Guest Blogger: Ashley A. Scott-Van Zeeland, Ph.D., postdoctoral fellow at Scripps Genomic Medicine, Scripps Translational Science Institute. Dr. Scott-Van Zeeland was just awarded the INSAR prize for the best research dissertation in autism at IMFAR on Thursday evening.
An introduction to the cutting-edge field of neuro-imaging genetics kicked off the Invited Educational Symposium series for IMFAR 2010. Moderated by Dr. Lea Davis, attendees were treated to three presentations describing how the combination of neuroimaging and genetics could be leveraged to gain insight into autism.
The basic tenant of imaging genetics is that brain function and structure are a step closer to the gene ‘action’, and can better reveal associations between specific brain processes and genes. This is in contrast to traditional genetics studies in which a categorical classification of “Autism” versus “Control” is typically used. Neuroimaging presents a unique opportunity to look at the living brain and search for genes that influence patterns of brain function or structure. Importantly, measures of brain structure tend to be stable over time and highly heritable (similar between family members), making these measures appropriate for genetic studies.
Dr. Judith Piggot, an Assistant Professor from UCLA, presented the first talk of the session. In addition to introducing the audience to the concept of imaging genetics, she described some of the hurdles that imaging genetics in autism, in particular, must address. Dr. Piggot noted that although autism is one of the most genetic of complex neurodevelopmental disorders, the search for the causative genes has been hampered by the large amount of heterogeneity, or unique causes and presentations of autism. One way imaging genetics can move the field forward is to use brain imaging to identify more similar patient groups in which the genetic study can be performed. For example, a researcher could first identify a group of individuals who share abnormal brain activity during a face-processing task, and then use this brain imaging-based outcome to search for associated genes. Additional hurdles include difficulties in collecting the brain imaging and blood samples necessary to do this work, as well as issues related to statistical analysis.
Next, Dr. Joseph Callicott, Chief of the Unit on Dynamic Imaging Genetics (UDIG) within the Clinical Brain Disorders Branch of the NIMH, described imaging genetics approaches that have been utilized in the study of schizophrenia, highlighting how the autism community can avoid some of the pitfalls that were encountered in the very early days of this state-of-the art technique. Dr. Callicott’s group looks not only at individuals affected with schizophrenia and healthy controls, but also includes unaffected siblings of the patient. Siblings share 50% of their genetic makeup, likely including some of the genes that predispose to the disorder, yet remain unaffected. Utilizing this information can help pinpoint which genes contribute to shared features of brain function and provide greater insight into how multiple genes contribute to “building a brain that is vulnerable to illness.” He also presented results from previous imaging genetics studies that found certain genes have a broad and generalized effect on brain function, whereas others show effects limited to certain cognitive functions and brain regions. Results like these fulfill the greatest promise for the application of imaging genetics studies to autism, because they have significant impacts for drug targets and should be considered during drug development.
Dr. Thomas Wassink from the University of Iowa concluded the session, presenting recent work his group has done on the serotonin pathway and brain function in children with autism and children with Fragile X (FraX), a related disorder. Between 1-3% of children identified with an autism spectrum disorder are also found to have the FraX mutation, and there is significant overlap in clinical and related features of the two disorders. Both FraX and autism show increased grey matter (cell bodies) and white matter (connections between cells) compared to typical populations. Dr. Wassink’s studies focused on two genes involved in serotonin levels in the brain, the serotonin transporter (SERT) and an enzyme that inactivates serotonin, monoamine oxidase A (MAOA). One of the most dramatic findings presented was that the low activity version of MAOA translated to a roughly 4% increase in grey matter volume in both FraX and autism (Davis, L.K., et al. 2009). This links the serotonin pathway to the shared feature of enlarged brain volume in both autism and FraX.
A consistent and important message to researchers was conveyed during this educational seminar: Although there may be some unique practical difficulties associated with both neuroimaging and genetics, neuroimaging laboratories should strive to collect DNA samples from every participant to fulfill the promise of imaging genetics to identify the effects of candidate genes in the brain and potentially impact drug development.
To read complete coverage from IMFAR, please visit
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our ninth item, Copy Number Variations, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
Three studies published in 2007 pointed autism researchers toward the importance not only of mutations within the DNA code of specific genes, but also of variations in the number of copies of genes, known as Copy Number Variations (CNV). Created by submicroscopic deletions or duplications of DNA sequences, recent advances have only now allowed CNV to become routinely detectable, establishing an entirely new avenue of genetic research.
Armed with the latest technology and three different collections of patient DNA, including Autism Speaks’ Autism Genetic Resource Exchange (AGRE), researchers at Cold Spring Harbor scanned the genome for the presence of CNV in autism. In February 2007 they reported that not only do individuals with autism have more CNV than individuals without autism, but that CNV in autism occur more often as “de novo” or spontaneous mutations (mutations not found in the DNA of either parent). They also found that these spontaneous CNV appear to be more common in families with only one child with autism (simplex) than those with multiple affected children (multiplex).
With their data suggesting that genetic mechanisms may be different in different types of autism, the researchers then carefully studied the inheritance pattern of autism in the many families in Autism Speaks’ AGRE and IAN databases. In July they published that they could fit the data to a model in which there are at least two distinct ways that genes may play a role in the development of autism: spontaneous CNV might help to explain autism in simplex families, whereas inherited gene mutations may be at the root of autism spectrum disorders in a greater portion of multiplex families. Such a model is significant because although autism has been thought to have a strong genetic component, so far it has not been shown to be as clearly inherited as other simple genetic disorders.
The team from Cold Spring Harbor has provided a new theory of autism risk that stands to influence how future autism genetic research is conceptualized. Although their results require replication, it also now leads to the question of what causes this increase in spontaneous CNV, opening the door to an exploration of the interplay between genetics and environmental factors. Possible risk factors include age of the parents, specific toxicological factors and accumulated exposures, as well as genetic predisposition.
Update since this story was first run: Improvement in DNA technology since the publication of this first major autism CNV study has meant that new insights into the role of CNV are actively being pursued. The largest and most comprehensive autism CNV study to date was published in April 2009 in the top research journal, Nature. The new study focused on inherited rather than spontaneous CNV, with the researchers finding CNV variations in genes important for neural development [for more details, see
]. Researchers in autism are continuing to lead geneticists in other fields with an intense focus on CNV and early recognition of their importance as potential disease risk factors.