insights into the genetic determination of fruit traits of pear
Studies of fruit quality traits in pears are lagging behind the other major fruit trees. Here, the authors conduct GWAS of fruit quality and phenological traits in a panel of 312 sand pear accessions using SNPs called from resequencing data, and reveal the involvement of a lignin formation-related protein in regulating stone cell development.
- Ming-Yue Zhang
- , Cheng Xue
- & Jun Wu
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Article
| Open AccessPopulation-specific causal disease effect sizes in functionally important regions impacted by selection
Trans-ethnic genetic correlation is significantly less than 1 for many diseases. Here, the authors stratify this correlation by genomic annotations, finding that loci whose causal disease effect sizes differ between ethnicities are likely impacted by selection, particularly positive selection.
- Huwenbo Shi
- , Steven Gazal
- & Alkes L. Price
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Article
| Open AccessGenetic determinants of risk in autoimmune pulmonary alveolar proteinosis
Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.
- Saori Sakaue
- , Etsuro Yamaguchi
- & Yukinori Okada
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| Open AccessRare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism
Metabolites are indicators of health and disease; genetic studies can reveal variants influencing their levels. Here, the authors investigate the contribution of rare, exonic variants on the levels of urine metabolites and generate predictions on metabolic consequences underlying metabolic disease.
- Yurong Cheng
- , Pascal Schlosser
- & Anna Köttgen
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Article
| Open AccessGenetic determinants of daytime napping and effects on cardiometabolic health
The genetic basis of daytime napping and the directional effect of daytime napping on cardiometabolic health are unknown. Here, the authors perform a genome-wide association study on self-reported daytime napping in the UK Biobank and Mendelian randomization to explore causal associations.
- Hassan S. Dashti
- , Iyas Daghlas
- & Richa Saxena
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| Open AccessGenetic predictors of participation in optional components of UK Biobank
Large BioBank studies are commonly used in GWAS, but may be biased by factors affecting participation and dropout. Here the authors show that some of the factors affecting participation may have underlying genetic components.
- Jessica Tyrrell
- , Jie Zheng
- & Kate Tilling
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Article
| Open AccessGenome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology
Serum liver enzymes are used as markers of liver disease, their concentration influenced in part by genetic factors. Here the authors meta-analyse genome-wide association studies on the UK Biobank and BioBank Japan to evaluate the association of three liver enzymes with liver and other metabolic diseases.
- Vincent L. Chen
- , Xiaomeng Du
- & Elizabeth K. Speliotes
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Article
| Open AccessIdentification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups
The presentation of systemic lupus erythematosus has been known to differ by ancestry, but the underlying genetic factors remain unclear. Here, the authors report ancestry-specific susceptibility loci and better risk prediction when using data from matched ancestral groups.
- Yong-Fei Wang
- , Yan Zhang
- & Wanling Yang
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Article
| Open AccessA fast and efficient colocalization algorithm for identifying shared genetic risk factors across multiple traits
Statistical colocalisation is a method to identify causal genes and shared genetic aetiology across traits. Here, the authors describe HyPrColoc, an efficient Bayesian divisive clustering algorithm which integrates summary statistics from genome-wide association studies to detect clusters of colocalised traits from large numbers of traits.
- Christopher N. Foley
- , James R. Staley
- & Joanna M. M. Howson
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Article
| Open AccessRisk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder
ADHD is often found to be comorbid with disruptive behavior disorders, but the genetic loci underlying this comorbidity are unknown. Here, the authors have performed a GWAS meta-analysis of ADHD with disruptive behavior disorders, finding three genome-wide significant loci in Europeans, and replicating one in a Chinese cohort.
- Ditte Demontis
- , Raymond K. Walters
- & Anders D. Børglum
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| Open AccessGraphical analysis for phenome-wide causal discovery in genotyped population-scale biobanks
Mendelian randomization is a popular method to detect causal relationships between traits, but can be confounded by instances of horizontal pleiotropy. Here, the authors present a Mendelian randomization workflow which includes causal discovery analysis and filtering of genetic instruments based on their conditional independencies.
- David Amar
- , Nasa Sinnott-Armstrong
- & Manuel A. Rivas
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Article
| Open AccessSex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
- Vasiliki Lagou
- , Reedik Mägi
- & Inga Prokopenko
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Article
| Open AccessLoss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease
Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.
- Jonas B. Nielsen
- , Oren Rom
- & Kristian Hveem
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Comment
| Open AccessFunctional studies of GWAS variants are gaining momentum
Rapidly advancing genomic technologies and cross-disciplinary partnerships are accelerating the biological and clinical interpretation of genome-wide association studies, with some therapies developed based on these findings already being tested in clinical trials. The next decade promises further progress in understanding the function of genetic variants.
- Florence Lichou
- & Gosia Trynka
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Article
| Open AccessCerebral small vessel disease genomics and its implications across the lifespan
White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.
- Muralidharan Sargurupremraj
- , Hideaki Suzuki
- & Stéphanie Debette
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Article
| Open AccessIdentity-by-descent detection across 487,409 British samples reveals fine scale population structure and ultra-rare variant associations
Accurately measuring genetic relatedness by Identical-By-Descent (IBD) segments is challenging in biobank-level genome data. The authors present IBD method FastSMC, which when applied to the UK Biobank gives a detailed picture of genetic relatedness and evolutionary history in the UK over the past 2000 years.
