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

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

10.1101/2020.09.23.20200428 ◽

2020 ◽

Author(s):

Helene Choquet ◽

Ronald B. Melles ◽

Deepti Anand ◽

Jie Yin ◽

Gabriel Cuellar-Partida ◽

...

Keyword(s):

Meta Analysis ◽

The Elderly ◽

Effect Sizes ◽

Uk Biobank ◽

Altered Gene Expression ◽

Specific Effects ◽

Genome Wide ◽

Altered Gene ◽

Mouse Lens ◽

Gene Perturbation

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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Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1521754113 ◽

2016 ◽

Vol 113 (16) ◽

pp. 4434-4439 ◽

Cited By ~ 40

Author(s):

Aoi Wakabayashi ◽

Jacob C. Ulirsch ◽

Leif S. Ludwig ◽

Claudia Fiorini ◽

Makiko Yasuda ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Transcriptional Activity ◽

Regulatory Elements ◽

Binding Motif ◽

Targeted Disruption ◽

Altered Gene Expression ◽

Whole Exome ◽

Altered Gene ◽

Insight Into

Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders.

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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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Abstract P323: HIV- and Subclinical Cardiovascular Disease-specific Transcriptomes in Nonclassical Monocytes: The Women’s Interagency HIV Study

Circulation ◽

10.1161/circ.141.suppl_1.p323 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Juan Lin ◽

David B Hanna ◽

Qibin Qi ◽

tao wang ◽

Karin A Mueller ◽

...

Keyword(s):

Gene Expression ◽

Lipid Homeostasis ◽

Checkpoint Inhibition ◽

Protein Coding ◽

Altered Gene Expression ◽

Subclinical Cardiovascular Disease ◽

Altered Gene ◽

Transcriptomic Changes ◽

Insight Into ◽

Chronic Hiv Infection

Objectives: Nonclassical monocytes (NCM) have patrolling functions relevant to atherosclerosis. While NCM have low surface CXCR4 expression in people with concurrent HIV and CVD (Mueller Cardiovasc Res 2019), the extent of CVD-related gene expression and the pathways involved are unknown. We described the gene transcription signature of NCM to provide insight into potential mechanisms of HIV-associated CVD. Methods: We identified transcriptomic changes in circulating NCM among women with and without chronic HIV infection. CVD was defined by plaques found on B-mode carotid artery ultrasound. The study included 23 HIV - CVD - , 21 HIV + CVD - , 20 HIV - CVD + , and 21 HIV + CVD + women, with these four groups matched by age (median = 45), race (95% minority) and smoking (86% ever-smokers). Using cryopreserved cells, we flow-sorted NCM (CD14 dim CD16+) and deep-sequenced their mRNA (average depth >40 million reads) to identify differentially expressed genes (DEG) contrasting HIV alone, CVD alone, and concurrent HIV + CVD + groups, versus HIV - CVD - , based on FDR-adjusted P<0.05. Results: After filtering to genes with raw counts >10 in >60% of participants, 11,343 protein coding genes were analyzed. HIV alone was associated with 10 DEGs on NCM (Figure). Women affected by both HIV and CVD had 93 DEGs, only six of which were shared by the HIV alone DEG signal. CVD alone was associated only with upregulated CDK18, which was also identified as a DEG in the HIV + CVD + group. Conclusion: Concurrent HIV and CVD (HIV + CVD + ) is associated with altered gene expression in NCMs relative to HIV - CVD - , generating responses that involve interleukins (IL32, IL4R), immune checkpoint inhibition (LAG3), chemokines (CCL4, CCL5) and lipid homeostasis (ABCD2).

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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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A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

Molecular Psychiatry ◽

10.1038/mp.2013.185 ◽

2014 ◽

Vol 19 (12) ◽

pp. 1326-1335 ◽

Cited By ~ 22

Author(s):

V Chouraki ◽

◽

R F A G De Bruijn ◽

J Chapuis ◽

J C Bis ◽

...

Keyword(s):

Meta Analysis ◽

The Elderly ◽

Genome Wide Association ◽

Aβ Peptides ◽

Genome Wide ◽

A Genome

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Novel Drosophila model of myotonic dystrophy type 1: phenotypic characterization and genome-wide view of altered gene expression

Human Molecular Genetics ◽

10.1093/hmg/ddt127 ◽

2013 ◽

Vol 22 (14) ◽

pp. 2795-2810 ◽

Cited By ~ 21

Author(s):

Lucie Picchio ◽

Emilie Plantie ◽

Yoan Renaud ◽

Preethi Poovthumkadavil ◽

Krzysztof Jagla

Keyword(s):

Gene Expression ◽

Myotonic Dystrophy ◽

Phenotypic Characterization ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Altered Gene Expression ◽

Genome Wide ◽

Drosophila Model ◽

Altered Gene

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Specific increase in leptin production in obese (falfa) rat adipose cells

Biochemical Journal ◽

10.1042/bj3620113 ◽

2002 ◽

Vol 362 (1) ◽

pp. 113-118 ◽

Cited By ~ 13

Author(s):

Sophie TURBAN ◽

Isabelle HAINAULT ◽

Johan TRUCCOLO ◽

Jocelyne ANDRE ◽

Pascal FERRE ◽

...

Keyword(s):

High Fat Diet ◽

Zucker Rats ◽

High Fat ◽

Altered Gene Expression ◽

Mrna Gene ◽

Specific Increase ◽

Obese Zucker Rats ◽

Altered Gene ◽

Adipose Cells ◽

Insight Into

In the obese state, enlarged adipose cells display an altered gene-expression profile and metabolic capacity. The aim of this study was to gain insight into their secretory function, by assessing two secreted proteins, leptin and angiotensinogen, in adipose cells of obese (fa/fa) Zucker rats. A marked and co-ordinate increase in leptin mRNA, gene transcription and promoter activity was observed in obese compared with lean (Fa/fa) rat adipose cells, and this resulted in increased leptin release in culture. Two sets of observations suggest that this effect is due to the fa mutation. First, adipose-cell leptin release was higher in heterozygous (Fa/fa) than in homozygous (Fa/Fa) lean rats. Second, leptin release was not enhanced in enlarged adipose cells of FalFa rats fed a high-fat diet for 15 days. At variance with leptin, angiotensinogen production was not significantly increased in the obese cells. Dexamethasone stimulated both leptin and angiotensinogen release in lean and obese rat adipose cells. The magnitude of leptin stimulation was higher in fa/fa than in Fa/fa rats, whereas angiotensinogen release was increased to the same extent in both genotypes. These observations suggest that leptin production is specifically enhanced in enlarged adipose cells of obese Zucker rats and that cell hypertrophy is not the sole determinant of this feature. Increased leptin production might be related to disruption of leptin signalling by the fa mutation.

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