Sumstats Transcriptomics Project

Established in 2015 by the National Institute of Mental Health, the PsychENCODE Consortium brings together multidisciplinary teams to study the molecular basis of neuropsychiatric diseases. Genetic influences on brain function are remarkably complex, characterized by a highly polygenic risk architecture and often located in the non-coding regions of the genome. PsychENCODE members generate large-scale gene expression and regulatory data from human postmortem brain tissues in major psychiatric disorders across multiple developmental stages. The goal is to map and functionally validate disease‐associated genetic variants, regulatory elements, genes and cell types. Phase II of the project focused on single-cell and spatial data, culminating in a collection of 14 papers published on May 24, 2024 (9 in Science, 3 in Science Advances, 1 in Scientific Reports, and 1 in Molecular Psychiatry). Phase I of the project was published in 2018 in a collection of 11 papers in Science, Science Translational Medicine, and Science Advances.

Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many common variants located primarily in regulatory regions of the genome. Understanding precisely how these variants contribute to disease will require a deeper appreciation for the mechanisms of gene regulation in the developing and adult human brain. The PsychENCODE project aims to produce a public resource of multidimensional genomic data using tissue- and cell type–specific samples from approximately 1,000 phenotypically well-characterized, high-quality healthy and disease-affected human post-mortem brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems. We are beginning with a focus on autism spectrum disorder, bipolar disorder and schizophrenia, and expect that this knowledge will apply to a wide variety of psychiatric disorders. This paper outlines the motivation and design of PsychENCODE.

Phase I of the project was published on Dec 14, 2018 in a collection of 11 papers in Science, Science Translational Medicine, and Science Advances.

Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.

Project overview

Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.