A5019397913- Hemoglobinopathies and Related Disorders
- CRISPR and Genetic Engineering
- Iron Metabolism and Disorders
- Prenatal Screening and Diagnostics
- Genetic Associations and Epidemiology
- Epigenetics and DNA Methylation
- Erythrocyte Function and Pathophysiology
- RNA Research and Splicing
- RNA modifications and cancer
- Bioinformatics and Genomic Networks
- Blood groups and transfusion
- Sleep and related disorders
- Sleep and Wakefulness Research
- Machine Learning in Healthcare
- Viral Infections and Vectors
- Genomics and Chromatin Dynamics
- Peripheral Neuropathies and Disorders
- Caveolin-1 and cellular processes
- Pregnancy and preeclampsia studies
- Immune Cell Function and Interaction
- Pluripotent Stem Cells Research
- Hereditary Neurological Disorders
- Nutrition, Genetics, and Disease
- BRCA gene mutations in cancer
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Sanofi (United States)
2019-2025
Institute for Molecular Medicine Finland
2023
University of Helsinki
2023
Sanofi (France)
2019-2022
Université de Montréal
2015-2020
Montreal Heart Institute
2013-2020
Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that variation at BCL11A associated with fetal hemoglobin (HbF) level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine-mapping uncovers a motif-disrupting variant reduced transcription factor (TF) binding, modestly diminished expression, and elevated HbF. The surrounding function vivo as...
Significance CRISPR-Cas9 holds enormous potential for therapeutic genome editing. Effective therapy requires treatment to be efficient and safe with minimal toxicity. The sequence-based targeting CRISPR systems necessitates consideration of the unique genomes each patient targeted therapy. We show using 7,444 whole-genome sequences that SNPs indels can reduce on-target activity increase off-target when therapeutically implicated loci; however, these occurrences are relatively rare. further...
The introduction of frameshift indels by genome editing has emerged as a powerful technique to study the functions uncharacterized genes in cell lines and model organisms. Such mutations should lead mRNA degradation owing nonsense-mediated decay or production severely truncated proteins. Here, we show that engineered can also skipping "multiple three nucleotides" exons. splicing events result in-frame may encode fully partially functional We characterize segregating nonsense variant...
The lack of mechanistic explanations for many genotype-phenotype associations identified by GWAS precludes thorough assessment their impact on human health. Here, we conducted an expression quantitative trait locus (eQTL) mapping analysis in erythroblasts and found erythroid-specific eQTLs ATP2B4, the main calcium ATPase red blood cells (rbc). same SNPs were previously associated with mean corpuscular hemoglobin concentration (MCHC) susceptibility to severe malaria infection. We showed that...
Abstract Background Therapeutic targets supported by genetic evidence from genome-wide association studies (GWAS) show higher probability of success in clinical trials. GWAS is a powerful approach to identify links between variants and phenotypic variation; however, identifying the genes driving associations identified remains challenging. Integration molecular quantitative trait loci (molQTL) such as expression QTL (eQTL) using mendelian randomization (MR) colocalization analyses can help...
Co-inheritance of α-thalassemia has a significant protective effect on the severity complications sickle cell disease (SCD), including stroke. However, little information exists association and interactions for common African ancestral mutation (−α3.7 deletion) β-globin traits (HbS trait [SCT] HbC trait) important clinical phenotypes such as red blood parameters, anemia, chronic kidney (CKD). In community-based cohort 2,916 Americans from Jackson Heart Study, we confirmed expected...
In humans, fetal erythropoiesis takes place in the liver whereas adult occurs bone marrow. Fetal and erythroid cells are not only produced at different sites, but also distinguished by their respective transcriptional program. particular, express γ-globin chains to produce hemoglobin (HbF), β-globin generate hemoglobin. Understanding regulation of fetal-to-adult switch is clinically important as re-activation HbF production would represent a promising therapy for disorders sickle cell...
