# Profiling the Functional Genetics of Health and Disease using BrainGENIE: The Brain Gene Expression and Network Imputation Engine

> **NIH NIH R21** · UPSTATE MEDICAL UNIVERSITY · 2022 · $202,500

## Abstract

Abstract
The pathophysiology of brain disorders remains unknown because we cannot study the relevant tissue in living
human subjects. Postmortem brain tissue is useful, but expensive, rare, and critically confounded by
antemortem and agonal factors. These two facts have inspired the search for alternative strategies, such as
the use of surrogate markers like blood-based gene expression. To improve the rigor of this widely used
approach, we developed a novel computational method called the Brain Gene Expression and Network
Imputation Engine (BrainGENIE) that leverages biological comparability between blood and brain gene
expression to predict transcriptome profiles for brain tissue based on blood gene-expression profiles.
BrainGENIE is fundamentally different from other transcriptome-imputation methods, and captures a much
larger proportion of the variance in—and larger fraction of—the brain transcriptome. BrainGENIE is capable of
predicting approximately 9–57% of the brain transcriptome, which yields an approximate 1.8-fold increase in
coverage relative to the “gold standard” method PrediXcan, and which greatly improves our statistical power to
detect genes and pathways associated with disease. Our proposal contains three Specific Aims to improve our
method and shed light on biological pathways underlying neuropsychiatric disorders. Aim 1: Refine
BrainGENIE to capture additional genes that are not currently well predicted by our method. Aim 2: Apply
BrainGENIE to our collection of publicly available and in-house data to predict brain-region-specific gene
expression profiles for over 8,000 living persons, and discover region-specific gene-expression patterns
associated with neuropsychiatric disorders and neurodegenerative diseases. Aim 3: Disseminate BrainGENIE
as stand-alone software for other researchers to use freely. Guided by recent genetic and genomic studies, we
hypothesize that comparable patterns of gene dysregulation will be found across neuropsychiatric disorders
among pathways involving innate immunity, chromatin remodeling, neurodevelopment, and neurotransmission.
Inclusion of neurodegenerative disorders in our analysis will allow us to determine whether gene expression
patterns are shared across a broader range of brain disorders. We also expect to identify disorder-specific and
brain-region-specific transcriptomic associations. Our project will enable new lines of inquiry into biological
changes that emerge in the brains of living persons, and create opportunities to improve diagnostics,
intervention, and treatment.

## Key facts

- **NIH application ID:** 10435527
- **Project number:** 5R21MH126494-02
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Stephen J Glatt
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $202,500
- **Award type:** 5
- **Project period:** 2021-06-21 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435527

## Citation

> US National Institutes of Health, RePORTER application 10435527, Profiling the Functional Genetics of Health and Disease using BrainGENIE: The Brain Gene Expression and Network Imputation Engine (5R21MH126494-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10435527. Licensed CC0.

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