Project description
Translating GWAS findings into disease mechanisms
Genome-wide association studies (GWAS) aim to find connections between phenotypes and genotypes by screening thousands of genetic variants across multiple loci. GWAS have identified genomic loci that contribute to risk of traits or diseases of interest including brain disorders. However, this information has not led to a better understanding of disease mechanisms, mainly due to the observed heterogeneity. Scientists of the EU-funded GWAS2FUNC project propose to address this issue by developing tools to bridge the gap between GWAS and function. More efficient translation of GWAS findings into mechanistic insight will advance our knowledge on brain disorder pathogenesis.
Objective
Genome-wide association studies (GWAS) of unprecedented sample size have recently provided robust insight into the polygenic architecture of many different brain disorders. Despite this exciting potential, GWAS results have rarely translated into mechanistic disease insight. This is because the detected genetic effects are small and numerous, and hardly ever directly actionable for functional follow-up. In addition, the polygenic nature of brain disorders comes with large genetic heterogeneity, where different patients with the same disorder may carry completely different combinations of genetic risk variants, possibly corresponding to different etiological mechanisms, requiring different treatment regimens. To benefit from GWAS, extensive biological interpretation and insight into genetic heterogeneity is needed. In this ERC I will develop much needed tools for (i) extensive biological interpretation at cellular resolution and (ii) assessing genetic heterogeneity, both aimed at formulating hypotheses that take into account the polygenic nature of brain disorders and can be tested in functional experiments. I will apply the developed tools to a wide range of brain-related traits, providing ample starting points for functional follow-up. As a proof-of-concept I will test the viability of two neuroscientific approaches (iPSC and DREADDs) for functional follow-up of GWAS results. First, I will conduct scRNA sequencing and electrophysiological assessments on iPSC derived neurons and astrocytes from genetically selected (schizophrenia) patients and controls. Second, I will use in vivo chemogenetic manipulation to target specific cell types that have been implicated by GWAS (for insomnia). The primary goal of this proposal is to bridge the gap between GWAS and function. The results will facilitate the translation of GWAS findings for brain disorders into functional mechanisms that are biologically important in disease pathogenesis and, ultimately, treatment design.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
1081 HV Amsterdam
Netherlands