A multiethnic GWAS meta-analysis of 585,243 individuals identifies new risk loci associated with cataract and reveals sex-specific effects

Cataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States1-3. The etiology remains largely unclear, and to contribute to its elucidation we conducted a multiethnic genome-wide association meta-analysis of cataract, combining results from the GERA and UK Biobank cohorts, and tested for replication in the research cohort from 23andMe, Inc.. We report 54 genome-wide significant loci, 37 of which were previously unknown. Sex-stratified analyses identified two additional novel loci (CASP7 and GSTM2) specific to women and sex differences in effect sizes and significance of association at five other loci. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages. Further, 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology.

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A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects

Nature Communications ◽

10.1038/s41467-021-23873-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hélène Choquet ◽

Ronald B. Melles ◽

Deepti Anand ◽

Jie Yin ◽

Gabriel Cuellar-Partida ◽

...

Keyword(s):

Meta Analysis ◽

The Elderly ◽

The United States ◽

Altered Gene Expression ◽

Specific Effects ◽

Genome Wide ◽

Altered Gene ◽

Mouse Lens ◽

Insight Into ◽

Gene Perturbation

AbstractCataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States. As the genetic etiology of cataract formation remains unclear, we conducted a multiethnic genome-wide association meta-analysis, combining results from the GERA and UK Biobank cohorts, and tested for replication in the 23andMe research cohort. We report 54 genome-wide significant loci, 37 of which were novel. Sex-stratified analyses identified CASP7 as an additional novel locus specific to women. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages as per iSyTE analysis. Furthermore, iSyTE shows 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology. Our work provides further insight into the complex genetic architecture of cataract susceptibility.

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Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-021-02494-4 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Maria Bruzelius ◽

Susanna C. Larsson

Keyword(s):

Renal Function ◽

Venous Thromboembolism ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Increased Risk ◽

Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

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Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003148 ◽

2021 ◽

Author(s):

Mengyao Yu ◽

Sergiy Kyryachenko ◽

Stephanie Debette ◽

Philippe Amouyel ◽

Jean-Jacques Schott ◽

...

Keyword(s):

Mitral Valve ◽

Association Study ◽

Genome Wide Association Study ◽

Cardiac Development ◽

Meta Analysis ◽

Genome Wide Association ◽

Uk Biobank ◽

Additional Risk ◽

Genome Wide ◽

The Uk

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study have identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank. Methods: We reanalyzed 1007/479 cases from the MVP-France study, 1469/862 controls from the MVP-Nantes study for reimputation genotypes using HRC and TOPMed panels. We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used FUMA for post-genome-wide association study annotations and MAGMA for gene-based and gene-set analyses. Results: We found TOPMed imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1 . We identified an additional risk locus on Chr1 ( SYT2 ) and 2 suggestive risk loci on chr8 ( MSRA ) and chr19 ( FBXO46 ), all driven by common variants. Gene-based association using MAGMA revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

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Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci

Molecular Psychiatry ◽

10.1038/mp.2016.49 ◽

2016 ◽

Vol 21 (6) ◽

pp. 749-757 ◽

Cited By ~ 113

Author(s):

D J Smith ◽

V Escott-Price ◽

G Davies ◽

M E S Bailey ◽

L Colodro-Conde ◽

...

Keyword(s):

Medical Research ◽

Genetic Correlation ◽

Meta Analysis ◽

Small Sample ◽

Chromosome 8 ◽

Chromosome 17 ◽

Chromosome 1 ◽

Eysenck Personality Questionnaire ◽

Uk Biobank ◽

Genome Wide

Abstract Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form’s Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10−15) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

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The Effects of Exercise on Mood in Older Adults: A Meta-Analytic Review

Journal of Aging and Physical Activity ◽

10.1123/japa.8.4.407 ◽

2000 ◽

Vol 8 (4) ◽

pp. 407-430 ◽

Cited By ~ 149

Author(s):

Shawn M. Arent ◽

Daniel M. Landers ◽

Jennifer L. Etnier

Keyword(s):

Older Adults ◽

Exercise Prescription ◽

Meta Analysis ◽

The Elderly ◽

Exercise Group ◽

Effect Sizes ◽

Control Groups ◽

Moderating Variables ◽

Analytic Review ◽

Experimental Versus

This meta-analysis examined the exercise-mood relationship in older adults. 158 effect sizes (ESs) from 32 studies were grouped intoexperimental-versus-control, gains, and correlational ESs. Each study was coded for moderator variables related to descriptive, design, participant, exercise, and mood-assessment characteristics. Experimental-versus-control ESs for negative (NA) and positive affect (PA) were 0.35 (p < .05) and 0.33 (p > .05), respectively, with an overall ES of 0.34, p < .05. The gains ESs for NA and PA in an exercise group were 0.39 (p < .05) and 0.35 (p < .05), respectively, with an overall ES of 0.38, p < .05. All effects were significantly greater than those for the control groups. Correlational ESs of 0.47 and 0.42 were found for NA and PA. respectively. It was concluded that chronic exercise is associated with improved mood in the elderly. Moderating variables and implications for exercise prescription to improve mood in the elderly are discussed.

