ORCID Profile
0000-0002-2370-0128
Current Organisation
University of Oxford
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2020
DOI: 10.1101/2020.02.02.20020065
Abstract: Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2023
DOI: 10.1101/2023.07.24.23293070
Abstract: Autosomal recessive (AR) coding variants are a well-known cause of rare disorders. We quantified the contribution of these variants to developmental disorders (DDs) in the largest and most ancestrally erse s le to date, comprising 29,745 trios from the Deciphering Developmental Disorders (DDD) study and the genetic diagnostics company GeneDx, of whom 20.4% have genetically-inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide AR coding variants ranged from ∼2% to ∼18% across genetically-inferred ancestry groups, and was significantly correlated with the average autozygosity (r=0.99, p=5x10 -6 ). Established AR DD-associated (ARDD) genes explained 90% of the total AR coding burden, and this was not significantly different between probands with genetically-inferred European versus non-European ancestries. Approximately half the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. We estimated that ∼1% of undiagnosed patients in both cohorts were attributable to damaging biallelic genotypes involving missense variants in established ARDD genes, highlighting the challenge in interpreting these. By testing for gene-specific enrichment of damaging biallelic genotypes, we identified two novel ARDD genes passing Bonferroni correction, KBTBD2 (p=1x10 -7 ) and CRELD1 (p=9x10 -8 ). Several other novel or recently-reported candidate genes were identified at a more lenient 5% false-discovery rate, including ZDHHC16 and HECTD4 . This study expands our understanding of the genetic architecture of DDs across erse genetically-inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may allow us to diagnose more patients than discovering the remaining genes.
Publisher: Springer Science and Business Media LLC
Date: 10-07-2019
DOI: 10.1038/S41467-019-11039-6
Abstract: There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
DOI: 10.1038/NG.3863
Publisher: Cold Spring Harbor Laboratory
Date: 25-04-2023
DOI: 10.1101/2023.04.20.23288860
Abstract: Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi- cis -expression quantitative trait loci ( cis -eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6,987 probands from the Deciphering Developmental Disorders (DDD) study and 9,720 controls, and found one gene, RAB2A , that passed multiple testing correction (p = 6.7×10 −7 ). We then investigated whether cis -eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1,700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7×10 −3 ). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that common cis -eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.
Publisher: Cold Spring Harbor Laboratory
Date: 08-09-2022
DOI: 10.1101/2022.09.08.507084
Abstract: Our understanding of the genetic architecture of the human cerebral cortex is limited both in terms of the ersity of brain structural phenotypes and the anatomical granularity of their associations with genetic variants. Here, we conducted genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,843 in iduals from the UK Biobank and the ABCD cohorts. These phenotypes include cortical thickness, surface area, grey matter volume, and measures of folding, neurite density, and water diffusion. We identified 4,349 experiment-wide significant loci associated with global and regional phenotypes. Multiple lines of analyses identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with surface area and volume specifically are associated with cephalic disorders. Finally, we identified complex inter-phenotype and inter-regional genetic relationships among the 13 phenotypes which reflect developmental differences among them. These analyses help refine the role of common genetic variants in human cortical development and organisation. GWAS of 2,347 neuroimaging phenotypes shed light on the global and regional genetic organisation of the cortex, underlying cellular and developmental processes, and links to neurodevelopmental and cephalic disorders.
Publisher: Elsevier BV
Date: 09-2020
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Emilie Wigdor.