# Functional genomic investigation of complement signaling in the human brain

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $37,894

## Abstract

PROJECT SUMMARY/ABSTRACT
Large-scale genome-wide association studies (GWAS) have successfully identified hundreds of genetic risk
factors associated with common but complex neuropsychiatric disorders. Increased expression of complement
component 4A (C4A) is one such factor that has been implicated in schizophrenia (SCZ) pathophysiology.
However, the exact biological mechanisms in the human brain through which C4A—and the broader complement
system—confer risk for SCZ remains unclear, due to its modest effect size and the lack of an appropriate
experimental system adequately recapitulating disease-relevant context. Furthermore, whereas recent work has
revealed substantial genetic overlap across neuropsychiatric disorders, little is known about the extent to which
the complement system contributes to other disorders with shared genetic influences. Here, we propose a
comprehensive set of functional genomic analyses to investigate the dysregulation of the complement system in
the human brain and its relation to risk for autism spectrum disorder (ASD), SCZ, bipolar disorder (BD), and
major depressive disorder (MDD). Given the strength of the C4A association with SCZ and the significant genetic
correlations among these disorders, we hypothesize that the complement system will be broadly involved in the
pathophysiology of neuropsychiatric disorders. To test this hypothesis, we will build upon our recent work with
PsychENCODE to compile a large-scale genotype array and RNA-seq dataset of ~3,000 adult human brain
samples, including several hundred individuals with ASD, SCZ, BD, and MDD. Leveraging this dataset, we will
assess case-control differential expression of the complement system across these four disorders (Aim 1). Next,
we will identify genetic regulators of complement system gene expression and determine their relation to
established neuropsychiatric genetic risk factors (Aim 2). Finally, to begin to elucidate the functional role of the
complement system during human brain development, we will examine how complement system gene
expression is related to variability in brain structure and behavior in the Adolescent Brain Cognitive Development
(ABCD) study and how these relationships are moderated by sex and environmental factors (Aim 3). Taken
together, these aims will systematically characterize the overall contribution of the complement system to a broad
range of genetically related neuropsychiatric disorders, which is in line with the NIMH mission to elucidate the
neurobiological mechanisms underlying mental illnesses. These studies will be conducted by Minsoo Kim, a MD-
PhD student at UCLA, and will provide comprehensive training in psychiatric genetics and genomics. Mentorship
will be provided by Drs. Michael J. Gandal and Daniel H. Geschwind, experts in the fields of cross-disorder
genomics and neurobehavioral genetics.

## Key facts

- **NIH application ID:** 10389218
- **Project number:** 1F30MH125523-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Minsoo Kim
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,894
- **Award type:** 1
- **Project period:** 2021-08-25 → 2022-08-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389218

## Citation

> US National Institutes of Health, RePORTER application 10389218, Functional genomic investigation of complement signaling in the human brain (1F30MH125523-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10389218. Licensed CC0.

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