A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk
Identification of the genes and processes mediating genetic association signals for complex diseases represents a major challenge. As many of the genetic signals for type 2 diabetes (T2D) exert their effects through pancreatic islet-cell dysfunction, we performed a genome-wide pooled CRISPR loss-of-function screen in a human pancreatic beta cell line. We assessed the regulation of insulin content as a disease-relevant readout of beta cell function and identified 580 genes influencing this phenotype. Integration with genetic and genomic data provided experimental support for 20 candidate T2D effector transcripts including the autophagy receptor CALCOCO2. Loss of CALCOCO2 was associated with distorted mitochondria, less proinsulin-containing immature granules and accumulation of autophagosomes upon inhibition of late-stage autophagy. Carriers of T2D-associated variants at the CALCOCO2 locus further displayed altered insulin secretion. Our study highlights how cellular screens can augment existing multi-omic efforts to support mechanistic understanding and provide evidence for causal effects at genome-wide association studies loci.
- 29/05/2024
- 6 samples
- DAC: EGAC00001002601
- Technology: NextSeq 500
Data Access Policy of the Datasets from the Translational Genomics of Diabetes Lab at Stanford University
DATA ACCESS AGREEMENT This agreement governs the terms on which access will be granted to the RNA sequencing data generated as part of the CALCOCO2 study. In signing this agreement, You are agreeing to be bound by the terms and conditions of access set out in this agreement. For the sake of clarity, the terms of access set out in this agreement apply both to the User and the User’s Institution (as defined below). User Institution and User are referred to within the agreement as “You” and “Your” shall be construed accordingly. Definitions: Investigators means the group of investigators based in Stanford, US and Oxford, UK which have generated the Data. Data means all and any human genetic data obtained from the Investigators. Data Subject means a person, who has been informed of the purpose for which the Data is held and has given his/her informed consent thereto. User means a researcher whose User Institution has previously completed this Data Access Agreement and has received acknowledgement of its acceptance. Publications means, without limitation, articles published in print journals, electronic journals, reviews, books, posters and other written and verbal presentations of research. User Institution means the organization at which the User is employed, affiliated or enrolled. Terms and Conditions: In signing this Agreement: 1. You agree to use the Data only for the advancement of medical research, according to the consent obtained from sample donors. 2. You agree not to use the Data or any part thereof for the creation of products for sale or for any commercial purpose. 3. You agree to preserve, at all times, the confidentiality of information and Data pertaining to Data Subjects. In particular, You undertake not to use, or attempt to use the Data to compromise or otherwise infringe the confidentiality of information on Data Subjects and their right to privacy. 4. You agree not to attempt to link the data provided under this agreement to other information or archive data available for the data sets provided, even if access to that data has been formally granted to you, or it is freely available without restriction, without specific permission being sought from the relevant access committees. 5. You agree not to transfer or disclose the Data, in whole or part, or any identifiable material derived from the Data, to others, except as necessary for data/safety monitoring or programme management. Should You wish to share the Data with a collaborator outside the same Institution, the third party must make a separate application for access to the Data. 6. You agree to use the data for the approved purpose and project described in your application; use of the data for a new purpose or project will require a new application and approval. 7. You agree to acknowledge in any work based in whole or part on the Data, the published paper from which the Data derives. 8. You accept that the Investigators, the original data creators, depositors or copyright holders, or the funders of the Data or any part of the Data supplied: a. bear no legal responsibility for the accuracy or comprehensiveness of the Data; and b. accept no liability for indirect, consequential, or incidental, damages or losses arising from use of the Data, or from the unavailability of, or break in access to, the Data for whatever reason. 9. You understand and acknowledge that the Data is protected by copyright and other intellectual property rights, and that duplication, except as reasonably required to carry out Your research with the Data, or sale of all or part of the Data on any media is not permitted. 10. You recognise that nothing in this agreement shall operate to transfer to the User Institution any intellectual property rights relating to the Data. The User Institution has the right to develop intellectual property based on comparisons with their own data. 11. You accept that this agreement will terminate immediately upon any breach of this agreement by You and You will be required to destroy any Data held. 12. You accept that it may be necessary for the Investigators or its appointed agent to alter the terms of this agreement from time to time in order to address new concerns. In this event, the Investigators or its appointed agent will contact You to inform You of any changes and You agree that Your continued use of the Data shall be dependent on the parties entering into a new version of the Agreement. 13. You accept that the Data is protected by and subject to international laws and that You are responsible for ensuring compliance with any such applicable law. The Translational Genomics of Diabetes Lab Data Access Committee reserves the right to request and inspect data security and management documentation to ensure the adequacy of data protection measures in countries that have no national laws comparable to that which pertain in the EAA. 14. This agreement shall be construed, interpreted and governed by the laws of US and UK and shall be subject to the non-exclusive jurisdiction of the US and UK courts.
Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.
Study ID | Study Title | Study Type |
---|---|---|
EGAS00001006127 | Other |
This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.