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| Open AccessUnderstanding the genetic determinants of the brain with MOSTest
Regional brain morphology has a complex genetic architecture. Here the authors present MOSTest, a multivariate statistical framework, apply it to UK Biobank data, and discover hundreds of loci associated with regional brain morphology.
- Dennis van der Meer
- , Oleksandr Frei
- & Anders M. Dale
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Article
| Open AccessA genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine
The association between blood pressure (BP) and migraine is poorly understood. Here, the authors explore this relationship using summary-level GWAS data for BP and migraine. Cross-trait meta-analysis reveals shared loci between BP and migraine, while Mendelian randomization suggests that diastolic BP specifically plays a key role in migraine susceptibility.
- Yanjun Guo
- , Pamela M. Rist
- & Daniel I. Chasman
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| Open AccessA sequential methodology for the rapid identification and characterization of breast cancer-associated functional SNPs
It is often difficult to identify functional SNPs from disease-associated SNPs in linkage disequilibrium. Here, the authors present Reel-seq, SDCP-MS and AIDP-Wb, three sequential methodologies for fSNP identification and characterization.
- Yihan Zhao
- , Di Wu
- & Gang Li
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Article
| Open AccessGenome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer
Previous genome-wide association studies have identified risk loci for pancreatic cancer but were centered on individuals of European ancestry. Here the authors identify GP2 gene variants associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
- Yingsong Lin
- , Masahiro Nakatochi
- & Keitaro Matsuo
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Article
| Open AccessAdaptive reduction of male gamete number in the selfing plant Arabidopsis thaliana
Reduction of pollen grain number is widespread in selfing plants, but the determining gene is unknown. Here, the authors show that a ribosome-biogenesis factor encoding gene RDP1 is responsible for adaptive reduction of male gamete number in Arabidopsis thaliana.
- Takashi Tsuchimatsu
- , Hiroyuki Kakui
- & Kentaro K. Shimizu
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Article
| Open AccessMulti-trait analysis of rare-variant association summary statistics using MTAR
Methods to integrate association evidence across multiple traits often focus on individual common variants GWAS. Here the authors present multi-trait analysis of rare-variant associations (MTAR), a framework for joint analysis of association summary statistics between multiple rare variants and different traits.
- Lan Luo
- , Judong Shen
- & Zheng-Zheng Tang
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Article
| Open AccessMassively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma
There are more than 20 known melanoma susceptibility genes. Here, using a massively parallel reporter assay, the authors identify risk-associated variants that alter gene transcription, and demonstrate that expression of one such gene, MX2, leads to the promotion of melanoma in a zebrafish model.
- Jiyeon Choi
- , Tongwu Zhang
- & Kevin M. Brown
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| Open AccessMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
- Ioanna Ntalla
- , Lu-Chen Weng
- & Patricia B. Munroe
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Article
| Open AccessA phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank
Depression is correlated with many brain-related traits. Here, Shen et al. perform phenome-wide association studies of a depression polygenic risk score (PRS) and find associations with 51 behavioural and 26 neuroimaging traits which are further followed up on using Mendelian randomization and mediation analyses.
- Xueyi Shen
- , David M. Howard
- & Andrew M. McIntosh
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| Open AccessAnalysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy
Structural changes to the left ventricle are characteristic of dilated cardiomyopathy (DCM), a disease for which many rare genetic variants are known. Here, Pirruccello et al. report GWAS of seven cardiac MRI measurements in the left ventricle and describe shared loci and polygenic association with DCM.
- James P. Pirruccello
- , Alexander Bick
- & Krishna G. Aragam
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Article
| Open AccessDemographic and genetic factors influence the abundance of infiltrating immune cells in human tissues
Immune infiltration provides critical information for health and disease, yet it is unclear what factors influence infiltration levels. Here, the authors analyze human tissue transcriptomes from the Genotype-Tissue Expression project to find infiltration patterns regulated by age, sex and host genetic information.
- Andrew R. Marderstein
- , Manik Uppal
- & Olivier Elemento
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Article
| Open AccessGenome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants
Cerebral small vessel disease (CSVD) is a major cause of stroke and associated with structural changes of the brain. Here, Persyn et al. perform genome-wide association studies for magnetic resonance imaging (MRI) markers of CSVD, explore genetic correlations and prioritize candidate genes.
- Elodie Persyn
- , Ken B. Hanscombe
- & Hugh S. Markus
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| Open AccessGenome-wide association studies and Mendelian randomization analyses for leisure sedentary behaviours
Epidemiological studies have shown an association between sedentary behaviours and cardiovascular disease risk. Here, van de Vegte et al. perform GWAS for self-reported sedentary behaviours (TV watching, computer use, driving) and Mendelian randomization analyses to explore potential causal relationships with coronary artery disease.
