Jeremy Schwartzentruber

An Alzheimer’s disease-associated common regulatory variant in a PTK2B intron alters microglial function

Erica Bello, Kathleen Long, Sho Iwama, Juliette Steer et autres

expression. Nonetheless, this variant affects both the transcriptome and phenotype of the cells: interferon gamma-responsive genes are downregulated, secreted chemokine levels are reduced, and microglial chemotaxis is affected. We propose the variant acts by altering microglial reactivity, consistent with the established role …

gb, ee, jp (code pays fourni par la source)

Estimation and mapping of the missing heritability of human phenotypes

Pierrick Wainschtein, Yuanxiang Zhang, Jeremy Schwartzentruber, Irfahan Kassam et autres

Rare coding variants shape inter-individual differences in human phenotypes1. However, the contribution of rare non-coding variants to those differences remains poorly characterized. Here we analyse whole-genome sequence (WGS) data from 347,630 individuals with European ancestry in the UK Biobank2,3 to quantify the …

au, us, gb (code pays fourni par la source)

Flexibly Modeling Rare Variant Pathogenicity Improves Gene Discovery for Complex Traits

Jeremy Schwartzentruber, Petko Fiziev, Jeremy F. McRae, Jacob C. Ulirsch et autres

Abstract Rare variant burden tests can directly identify genes that influence complex traits, but their power is limited by our ability to separate functional from benign alleles. We introduce FlexRV, an approach that greatly improves the power to detect gene-based associations in …

us (code pays fourni par la source)

Predicting expression-altering promoter mutations with deep learning

Kishore Jaganathan, Nicole M. Ferraro, Gherman Novakovsky, Yuchuan Wang et autres

Only a minority of patients with rare genetic diseases are presently diagnosed by exome sequencing, suggesting that additional unrecognized pathogenic variants may reside in noncoding sequence. In this work, we describe PromoterAI, a deep neural network that accurately identifies noncoding promoter variants …

us, gb (code pays fourni par la source)

Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery

Annalisa Buniello, Dániel Süveges, Carlos Cruz-Castillo, Manuel Bernal Llinares et autres

The Open Targets Platform (https://platform.opentargets.org) is a unique, open-source, publicly-available knowledge base providing data and tooling for systematic drug target identification, annotation, and prioritisation. Since our last report, we have expanded the scope of the Platform through a number of significant enhancements …

gb (code pays fourni par la source)

Author Reply to Peer Reviews of An Alzheimer's disease-associated common regulatory variant in a PTK2B intron alters microglial function

Erica Bello, Kathleen Long, Sho Iwama, Juliette Steer et autres

gb, ee, jp (code pays fourni par la source)

An Alzheimer’s disease-associated common regulatory variant in a PTK2B intron alters microglial function

Erica Bello, Kathleen Long, Sho Iwama, Juliette Steer et autres

Summary Genome-wide association studies (GWAS) are revealing an ever-growing number of genetic associations with disease, but identifying and functionally validating the causal variants underlying these associations is very challenging and has only been done for a vanishingly small number of variants. Here …

gb, ee, jp (code pays fourni par la source)

Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity

Clare E. West, Mohd Anisul Karim, Maria J. Falaguera, Leo Speidel et autres

Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We …

ca, gb (code pays fourni par la source)

Artificial intelligence for dementia genetics and omics

Conceição Bettencourt, Nathan Skene, Sara Bandrés‐Ciga, Emma L. Anderson et autres

Genetics and omics studies of Alzheimer's disease and other dementia subtypes enhance our understanding of underlying mechanisms and pathways that can be targeted. We identified key remaining challenges: First, can we enhance genetic studies to address missing heritability? Can we identify reproducible …

gb, us, es, it (code pays fourni par la source)

Systematic disease-agnostic identification of therapeutically actionable targets using the genetics of human plasma proteins.

Mohd Anisul Karim, Bruno Ariano, Jeremy Schwartzentruber, Juan María Roldán‐Romero et autres

gb, de, us, in (code pays fourni par la source)

Systematic disease-agnostic identification of therapeutically actionable targets using the genetics of human plasma proteins

Mohd Anisul Karim, Bruno Ariano, Jeremy Schwartzentruber, Juan María Roldán‐Romero et autres

Abstract Proteome-wide Mendelian randomization (MR) has emerged as a promising approach in uncovering novel therapeutic targets. However, genetic colocalization analysis has revealed that a third of MR associations lacked a shared causal signal between the protein and disease outcome, raising questions about …

gb, de, us (code pays fourni par la source)

Mapping interindividual dynamics of innate immune response at single-cell resolution

Natsuhiko Kumasaka, Raghd Rostom, Ni Huang, Krzysztof Polański et autres

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy …

gb, jp, de, il (code pays fourni par la source)