Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms

Area of Science:

• Neurogenetics
• Developmental Neuroscience
• Psychiatric Genetics

Background:

• Tissue-specific regulatory regions are crucial for genetic disease risk.
• Brain development is a key period for neuropsychiatric disease susceptibility.

Purpose of the Study:

• To characterize the genetic control of the transcriptome during mid-gestational human brain development.
• To identify prenatal regulatory regions associated with neuropsychiatric disease risk.
• To uncover novel candidate risk genes and shared/stage-specific mechanisms in schizophrenia and autism spectrum disorder.

Main Methods:

• Analysis of gene expression quantitative trait loci (eQTL) and splice quantitative trait loci (sQTL) in 201 mid-gestational human brains.
• Integration of eQTL and sQTL data with genome-wide association studies (GWAS) using transcriptome-wide association.
• Gene network analysis to identify affected co-expression modules in schizophrenia and autism spectrum disorder.

Main Results:

• Identification of 7,962 eQTL and 4,635 sQTL, including thousands of prenatal-specific regulatory regions.
• Demonstration that genetic liability for neuropsychiatric diseases is linked to prenatal eQTL and sQTL.
• Discovery of dozens of novel candidate risk genes for schizophrenia, highlighting shared and stage-specific mechanisms.
• Evidence that schizophrenia and autism spectrum disorder impact distinct developmental gene co-expression modules.
• Convergence of common and rare genetic variation within modules, implicating superficial cortical neurons in autism spectrum disorder.

Conclusions:

• Prenatal gene regulation plays a significant role in neuropsychiatric disease susceptibility.
• Shared and distinct genetic mechanisms underlie schizophrenia and autism spectrum disorder during development.
• Developmental events have a broad impact on adult brain function and behavior, influenced by genetic variation.