GENESIS Consortium

The objective of the proposed research is to elucidate the cell-type-specific molecular mechanisms through which genetic risk variants contribute to serious mental and neurological disorders (SMND), including Alzheimer's disease (AD), Parkinson’s disease (PD), and schizophrenia (SCZ). While genome-wide association studies (GWAS) have identified thousands of risk loci, the majority are non-coding and lie in regions of high linkage disequilibrium, making it challenging to define causal variants and their biological mechanisms. To overcome these limitations, we propose to establish the BrainCellQTL Consortium—a multi-institutional effort to generate and harmonize brain single-cell expression QTL (eQTL) and other molecular QTL data.

This study will aggregate and harmonize over 10,000 single-cell transcriptomic libraries from more than 3,000 unique postmortem human brain donors across multiple cohorts. Our integrative analysis plan involves: (1) applying quality control pipelines to single-cell omics and genotype data, (2) harmonizing datasets and establishing a cross-cohort cell type taxonomy, (3) performing multi-ancestry QTL mapping for gene expression and epigenomic traits, (4) colocalizing molecular QTLs with GWAS loci for SMND, and (5) identifying credible causal variants, genes, and regulatory mechanisms. Phenotypic characteristics of interest include cell-type-specific gene expression and chromatin accessibility patterns across brain regions relevant to SMND, with an emphasis on shared and distinct pathways across disorders.

We will also develop a publicly accessible web portal and QTL browser to disseminate results, and provide tools and data to the research community.

The goal of this research is to create a detailed map of how genetic variants influence gene activity in specific brain cell types. This map, called a cell type-specific QTL atlas, will help researchers understand how genetic differences contribute to serious mental and neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia. By combining genetic data with information on gene expression and molecular changes in the brain, we aim to uncover the mechanisms that drive these conditions. This work will also help identify important genes and pathways involved in disease, support future genetic studies, and promote consistent data sharing and collaboration across research groups. The GENESIS Consortium will lead this effort by using cutting-edge single-cell data to overcome past challenges and improve our understanding of brain disorders at the level of individual cell types. The results will be shared with the scientific community through public tools and resources.