Investigator:
Zechuan Lin, PhD
Name of Institution:
Yale University
Project Title:
Translating GWAS into Target Genes for Parkinson’s
Investigator Bio:
Dr. Zechuan Lin is a faculty member and instructor at Yale School of Medicine’s Stephen & Denise Adams Center for Parkinson’s Disease Research. He investigates the genomic functions of complex brain diseases. Dr. Lin received his PhD in integrative biology from Peking University, with postdoctoral training in computational neurogenomics from Harvard Medical School/Brigham & Women’s Hospital.
Dr. Lin is an experienced statistical geneticist who leads the Parkinson’s functional genomics studies and brain single cell/spatial eQTL studies at Yale School of Medicine’s Stephen & Denise Adams Center for Parkinson’s Disease Research. Dr. Lin is also one of the leaders of the Quality Control Working Group on Single Cell Omics of the Aligning Science Across Parkinson’s Collaborative Research Network (ASAP CRN), a research community aimed at advancing basic research in Parkinson’s disease by fostering collaboration and resources.
Objectives/Background:
Inherited DNA changes account for about one-third or less of Parkinson’s disease (PD) risk. However, large studies comparing over a million people with and without PD have found thousands of non-coding DNA changes linked to the disease in areas of the genome that are not transcribed into RNA and protein themselves, but rather alter how other genes are turned on and off. These advances have not translated into new medicines because we don’t know which genes these DNA changes affect. Our earlier work analyzed over four million brain cells and identified 125 possible PD-related genes, and the specific brain cell types where they might act. We hypothesize that non-coding DNA changes associated with PD produce their effect by altering how these 125 genes work in the dopamine-making brain cells affected in PD.
It is our objective to find the specific genes linked to PD using genetic data from over 1,200 human brains.
Methods/Design:
This study will evaluate genes in the dopamine-producing brain cells which have been identified as being associated with PD. We will examine how DNA changes in non-coding regions work by altering the expression of these genes in dopaminergic neurons from people with and without PD, including early disease stages. Next, we will test these effects in brain tissue samples from 256 people. Finally, we will map exactly where these changes happen in the brain using high-resolution imaging of 100 midbrains.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This study will identify and confirm the brain-cell-specific genetic changes linked to PD, map exactly where they occur, and reveal new targets for treatment. This approach could also help connect genetic discoveries to brain function in other brain disorders.