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Mapping Underpinnings of Autism, Schizophrenia with Genetic and Genomic Tools

Published on August 19, 2024 in Cornerstone Blog · Last updated 8 months 1 week ago
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Michael Gandal and Liqing Jin

Michael Gandal, MD, PhD, an associate professor in the Lifespan Brain Institute, and staff scientist Liqing Jin, PhD, extract RNA from tissue samples before performing long-read sequencing.

By Lauren Ingeno

Over the last decade, large-scale genome-wide association studies (GWAS) have identified hundreds of genetic variants linked to brain disorders like autism and schizophrenia. These studies have helped researchers understand the foundational biology of disorders, which can help to inform more advanced diagnosis and treatment.

However, most of these variants lie in non-coding regions of the genome, which are generally thought to regulate the activity of nearby protein-coding genes, rather than make proteins themselves.

Since the functional roles of most non-coding regions of the genome remain unknown, it has been historically difficult to link these variants to their target genes and to uncover the specific brain signatures that contribute to the risk of developing psychiatric and neurodevelopmental disorders.

To address this knowledge gap, the National Institute of Mental Health launched the PsychENCODE initiative in 2015. The project challenges research teams to map the complex networks that regulate gene function in the human brain.

Michael Gandal, MD, PhD

Michael Gandal, MD, PhD, and colleagues have created an online atlas of cellular diversity in the developing human brain.

Among the PsychENCODE researchers is Michael Gandal, MD, PhD, an associate professor in the Lifespan Brain Institute at Children's Hospital of Philadelphia. His lab's goal is to use computational biology and genomics to understand the complex, underlying biological mechanisms that contribute to the development of neurodevelopmental and psychiatric disorders.

"In the field of psychiatry, genetics is used very little in clinical practice, which I think is a big, missed opportunity," said Dr. Gandal, who earned his MD/PhD at the University of Pennsylvania and joined CHOP as a research investigator in 2023. "My lab uses genetic and genomic tools to gain basic biological insights about these disorders, and to translate those insights into clinic practice, so that we can help better understand, diagnose, and treat neuropsychiatric disorders."

An initial set of PsychENCODE findings, reported in 2019, revealed new insights into the regulatory networks that can increase the risk of several disorders. Now, two studies led by Dr. Gandal provide new details into the genetic underpinnings of complex neurodevelopmental and psychiatric disorders.

"We do this by compiling and uniformly profiling brain samples for multiple layers of genomic readouts, starting from how a gene is turned on or off to whether regions of the genome are open or not, and then connecting those functions to nearby genetic variants," Dr. Gandal said.

The first study, co-led with researchers at UCLA, focused on using new single-molecule long-read sequencing technology to profile the full-length transcriptome of two key regions of the brain, uncovering more than 150,000 novel gene isoforms.

While there are only about 20,000 protein-coding genes in the human genome, most individual genes can form multiple distinct isoforms through a cellular process called alternative splicing, in which exons (coding sections of RNA) from the same gene are joined in different combinations, leading to different, but related, mRNA transcripts (carriers of genetic instructions).

Understanding the role of splicing and transcript-isoform diversity in the developing brain is key to understanding brain development and genetic risk for brain disorders, Dr. Gandal said. However, prior generations of genome-sequencing technologies limited this kind of research.

With an advanced new technology that enables the researchers to capture complete RNA molecules, Dr. Gandal and his collaborators were able to profile the full-length transcriptome of two regions in the developing human neocortex. They uncovered 214,516 unique isoforms, over 70% of which have never been previously studied.

The study also found that high-confidence risk genes for autism tend to have more isoforms.

Results from the study are publicly available in an online tool that scientists and clinicians can use to study genetic risk factors for children with rare or undiagnosed neurodevelopmental disorders.

In the group's second study, researchers created the largest cross-ancestry atlas of gene regulation in the human brain, connecting non-coding genetic variants with the expression of nearby genes across 700 samples. The atlas characterizes gene, isoform, and splicing regulation in the developing human brain.

To create the atlas, researchers identified 15,752 genes regulated by nearby genetic variants, including 49 genes associated with large, recurrent inversions, or sections where a large piece of a chromosome has broken off and reattached in the reverse direction.

This data revealed that gene expression heritability — the degree to which common genetic factors contribute in aggregate to a particular trait — drops during development. Additionally, isoform-level regulation, especially in the second trimester, mediated the largest proportion of heritability across five neuropsychiatric disorders.

Findings from both studies, Dr. Gandal said, could help to improve clinicians' ability to diagnose and treat developmental brain disorders, many of which have a genetic component that could easily be overlooked during medical evaluations.