- Yordi J. van de Vegte
- , M. Abdullah Said
- & Niek Verweij
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Article
| Open AccessGenome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma
Asthma is a common disease of the airways for which numerous genetic loci have been identified. Here, Han et al. carry out a genome-wide analysis for asthma to identify additional loci, report sex-stratified and genetic risk score analyses, and functionally follow-up one locus using a murine model of airway hyperreactivity.
- Yi Han
- , Qiong Jia
- & Hooman Allayee
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| Open AccessGenome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration
Vitamin D is a precursor of the steroid hormone 1,25-dihydroxyvitamin D3, and its deficiency is associated with many adverse health outcomes. Here, Revez et al. perform a genome-wide association study for circulating 25-hydroxyvitamin D in 417,580 individuals and test for potential causal relationships with other traits using Mendelian randomization.
- Joana A. Revez
- , Tian Lin
- & John J. McGrath
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Article
| Open AccessThe genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects.
- Jingyuan Xie
- , Lili Liu
- & Krzysztof Kiryluk
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Article
| Open AccessGenomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan
Age at voice-breaking is used to determine puberty timing in men, recall of which is considered less accurate than age at first menarche in women. Here, the authors perform multi-trait GWAS for male puberty timing by including both age at voice breaking and age of first facial hair for improved phenotype definition and power.
- Ben Hollis
- , Felix R. Day
- & John R. B. Perry
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Article
| Open Access8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer
Inherited alterations of the 8q24 genomic locus are linked to cancer etiology. Here, the authors investigate hereditary prostate cancer to reveal ancestral risk-altering haplotypes, the sentinel genetic variants optimally predicting risk, and causal mutation candidates.
- William D. Dupont
- , Joan P. Breyer
- & Jeffrey R. Smith
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| Open AccessComprehensive genomic analysis of dietary habits in UK Biobank identifies hundreds of genetic associations
The choice of food intake is at least partially influenced by genetics, even though the effect sizes appear rather modest. Here, Cole et al. perform GWAS for food intake (85 individual food items and 85 derived dietary patterns) and test potential causal relationships with cardiometabolic traits using Mendelian randomization.
- Joanne B. Cole
- , Jose C. Florez
- & Joel N. Hirschhorn
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| Open AccessGenome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure
Heart failure has a heterogeneous etiology and the genetic underpinnings are not well understood. Here, Arvanitis et al. perform GWAS meta-analysis including 10,976 heart failure cases and 437,573 controls, identify new loci near ABO and ACTN2 and show that deletion of a ACTN2 enhancer leads to reduced ACTN2 expression in differentiating cardiomyocytes.
- Marios Arvanitis
- , Emmanouil Tampakakis
- & Alexis Battle
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| Open AccessMulti-resolution localization of causal variants across the genome
GWAS analysis currently relies mostly on linear mixed models, which do not account for linkage disequilibrium (LD) between tested variants. Here, Sesia et al. propose KnockoffZoom, a non-parametric statistical method for the simultaneous discovery and fine-mapping of causal variants, assuming only that LD is described by hidden Markov models (HMMs).
- Matteo Sesia
- , Eugene Katsevich
- & Chiara Sabatti
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| Open AccessInsights into the aetiology of snoring from observational and genetic investigations in the UK Biobank
Snoring is common in the population and tends to be more prevalent in older and/or male individuals. Here, the authors perform GWAS for habitual snoring, identify 41 genomic loci and explore potential causal relationships with anthropometric and cardiometabolic disease traits.
- Adrián I. Campos
- , Luis M. García-Marín
- & Miguel E. Rentería
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Article
| Open AccessGenome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma
The authors perform a meta-analysis of cutaneous squamous cell carcinoma, identifying causal variants within skin-specific regulatory elements.
- Kavita Y. Sarin
- , Yuan Lin
- & Jiali Han
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Article
| Open AccessFAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease
In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.
- Tingxiang Yan
- , Jingjing Liang
- & Xinglong Wang
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Article
| Open AccessEighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis
Asthma is a common allergic airway disease with significant inter-individual heterogeneity. Here, Olafsdottir et al. report a genome-wide meta-analysis of two large population-based cohorts to identify sequence variants that associate with asthma risk and perform follow-up functional analyses on a protective loss-of-function variant in TNFRSF8.