Abstract Background Psoriasis is a common inflammatory skin disease with heterogeneous presentation. Up to 30% of individuals have severe greater surface area involvement, co-morbidity burden and impact on quality life. Prognostic biomarkers psoriasis severity could improve allocation clinical resources enable earlier intervention prevent progression, genetic biomarker would be cost-effective, stable over time, unaffected by treatment or comorbidity. Methods was studied in four European...
DNA methylation is believed to regulate gene expression during adulthood in response the constant changes environment. The methylome therefore proposed be a biomarker of health through age. ANGPTL2 circulating pro-inflammatory protein that increases with age and prematurely patients coronary artery diseases; integrating pattern promoter may help differentiate age- vs. disease-related change its expression. We believe environment, differentially methylated, regulating To test this hypothesis...
Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established recessive Mendelian diseases, we have not yet explored how such knockouts (KOs) could influence complex human phenotypes. Here, developed a statistical framework to test association between KOs and quantitative traits. Our method flexible, publicly available, compatible with common genotype format files (e.g. PLINK vcf). We characterized 4498 participants from NHLBI Exome...
Regulatory elements (REs) consist of enhancers and promoters that occupy a significant portion the noncoding genome control gene expression programs either in cis or trans Putative REs have been identified largely based on their regulatory features (co-occupancy ESC-specific transcription factors, enhancer histone marks, DNase hypersensitivity) mouse embryonic stem cells (mESCs). However, less has established regarding functions native context. We deployed cis- trans-regulatory scanning...
Abstract We performed a genome-wide epistasis search across 502 phenotypes in case control matched cohorts from the UK Biobank. identified 152,519 genome wide significant interactions 68 distinct phenotypes, and 3,398 19 were successfully replicated independent Finngen consortium. Most (79%) involved variants that did not present marginal association might explain part of missing heritability for these diseases. In 10 we show presence between common with intermediate to large effect size (...
ABSTRACT BACKGROUND : Therapeutic targets supported by genetic evidence from genome-wide association studies (GWAS) show higher probability of success in clinical trials. GWAS is a powerful approach to identify links between variants and phenotypic variation; however, identifying the genes driving associations identified remains challenging. Integration molecular quantitative trait loci (molQTL) such as expression QTL (eQTL) using mendelian randomization (MR) colocalization analyses can help...
Abstract Objective Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP unclear no genome-wide association study (GWAS) has been reported so far. In this study, we aimed identify CIDP-related risk loci , genes pathways. Methods To increase power, first included all patients with diagnosis (IP) as cases. We performed GWAS...
Introduction Up to 30% of individuals with hemophilia A develop inhibitors replacement factor VIII (FVIII), rendering the treatment ineffective. The underlying mechanism inhibitor development remains poorly understood. My Life, Our Future Research Repository (MLOF RR) has gathered F8 and F9 mutational information, phenotypic data, biological material from over 11,000 participants (HA) B as well carriers enrolled across US centers, including 5,000 whole-genome sequences. Identifying genes...
Serum and glucocorticoid-regulated kinase 1 (SGK1) modulates activity of downstream effectors including inhibition the transcription factor FOXO3a, previously shown to increase fetal hemoglobin (HbF) expression in erythroid cells. We hypothesized that SGK1 alleviates FOXO3a subsequently increases HbF red blood cells (RBC).We used a potent selective inhibitor SGK1, Compound 16y (Comp16y), 2 currently development for cardiomyopathies some types cancer.After Comp16y treatment during...
ABSTRACT Sickle cell disease (SCD) remains a major health burden with limited treatment options. Despite promising gene-editing clinical trials, there is an unmet need for cost-effective therapies. As induction of fetal hemoglobin (HbF) established therapeutic strategy SCD, we conducted genome-wide association study circulating HbF levels in ~11,000 participants to identify further modulators. We identified associations 11 genomic regions, including eight novel loci such as ABCC1 (encoding...
Acne vulgaris is a common skin disease that affects >85% of teenage young adults among which >8% develop severe lesions leaves permanent scars. Genetic heritability studies acne in twin cohorts have estimated the for 80%. Previous genome-wide association (GWAS) identified 50 genetic loci associated with increased risk developing when compared to healthy individuals. However only few investigated severity. GWAS progression may provide more effective approach unveil potential modifying...