Researchers from the Duke Center for Genomic and Computational Biology, 大象传媒鈥檚 Department of Genetics, and Yale University have teamed up to narrow down areas of the genome previously marked relevant to schizophrenia risk.
A new $8-million NIH grant seeks to uncover more clues into what genes increase the risk of developing schizophrenia.
Greg Crawford, Charlie Gersbach, Tim Reddy and Raluca Gord芒n from the Duke Center for Genomic and Computational Biology have teamed up with Patrick Sullivan, Yun Li, Michael Love, and Paola Giusti-Rodriguez at 大象传媒-Chapel Hill and Flora Vaccarino at Yale University to narrow down areas of the genome previously marked relevant to schizophrenia risk.
鈥淪chizophrenia is incredibly complex at every level,鈥� Sullivan said, 鈥渇rom DNA to its clinical manifestations.鈥�
Previous genetic studies 鈥搒ome piloted by Sullivan 鈥� have narrowed down the search space. Using samples from 25,000 patients who had schizophrenia and 97,000 samples from those who didn鈥檛, researchers discovered 270 different regions of interest in the genome. These regions vary in size, but each on average span hundreds of thousands of base pairs.
鈥淏ut there鈥檚 still a lot we don鈥檛 know,鈥� Crawford added. 鈥淲e don鈥檛 know that within each of these regions, which are the most important parts that confer schizophrenia risk, and what the target genes are.鈥� Other mysteries include how genetic differences manifest themselves, and if all or some of those 270 regions are working together.
With this grant, the team will work to narrow down each of those 270 regions to their most important parts. One tactic they will use is high throughput CRISPR screens to silence and/or activate any region of interest in the genome to see which subregions respond and how. This builds upon nearly 10 years of research between Gersbach and Crawford who have previously collaborated to use CRISPR to regulate human genes in their natural position genome, perturb distal gene regulatory elements in non-coding regions, and scale their efforts up to high throughput screening of hundreds of elements on single genes.
鈥淣ow we are continuing to expand the scale and scope of this work,鈥� Gersbach said, 鈥渂y assessing thousands of elements on hundreds of genes and applying that to decipher complex disease mechanisms that were previously intractable with a focus on schizophrenia.鈥�
The team will also take those important regions and use stem cells derived from individuals both with and without schizophrenia and make brain organoids 鈥� cells in a dish that recapitulate different cells in the brain 鈥� and conduct experiments to see what happens if they silence specific regions of the genome.
Through these efforts, they hope to better understand the basic 鈥減arts list鈥� for schizophrenia with greater rigor and certainty than ever before. 鈥淲e aren鈥檛 going to solve everything,鈥� Crawford said, 鈥渂ut we will be able to get a better understanding of what鈥檚 going on in each of those 270 regions.鈥�
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