- Thorunn A. Olafsdottir
- , Fannar Theodors
- & Kari Stefansson
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Article
| Open AccessA network analysis to identify mediators of germline-driven differences in breast cancer prognosis
In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.
- Maria Escala-Garcia
- , Jean Abraham
- & Marjanka K. Schmidt
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| Open AccessExtreme genetic signatures of local adaptation during Lotus japonicus colonization of Japan
Local adaptation contributes to plant colonization across extreme environmental gradients. Here, the authors reconstruct the colonization history of Lotus japonicus in Japan and identify extreme genetic signatures of local adaptation to a cold climate using genome resequencing and common garden experiments.
- Niraj Shah
- , Tomomi Wakabayashi
- & Stig Uggerhøj Andersen
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Article
| Open AccessRare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations
Associations of copy number variations (CNVs) with complex traits are challenging to study because of their low frequency. Here, the authors analyse SNP array and array comparative genomic hybridization data of 100,028 individuals and report their associations with immune-related, cardiometabolic and neuropsychiatric diseases as well as cancer.
- Yun Rose Li
- , Joseph T. Glessner
- & Hakon Hakonarson
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Article
| Open AccessGenome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.
- Sonia Shah
- , Albert Henry
- & R. Thomas Lumbers
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Article
| Open AccessHeritability estimates for 361 blood metabolites across 40 genome-wide association studies
Blood metabolite levels are under the influence of environmental and genetic factors. Here, Hagenbeek et al. perform heritability estimations for metabolite measures and determine the contribution of known metabolite loci to metabolite levels using data from 40 genome-wide association studies.
- Fiona A. Hagenbeek
- , René Pool
- & Dorret I. Boomsma
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| Open AccessSelecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization
Multivariable Mendelian randomization (MR) extends the standard MR framework to consider multiple risk factors in a single model. Here, Zuber et al. propose MR-BMA, a Bayesian variable selection approach to identify the likely causal determinants of a disease from many candidate risk factors as for example high-throughput data sets.
- Verena Zuber
- , Johanna Maria Colijn
- & Stephen Burgess
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Article
| Open AccessGenomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke
Stroke risk is influenced by genetic and lifestyle factors and previously a genomic risk score (GRS) for stroke was proposed, albeit with limited predictive power. Here, Abraham et al. develop a metaGRS that is composed of several stroke-related GRSs and demonstrate improved predictive power compared with individual GRS or classic risk factors.
- Gad Abraham
- , Rainer Malik
- & Martin Dichgans
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Article
| Open AccessInsights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania
Four genome-wide associated loci are currently known for malaria susceptibility. Here, the authors expand on earlier work by combining data from 11 malaria-endemic countries and additional population sequencing informing an African-enriched imputation reference panel, with findings including a previously unreported association on chromosome 6.
- Gavin Band
- , Quang Si Le
- & Dominic P. Kwiatkowski
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Article
| Open AccessGenome-wide analysis identifies molecular systems and 149 genetic loci associated with income
Household income is used as a marker of socioeconomic position, a trait that is associated with better physical and mental health. Here, Hill et al. report a genome-wide association study for household income in the UK and explore its relationship with intelligence in post-GWAS analyses including Mendelian randomization.
- W. David Hill
- , Neil M. Davies
- & Ian J. Deary
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Article
| Open AccessBrain age prediction using deep learning uncovers associated sequence variants
Machine learning algorithms can be trained to estimate age from brain structural MRI. Here, the authors introduce a new deep-learning-based age prediction approach, and then carry out a GWAS of the difference between predicted and chronological age, revealing two associated variants.
- B. A. Jonsson
- , G. Bjornsdottir
- & M. O. Ulfarsson
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Article
| Open AccessIdentification of four novel associations for B-cell acute lymphoblastic leukaemia risk
B-cell acute lymphoblastic leukaemia (B-ALL) is a common childhood cancer. Here, the authors conducted a meta-analysis with four genome-wide association studies, totalling 5,321 cases and 16,666 controls of European descent, identifying B-ALL risk loci, whose integration with epigenomic profiling indicates cell-cycle and B-cell development deregulation as central mechanisms in B-ALL susceptibility, often in a subtype-specific fashion.
- Jayaram Vijayakrishnan
- , Maoxiang Qian
- & Jun J. Yang
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Article
| Open AccessGenetic variants of calcium and vitamin D metabolism in kidney stone disease
Kidney stones form in the presence of overabundance of crystal-forming substances such as Ca2+ and oxalate. Here, the authors report genome-wide association analyses for kidney stone disease, report seven previously unknown loci and find that some of these loci also associate with Ca2+ concentration and excretion.
