OpenTargets and the Identification, prioritisation and validation of genetic associations with Alzheimer’s disease using human cellular models and CRISPR screens

As part of our virtual 'Partners & Platforms Seminars' series, the UK DRI is delighted to welcome Dr Andrew Bassett.

'OpenTargets and the Identification, prioritisation and validation of genetic associations with Alzheimer’s disease using human cellular models and CRISPR screens'

Dr Andrew Bassett
Head of Cellular Operations at the Wellcome Sanger Institute

Thursday 7 May, 12:00 - 13:30 BST

This event is open to UK DRI researchers and support staff only. Registration and associated Zoom links will be distributed via Centre Manager emails nearer the time of the event.

About 

Genome-wide association studies (GWAS) have discovered numerous genomic loci associated with Alzheimer’s disease (AD), yet the causal genes and variants remain incompletely identified. We performed an updated genome-wide AD meta-analysis, that identifies novel associations near genes CCDC6, TSPAN14, NCK2, and SPRED2. We then used three SNP-level fine-mapping methods, colocalisation analyses across 109 gene expression quantitative trait loci (eQTL) datasets, and prioritization of genes using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we find that evidence converges on likely causal genes, including the above four genes, and those at previously discovered AD loci including BIN1, APH1B, PTK2B, PILRA, and CASS4.

Isogenic iPSC-derived neurons and microglia are a powerful way to identify and understand causative alleles, but are relatively slow to produce, and have inherent variability. Thus, to narrow down causative alleles for functional follow up, we have developed an arrayed CRISPR screening method, Genome engineering-based Interrogation of Enhancers (GenIE), which assesses the effects of defined alleles on transcription or splicing when introduced in their endogenous genomic location. We use this sensitive assay to validate the activity of transcriptional enhancers and splice regulatory elements in human induced pluripotent stem cells (hiPSCs), and develop a software package (R-GenIE) to analyse the data. We screen the 99% credible set of Alzheimer’s disease (AD) GWAS variants identified at the clusterin (CLU) locus to identify a subset of likely causal variants. Research statement We are interested in the development of novel genome editing techniques, cellular differentiation and cellular phenotyping systems, especially with respect to high-throughput investigation of gene and non-coding regulatory element function in neurodegenerative disease. We employ human induced pluripotent stem cell derived neurons and microglia coupled with arrayed and pooled CRISPR screening technologies and single cell ‘omics methods to model the cellular effects of neurodegenerative disease mutations.