Study shows some genetic variants have stronger effects on RNA expression even before birth

The prefrontal cortex of the human brain experiences a wider spectrum of developmental activity right from early prenatal development until childhood.

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A new genetic analysis by researchers from Yale University and the University of California-San Francisco (UCSF) shows that, in certain cases, the prefrontal cortex includes seeds of neuropsychiatric illnesses and conditions like autism spectrum disorder and schizophrenia.

Earlier studies have determined the variants of DNA associated with neuropsychiatric illnesses, but when those variations induce the functional changes in the dorsal lateral prefrontal cortex—a region closely related to cognitive, emotional, and neuropsychiatric disorders—is still not clear.

The new study, which was published in the Cell Reports journal on April 7^th, adds a new perspective to the earlier study.

The researchers also quantified the amount of RNA, which offers an overall picture of the genetic activity in 176 tissue samples over a range of developmental stages to identify when and how DNA variants influence brain function.

This is the first large cohort to profile DNA and RNA both in prenatal and postnatal human brain samples, making it an unprecedented resource for understanding how individual genetic differences might lead to functional differences.”

Sirisha Pochareddy, Study Co-Lead Author and Associate Research Scientist in Neuroscience, Yale University

According to the study authors, gaining insights into the link between genetic variation and changes in function can help researchers figure out how the modifications of brain development can cause autism and schizophrenia in later life.

Researchers can now determine the groups of genes that control unique biological processes and analyze how they cause disease, since thousands of variants linked to thousands of genes across the entire genome were monitored as part of the study.

Human brain development is an incredibly complex and dynamic process, and any disruption along the way can have profound consequences on later brain function. Interestingly, we found that some genetic variants have stronger effects on RNA expression before birth and other variants with strongest effects after birth.”

Donna Werling, Study Co-Lead Author, University of Wisconsin-Madison

Werling was formerly associated with UCSF. According to the researchers, investigation of these age-specific effects can pave the way for learning about the mechanisms that regulate brain disorders.

Nenad Sestan from Yale, who is the Harvey and Kate Cushing Professor in the Department of Neuroscience, and Stephan Sanders, who is an associate professor at the Weill Institute for Neurosciences at the University of California-San Francisco, are the co-senior authors of the study.

Pochareddy, Werling, and Joon-Yong An, formerly of UCSF, are the co-lead authors of the study. Jinmyung Choi, formerly of Yale, is another co-lead author.