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| 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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| 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 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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| 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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| 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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| 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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| 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 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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| 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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| 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
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| Open AccessGhostKnockoff 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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| Open AccessPleiotropic 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 AccessGenetic 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 AccessParent-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 AccessThe 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 AccessShared 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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| Open AccessMendelian 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 AccessWhole 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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| Open AccessVariation 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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| Open AccessGWAS, 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
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Article
| Open AccessGenomic analyses of rice bean landraces reveal adaptation and yield related loci to accelerate breeding
Rice bean is an underexploited legume crop that has many desirable properties against bio and abiotic stresses. Here, the authors report the genome assembly of this species, conduct population genetics studies and reveal the genetic variations associated with adaptation and yield traits.
- Jiantao Guan
- , Jintao Zhang
- & Lixia Wang
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Article
| Open AccessDNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types
Here the authors identify differences in cortical DNA methylation associated with Alzheimer’s disease pathology, and profiling nuclei from specific cell-types, find that most of these differences reflect variation occurring in non-neuronal cells.
- Gemma Shireby
- , Emma L. Dempster
- & Jonathan Mill
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Article
| Open AccessEfficient and accurate frailty model approach for genome-wide survival association analysis in large-scale biobanks
The proliferation of large biobanks necessitates statistical methods designed for genetic analysis on biobank data. Here, the authors have developed a frailty model-based method for GWAS analysis of time-to-event phenotypes in large biobanks that accounts for relatedness in samples and censoring of phenotypes.
- Rounak Dey
- , Wei Zhou
- & Xihong Lin
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| Open AccessIdentifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes
Genetic association studies for rare variants suffer from lack of power and thus there is a need for methods to improve rare variant discovery. Here, the authors present functionally informed association tests with increased statistical power to aid discovery and interpretation of rare variants.
- Remo Monti
- , Pia Rautenstrauch
- & Christoph Lippert
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Article
| Open AccessIdentification of risk loci for primary aldosteronism in genome-wide association studies
Detection of primary aldosteronism, the most common form of secondary arterial hypertension, is essential for targeted management and prevention of cardiovascular complications. Here, the authors identify genetic loci associated with primary aldosteronism, suggesting new mechanisms of disease.
- Edith Le Floch
- , Teresa Cosentino
- & Maria-Christina Zennaro
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Article
| Open AccessGenetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.
- William J. Young
- , Najim Lahrouchi
- & Patricia B. Munroe
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Article
| Open AccessWhole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals
Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.
- Usman A. Tahir
- , Daniel H. Katz
- & Robert E. Gerszten
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| Open AccessGWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.
- Peter H. Dixon
- , Adam P. Levine
- & Catherine Williamson
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Article
| Open AccessGenome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities
Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.
- Catherine M. Francis
- , Matthias E. Futschik
- & Paul M. Matthews
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Article
| Open AccessA common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors
Intracranial germ cell tumors (IGCTs) are rare brain tumors mainly diagnosed in children and young adults. Here, the authors conduct a genome-wide association study for IGCTs, identify a risk locus at BAK1, and characterize its functional consequences.
- Kyuto Sonehara
- , Yui Kimura
- & Keita Terashima
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Article
| Open AccessGenome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells
The genetic architecture underlying Sjögren’s syndrome is not fully understood. Here, the authors perform a genome-wide association study to identify 10 new genetic risk regions, implicating genes involved in immune and salivary gland function.
- Bhuwan Khatri
- , Kandice L. Tessneer
- & Christopher J. Lessard
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Article
| Open AccessPopulation genomics of Group B Streptococcus reveals the genetics of neonatal disease onset and meningeal invasion
Group B Streptococcus (GBS) causes neonatal disease and mortality worldwide. Here, the authors use genome-wide association analyses to identify bacterial genetic signatures associated with disease onset time and meningeal tissue infection in acute invasive neonatal GBS disease.
- Chrispin Chaguza
- , Dorota Jamrozy
- & Stephen D. Bentley
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Article
| Open AccessVariance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers
Understanding how our genes interact with the environment is critical to improving health. Using a large-scale discovery pipeline, here the authors investigate synergies between genetic variants and a broad range of environmental factors impacting cardiometabolic health.
- Kenneth E. Westerman
- , Timothy D. Majarian
- & Joanne B. Cole
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Article
| Open AccessThe impact of species-wide gene expression variation on Caenorhabditis elegans complex traits
Gene expression links genomic variation to organismal trait differences. Here, the authors identify regulatory loci underlying gene expression variation in C. elegans and demonstrate how this variation could impact other complex traits.
- Gaotian Zhang
- , Nicole M. Roberto
- & Erik C. Andersen
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Article
| Open AccessDistributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders
The hippocampus has been associated with memory traits and a variety of neurodegenerative and psychiatric disorders. Here, the authors have done a multivariate GWAS revealing 177 genetic loci, and overlap with various brain disorders may suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.
- Shahram Bahrami
- , Kaja Nordengen
- & Tobias Kaufmann
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Article
| Open AccessComprehensive genome-wide association study of different forms of hernia identifies more than 80 associated loci
Hernias involve protrusion of an organ or tissue through its surrounding cavity. Here the authors carry out GWAS for five types of hernia and find 81 variants, most of which are associated with inguinal hernia; downstream analysis suggests an important role for connective tissue morphology.
- João Fadista
- , Line Skotte
- & Frank Geller
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Article
| Open AccessIntegrating 3D genomic and epigenomic data to enhance target gene discovery and drug repurposing in transcriptome-wide association studies
Transcriptome-wide association studies can be used to test the effects of predicted gene expression in a cohort of individuals based on genetic data. Here, the authors developed a transcriptome-wide association method that integrates 3D genomic and epigenomic data with expression quantitative trait loci to improve gene expression predictions.
- Chachrit Khunsriraksakul
- , Daniel McGuire
- & Dajiang J. Liu
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Article
| Open AccessComprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease
Dysregulation of lipid metabolism is associated with coronary artery disease (CAD). Here, the authors perform GWAS of the serum lipidome to identify variants associated with lipid species that are putatively in the mechanistic pathway to CAD.
- Gemma Cadby
- , Corey Giles
- & Eric K. Moses