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Genome-wide association analysis of 350,000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema

10.1101/195933 ◽

2017 ◽

Cited By ~ 2

Author(s):

Åsa Johansson ◽

Mathias Rask-Andersen ◽

Torgny Karlsson ◽

Weronica E. Ek

Keyword(s):

Genetic Factors ◽

Hay Fever ◽

The Novel ◽

Genetic Contribution ◽

Uk Biobank ◽

Disease Phenotypes ◽

Specific Effects ◽

Genome Wide ◽

Causal Genes ◽

The Uk

AbstractEven though heritability estimates suggest that the risk of asthma, hay fever and eczema is largely due to genetic factors, previous studies have not explained a large part of the genetics behind these diseases. In this GWA study, we include 346,545 Caucasians from the UK Biobank to identify novel loci for asthma, hay fever and eczema. We further investigate if associated lead SNPs have a significantly larger effect for one disease compared to the other diseases, to highlight possible disease specific effects.We identified 141 loci, of which 41 are novel, to be associated (P≤3×10−8) with asthma, hay fever or eczema, analysed separately or as disease phenotypes that includes the presence of different combinations of these diseases. The largest number of loci were associated with the combined phenotype (asthma/hay fever/eczema). However, as many as 20 loci had a significantly larger effect on hay fever/eczema-only compared to their effects on asthma, while 26 loci exhibited larger effects on asthma compared with their effects on hay fever/eczema. At four of the novel loci, TNFRSF8, MYRF, TSPAN8, and BHMG1, the lead SNPs were in LD (> 0.8) with potentially casual missense variants.Our study shows that a large amount of the genetic contribution is shared between the diseases. Nonetheless, a number of SNPs have a significantly larger effect on one of the phenotypes suggesting that part of the genetic contribution is more phenotype specific. Identified loci and probable causal genes may in the future be used as targets for treatments of asthma, hay fever and eczema.

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Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

10.1101/294629 ◽

2018 ◽

Cited By ~ 9

Author(s):

BW Kunkle ◽

B Grenier-Boley ◽

R Sims ◽

JC Bis ◽

AC Naj ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Late Onset ◽

Association Studies ◽

Meta Analysis ◽

The Elderly ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Load Risk

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.

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Epigenetic drug combination induces genome-wide demethylation and altered gene expression in neuro-ectodermal tumor-derived cell lines

Cellular Oncology ◽

10.1007/s13402-013-0140-x ◽

2013 ◽

Vol 36 (5) ◽

pp. 351-362 ◽

Cited By ~ 9

Author(s):

Floor A.M. Duijkers ◽

Renee X. de Menezes ◽

Inès J. Goossens-Beumer ◽

Dominique J.P.M. Stumpel ◽

Pieter Admiraal ◽

...

Keyword(s):

Gene Expression ◽

Cell Lines ◽

Drug Combination ◽

Altered Gene Expression ◽

Genome Wide ◽

Epigenetic Drug ◽

Altered Gene

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Histone sumoylation promotes Set3 histone-deacetylase complex-mediated transcriptional regulation

Nucleic Acids Research ◽

10.1093/nar/gkaa1093 ◽

2020 ◽

Vol 48 (21) ◽

pp. 12151-12168

Author(s):

Hong-Yeoul Ryu ◽

Dejian Zhao ◽

Jianhui Li ◽

Dan Su ◽

Mark Hochstrasser

Keyword(s):

Histone Deacetylase ◽

Transcription Initiation ◽

Noncoding Rna ◽

Histone H2b ◽

Protein Coding ◽

Altered Gene Expression ◽

Genome Wide ◽

Spurious Transcription ◽

Altered Gene ◽

Active Genes

Abstract Histones are substrates of the SUMO (small ubiquitin-like modifier) conjugation pathway. Several reports suggest histone sumoylation affects transcription negatively, but paradoxically, our genome-wide analysis shows the modification concentrated at many active genes. We find that trans-tail regulation of histone-H2B ubiquitylation and H3K4 di-methylation potentiates subsequent histone sumoylation. Consistent with the known control of the Set3 histone deacetylase complex (HDAC) by H3K4 di-methylation, histone sumoylation directly recruits the Set3 complex to both protein-coding and noncoding RNA (ncRNA) genes via a SUMO-interacting motif in the HDAC Cpr1 subunit. The altered gene expression profile caused by reducing histone sumoylation matches well to the profile in cells lacking Set3. Histone H2B sumoylation and the Set3 HDAC coordinately suppress cryptic ncRNA transcription initiation internal to mRNA genes. Our results reveal an elaborate co-transcriptional histone crosstalk pathway involving the consecutive ubiquitylation, methylation, sumoylation and deacetylation of histones, which maintains transcriptional fidelity by suppressing spurious transcription.

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