Comprehensive human expressed sequences in brain (chess-brain) and their roles in neuropsychiatric illness

Ended Project Grant Awarded Last action

Award ID
R01MH123567
Recipient
Awarding agency
Obligated
$7,308,703

Award facts

Assistance listing
93.242 Mental Health Research Grants
Completion date
Funding
  • $6,863,483.96 Federal
  • $445,219.00 Non-federal
Place of performance
Baltimore, MD 21218, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The widespread use of RNA sequencing technology over the past decade has allowed scientists to discover a far larger and richer repertoire of genes and transcripts encoded by the human genome than were known just a decade ago. At least 90% of human genes have multiple isoforms, including splicing variants, alternative sites of transcription initiation and termination, exon skipping events, and more. The number of human transcripts in standard gene databases has grown enormously, from ~40,000 in the late 2000S to over 200,000 today, but IT is still likely far from complete. Our previous work using exon-exon splice junctions and other fragmentary transcripts has demonstrated the clinical relevance of unannotated but expressed genes in the human brain, including associations with schizophrenia and its genetic risk. This project will attempt to discover and characterize novel gene isoforms collected from both healthy and diseased brains, using the latest computational methods for transcriptome assembly and an extensive collection of brain RNA-SEQ datasets. The project is organized into three aims: first, we will develop new algorithms designed to assemble RNA-SEQ data from samples that have been sequenced using ribosomal RNA depletion, a technique that is widely used in human brain studies but that is not used in most other RNA-SEQ experiments, which instead use polya+ enrichment. We will implement these methods as extensions to the hisat and stringtie systems for RNA-SEQ alignment and assembly, both of which were developed in the PI's and CO-PI's labs. We will then apply these improved methods to thousands of publicly available RNA-SEQ samples from human brain tissue to create a new "chess-brain" (comprehensive human expressed sequences in brain) gene annotation database. This effort will also determine which transcripts are tissue-specific and brain-region specific; i.e., expressed at significantly higher or lower levels in brain tissues and in various brain regions as compared to other tissues. In the second aim, we will use these methods to quantify gene expression levels in hundreds of post-mortem brain RNA-SEQ samples from subjects diagnosed with schizophrenia (sczd), major depression (MDD), bipolar disorder (BPD), autism spectrum disorder (ASD), and post-traumatic stress disorder (ptsd), whom we will compare to matched controls to identify the contribution of unannotated transcription in these disorders. In our third aim we will perform expression quantitative trait loci (eqtl) mapping across the entire chess-brain dataset, both within and across brain regions and diagnoses, to identify genetic regulation of unannotated transcripts, including both coding and noncoding transcripts. This analysis will identify genes and transcripts whose expression levels change significantly in different tissues and diseases. We will combine these results to identify novel transcripts associated with genetic risk for each of the psychiatric disorders.

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Subawards

Subrecipient Amount Awarded
Lieber Institute Inc. 1. Provide access to processed LIBD-generated RNA sequencing data for the purpose stated in the grant research strategy. 2. Validate subsets of RNA sequencing… $1,443,172

Quick answers

Who received award R01MH123567?

R01MH123567 was awarded to The Johns Hopkins University by National Institute of Mental Health (National Institutes of Health) on March 2, 2021.

How much is award R01MH123567 worth?

$7,308,703 has been obligated on R01MH123567: $6,863,484 in federal funding and $445,219 in non-federal funding.

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