- Juba Nait Saada
- , Georgios Kalantzis
- & Pier Francesco Palamara
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Article
| Open AccessThe genetic architecture of sporadic and multiple consecutive miscarriage
Miscarriage affects around 15% of clinically confirmed pregnancies. Here the authors carry out a large genome-wide association study for sporadic and multiple consecutive miscarriage and suggest links with placental biology.
- Triin Laisk
- , Ana Luiza G. Soares
- & Cecilia M. Lindgren
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| Open AccessGenetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women
Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.
- Valgerdur Steinthorsdottir
- , Ralph McGinnis
- & Linda Morgan
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Comment
| Open Access15 years of genome-wide association studies and no signs of slowing down
Over the past 15 years, genome-wide association studies (GWASs) have generated a wealth of new information. Larger samples sizes, refined phenotypes and higher-resolution genome-screens will continue to drive gene discovery in years ahead. Meanwhile, GWAS loci are increasingly translated into new biology and opportunities for clinical care.
- Ruth J. F. Loos
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| Open AccessAutozygosity influences cardiometabolic disease-associated traits in the AWI-Gen sub-Saharan African study
The prevalence of cardiometabolic diseases (CMDs) is increasing rapidly across Africa. Here, the authors investigate autozygosity in CMD-associated traits in over 10,000 sub-Saharan African individuals, showing these traits are influenced by sex-specific inbreeding depression and environmental interactions.
- Francisco C. Ceballos
- , Scott Hazelhurst
- & Michèle Ramsay
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| Open AccessGenome-wide meta-analysis of brain volume identifies genomic loci and genes shared with intelligence
Brain volume and intelligence have been previously found to have shared genetic etiology, but the specific common genetic signals have not been identified. Here, the authors perform a genome-wide association study on brain volume, finding common genetic loci driving brain volume and intelligence.
- Philip R. Jansen
- , Mats Nagel
- & Danielle Posthuma
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Article
| Open AccessExpanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits
There is strong genetic evidence for cigarette smoking behaviors, yet little is known on nicotine dependence (ND). Here, the authors perform a genome-wide association study on ND in 58,000 smokers, identifying five genome-wide significant loci.
- Bryan C. Quach
- , Michael J. Bray
- & Dana B. Hancock
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Article
| Open AccessMEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk
Bone mineral density (BMD) is associated with fracture risk and many genetic loci with small effect sizes have been discovered by genome-wide association studies (GWAS). Here, the authors discover a large-effect rare loss-of-function genetic variant for BMD in the MEPE gene in the Norwegian HUNT study which replicates in the UK Biobank.
- Ida Surakka
- , Lars G. Fritsche
- & Cristen J. Willer
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Article
| Open AccessWhole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants
Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality. Here, the authors analyse whole genome sequence data and find new loci associated with lung function and COPD.
- Xutong Zhao
- , Dandi Qiao
- & Ani Manichaikul
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Article
| Open AccessIdentification of 31 loci for mammographic density phenotypes and their associations with breast cancer risk
Mammographic density represents one the strongest predictors of breast cancer risk. Here the authors perform genome-wide association study meta-analysis of women screened with full-field digital mammography and identify 31 previously unreported loci associated with mammographic density phenotypes.
- Weiva Sieh
- , Joseph H. Rothstein
- & Laurel A. Habel
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Article
| Open AccessDiscovery of beneficial haplotypes for complex traits in maize landraces
Genetic variations present in landraces are critical for crop genetic improvement. Here, the authors map haplotype-trait associations in ~1000 doubled haploid lines derived from three European maize landraces and identify beneficial haplotypes for quantitative traits that are not present in breeding lines.
- Manfred Mayer
- , Armin C. Hölker
- & Chris-Carolin Schön
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Article
| Open AccessRisk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture
Despite the identification of genetic risk loci for late-onset Alzheimer’s disease (LOAD), the genetic architecture and prediction remains unclear. Here, the authors use genetic risk scores for prediction of LOAD across three datasets and show evidence suggesting oligogenic variant architecture for this disease.
- Qian Zhang
- , Julia Sidorenko
- & Peter M. Visscher
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Article
| Open AccessGenetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults
Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.
- Edith Hofer
- , Gennady V. Roshchupkin
- & Sudha Seshadri
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Article
| Open AccessThe impact of transposable elements on tomato diversity
Transposable element insertion polymorphisms (TIPs) are a potential source of large effect alleles. Here, the authors use genome resequencing data for 602 tomato accessions together with transcriptomic and extensive phenotypic information to investigate the contribution of TIPs to tomato diversity.
- Marisol Domínguez
- , Elise Dugas
- & Leandro Quadrana
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Article
| Open AccessThe genetic architecture of human brainstem structures and their involvement in common brain disorders
The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.
- Torbjørn Elvsåshagen
- , Shahram Bahrami
- & Tobias Kaufmann
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Article
| Open AccessGWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer
Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. Here, the authors conduct a GWAS and suggest protective effect of higher TSH on risk of thyroid cancer and goitre.
- Wei Zhou
- , Ben Brumpton
- & Bjørn Olav Åsvold
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Article
| Open AccessTesting and controlling for horizontal pleiotropy with probabilistic Mendelian randomization in transcriptome-wide association studies
Transcriptome-wide association studies integrate GWAS and transcriptome data to examine the molecular mechanisms underlying disease etiology. Here the authors present PMR-Egger, a powerful TWAS method based on probabilistic Mendelian Randomization.
- Zhongshang Yuan
- , Huanhuan Zhu
- & Xiang Zhou