- Sarah A. Howles
- , Akira Wiberg
- & Dominic Furniss
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Article
| Open AccessMulti-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration
Sleep duration is associated with an adverse lipid profile. Here, the authors perform genome-wide gene-by-sleep interaction analysis and find 49 previously unreported lipid loci when considering short or long total sleep time.
- Raymond Noordam
- , Maxime M. Bos
- & Susan Redline
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Article
| Open AccessGenome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder characterised by asthma, eosinophilia and vasculitis. Here, the authors describe a genome-wide association study of EGPA that reveals clinical and genetic differences between subgroups stratified by autoantibody status (ANCA).
- Paul A Lyons
- , James E Peters
- & Kenneth G. C. Smith
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Article
| Open AccessGWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that affects the connective tissue. Here, López-Isac et al. identify 13 new risk loci for SSc as well as loci specific for limited cutaneous and diffuse SSc and, defining credible sets and performing functional annotation, highlight key pathways and cell types for SSc.
- Elena López-Isac
- , Marialbert Acosta-Herrera
- & Javier Martin
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Article
| Open AccessGenome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis
Uterine leiomyomata (UL) or fibroids are neoplasms of the uterine smooth muscle associated with heavy menstrual bleeding and other female reproductive tract morbidity. Here, the authors identify eight previously undescribed genetic loci for UL and further look into genetic overlap with heavy menstrual bleeding and endometriosis.
- C. S. Gallagher
- , N. Mäkinen
- & C. C. Morton
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Article
| Open AccessSequence variants with large effects on cardiac electrophysiology and disease
Aberrant morphology of the QRS complex in an electrocardiogram can be associated with cardiac morbidity and mortality. Here, the authors perform genome-wide association studies for ten measures of the QRS complex in 81,192 individuals and find 86 previously unreported loci that associate with at least one parameter.
- Kristjan Norland
- , Gardar Sveinbjornsson
- & Kari Stefansson
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Article
| Open AccessA comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context
Genome-wide association studies of metabolites have revealed hundreds of genetic associations using univariate analyses. Here, the authors use a multivariate approach to perform association analyses for 158 serum metabolites, followed by fine mapping and GxE interaction tests with statin use and age.
- Apolline Gallois
- , Joel Mefford
- & Hugues Aschard
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Article
| Open AccessGWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation
Mosaic loss of chromosome Y (mLOY) is associated with age and smoking but also genetic factors play a role. Here, Terao et al. perform GWAS for mLOY in 95,380 Japanese men and identify 46 loci that overlap with hematopoietic stem cell enhancers and transcription factor binding sites critical for hematopoiesis.
- Chikashi Terao
- , Yukihide Momozawa
- & Yoichiro Kamatani
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| Open AccessInternational meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci
Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.
- Caroline M. Nievergelt
- , Adam X. Maihofer
- & Karestan C. Koenen
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Article
| Open AccessGenome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth
Changes in body mass index (BMI) during infancy and childhood follow a well-characterized pattern. Here, Helgeland et al. perform genome-wide association studies for BMI at 12 time points between birth and 8 years of age and find transient associations at the LEP and LEPR loci.
- Øyvind Helgeland
- , Marc Vaudel
- & Pål Rasmus Njølstad
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| Open AccessCharacterizing rare and low-frequency height-associated variants in the Japanese population
Thousands of genetic loci are known to associate with human height, but these are mainly based on studies in European ancestry populations. Here, Akiyama et al. construct a genotype reference panel for the Japanese population followed by GWAS and report 573 height associated variants in 191,787 Japanese.
- Masato Akiyama
- , Kazuyoshi Ishigaki
- & Yoichiro Kamatani
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Article
| Open AccessGenetic architecture of human plasma lipidome and its link to cardiovascular disease
Cardiovascular diseases (CVD) are associated with plasma lipid levels. Here, Tabassum et al. perform genome-wide association studies for lipidomic profiles with 141 (non-standard) lipid species which highlights shared genetic loci with CVD and that traditional lipids have low genetic correlation with other lipids.
- Rubina Tabassum
- , Joel T. Rämö
- & Samuli Ripatti
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| Open AccessThe transferability of lipid loci across African, Asian and European cohorts
The majority of published GWAS was performed in European ancestry populations. Here, Kuchenbaecker et al., test to which extent lipid loci are shared and find that the major lipid loci are mostly transferrable between Europeans and Asians while there are notable exceptions for African populations.
- Karoline Kuchenbaecker
- , Nikita Telkar
- & Dieter Wolke