UCLA team first to map autism-risk genes by function
Dr. Daniel Geschwind
Pity the poor autism researcher. Recent studies have linked hundreds of gene mutations scattered throughout the brain to an increased risk for autism. Where does one start investigating?
UCLA neuroscientists may have an answer. They are the first to map groups of autism-risk genes by function and to identify where and when these genes affect early brain development.
In addition, they discovered disturbances in neural circuits that define key pathways between parts of the cerebral cortex that are known to be involved in autism. The research suggests that these disruptions are created by mutations in genes during fetal brain development and are not a result of autism itself.
Published in the Nov. 21 edition of Cell, the findings shed light on how genetic changes cause autism on a molecular level and will help prioritize targets for future studies.
"Identifying gene variants that boost risk is only the first step of unraveling a disease," said lead author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, professor of neurology at the David Geffen School of Medicine at UCLA and professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior. "We need to figure out where genetic changes appear in the brain, at what stages during development they occur and which biological processes they disrupt. Only then will we understand how mutations cause autism."
The authors examined data from BrainSpan — an atlas of gene-expression maps that includes risk genes at different stages of brain development, from eight weeks after conception through 12 months of age — looking for points of risk-gene convergence. In particular, they examined what happens during gene expression, when genes copy data from DNA to RNA in order to create proteins.
Geschwind and his colleagues found a high level of activity in the genes linked to autism risk during two processes critical to early brain development.
"We found that gene variants are expressed in the developing brain when cells define their future identities and roles in neural circuits," said first author Neelroop Parikshak, a graduate student researcher in Geschwind's lab. "Therefore, changes in the genes influence the brain's wiring by altering the synapse and shaping how neurons transmit signals to each other."
Secondly, the mutated genes also interfered with how the brain's layers and halves relate to one another, a phenomenon confirmed by previous imaging studies of the autistic brain
"We discovered gene-related disruption of circuits that connect the autistic brain's layers and hemispheres to each other," said Geschwind, who is director of the UCLA Neurogenetics Program and the Center for Autism Research and Treatment and co-director of the Center for Neurobehavioral Genetics at UCLA. "Our finding suggests that the mutated genes caused the miswiring; it's not a result of having the disease itself."
The UCLA team also demonstrated for the first time that, while the genes linked to increased risk for autism and increased risk for intellectual disability are similar, the genes behave uniquely for each disorder.
"People often lump intellectual disability together with autism, because the disorders' risk genes overlap," Parikshak said. "We showed that these genes have unique expression patterns in different brain regions at varying times during brain development.
"Genes linked to intellectual disability influence many biological processes in the body," Parikshak added. "But genes tied to autism tend to affect specific functions, such as the connections between brain regions that are essential to many human-specific behaviors, like speech and language."
Autism researchers have teamed up with families of children with autism to analyze their genomes and enhance our understanding of the disorder. The UCLA study’s findings will help place all these data into context, enabling neuroscientists to focus their attention on key genes from among the vast number of those that have been linked to autism and intellectual disability.
"We've made our analysis publicly available to allow other researchers to expand upon our study and explore the data in detail," Geschwind said. "We believe this will mark an important step forward in understanding the biology behind autism and other neurodevelopmental disorders."
The Simons Foundation and National Institute of Mental Health funded the study. Co-authors included Rui Luo, Alice Zhang, Hyejung Won, Jennifer Lowe, Vijayendran Chandran and Steve Horvath, all of UCLA.