The influence of human genetics on social behavior and brain development, function, and architecture is poorly understood. In yesterday’s plenary session, “Translating Genes, Brain, and Behavior: A Next Generation Human Framework,” Julie Korenberg, MD, PhD, described her groundbreaking work combining studies of genes, behavior, and imaging to decode the mysteries of human behavior and brain circuitry.

Korenberg noted that we know very little about the genetics and neurocircuitry of the human brain because most available information on brain genes comes from studying mouse brains, which are very different from human brains. She stressed that identifying genes associated with human behavior “must be validated by studies that involve humans.”

The multi-system approach Korenberg described combines gene expression studies and high-resolution imaging to identify the genes responsible for certain behaviors in humans. These genes are mapped both to the regions of the brain where they are expressed and the specific axonal circuitry where they are active. Korenberg explained how this model aligns gene expression information with neuroanatomy and neurocircuitry at very high resolution, allowing for reaching areas of the brain that have never been looked at before.

Korenberg applied this approach to study genetic disorders that affect behavior, including Down and Williams syndromes. Down syndrome, a neurodevelopmental disorder caused by an extra copy of chromosome 21 (trisomy 21), is the most common genetic cause of intellectual disability. Korenberg identified genes responsible for specific behaviors associated with Down syndrome by “studying rare Down syndrome cases with partial trisomy and linking these individuals’ cognitive phenotype to genes they do or do not have, thus narrowing down the focus to a small part of chromosome 21,” she explained. Her work led to identifying changes in the brain circuitry of Down syndrome patients that could explain the language and cognition problems associated with this syndrome and become a target for clinical trials.

A microdeletion of 26 to 28 genes on chromosome 7 causes Williams syndrome, a neurodevelopmental disorder characterized by mild to moderate intellectual disability, learning problems, distinctive facial features, and cardiovascular problems. Individuals with Williams syndrome have difficulty with visual-spatial tasks like drawing and assembling puzzles, but they tend to do well with tasks that involve spoken language, music, and learning by repetition. Additionally, these individuals have outgoing and engaging personalities.

Korenberg’s work identified two genes that could be linked to hallmarks of Williams syndrome: visual-spatial performance and social behavior. The pathways these genes are part of could become a target for assessing future therapies for this syndrome.

The multisystem approach linking genes with brain circuits and behavior in theory could be used for any mental disorder and could unveil the mysteries of how human brains develop and function, Korenberg explained. The high level of resolution achieved with this approach could bring us closer to what Korenberg described as a “personal brain model” where genetics, brain circuitry, and phenotype data can be fed into this tool to get key information for managing patients and expecting drug response.

The ultimate goal, noted Korenberg, is to find a way to assess how alterations in genes change behaviors in a measurable way. This capability will have diagnostic implications and accelerate therapeutics for Down and Williams syndromes as well as other mental disorders.