“Autism is one of the most highly heritable and complex disorders known, but a genetic cause or risk factor can be identified in only about 10% of autism cases,” says Lauren Weiss, Ph.D., One Mind sponsored Assistant Professor of Psychiatry at UCSF. “However, genome-wide association studies have begun to identify common and rare genetic variants associated with autism.” Dr. Weiss is a dynamo in autism research, conducting a multi-pronged approach to understand the disease’s roots. Her team has made some groundbreaking discoveries toward understanding gene interactions, cell pathology, and more.
Since starting her lab in October 2008, Dr. Weiss has successfully recruited hundreds of subjects in order to analyze variation in their DNA and understand the function of susceptibility genes and gene interactions. In 2009 she published a paper in Nature detailing her discovery that a common genetic variant near the gene encoding SEMA5A, a molecule that guides newly-formed neurons to their places in the brain, shows association with, and reduced brain expression in, autism. Since then her research has explored a network of hundreds of regions of the genome that appear to regulate the expression of SEMA5A, many of which are associated as risk factors for autism. In 2012-13, her lab has revealed that these regions include not only common genetic variations but also rare deletions and duplications, broadening the field. These discoveries suggest a striking hypothesis: that these multifarious genetic variants might actually contribute to autism risk through their influence on a single gene, SEMA5A. “If this hypothesis is indeed proven by further testing,” WeissÃ¢â‚¬â„¢ team posits, “it suggests a new understanding of the biology of autism, as well as new directions for biomarker and treatment targets in ASDs.”
Using an analytical approach similar to that she used in her SEMA5A research, Weiss and her team have this year begun to close in on genes in the 16p11.2 critical region that may influence the development of autism-and more. Weiss says, “Our preliminary data suggest that brain-expression drives not only the association of this region with autism, schizophrenia, and bipolar disorder, but also with body mass index (BMI)”.
Also, using similar analytical techniques, the team has investigated the consequences of a recently-discovered epigenetic mechanism called monoallelic expression (MAE). In investigating the potential consequences of brain MAE on genome regions also subject to copy number variation (CNV), they found an interesting disparity: While genes expressed in this way are represented homogeneously in common CNV regions in healthy control subjects, these genes are much scarcer in CNVs found in schizophrenia, autism, and other neuropsychiatric diseases. Although autism spectrum disorders are genetically complex diseases, discoveries like these are beginning to unravel the puzzle.
In 2013-14, WeissÃ¢â‚¬â„¢ team has collaborated with Dr. Lisa Croen at Kaiser Permanente Research to evaluate how genetic mutations in mothers might influence the development of autism in their children. Analyzing the genomes of 1600 subjects, they found that mothers of children with autism have more copy number variant deletions and duplications in their genetic sequences than mothers of healthy control subjects. This CNV disparity among the groups of mothers in their sample population was much more striking than between the groups of children themselves. Surprisingly, the team also found that in the general healthy population, females carry more large, rare, copy number variants than males.
In collaboration with Dr. Kate Rauen, Dr. WeissÃ¢â‚¬â„¢ questionnaire study of over 150 families with rare, Mendelian Ras/MAPK disorders has enabled her to estimate that at least 25% of people affected by these disorders show significant autism traits. Weiss hypothesizes that the deciding factor for the frequent presence of these traits in this population may be interactions of Ras/MAPK genes with other genes yet to be identified. Her questionnaire results and analysis of idiopathic autism data have indicated this population as a “uniquely powerful population in which to identify these interactions.” Indeed, the data WeissÃ¢â‚¬â„¢ lab has collected from autism patients in 2012-13 suggests the presence of such gene-gene interactions involving the Ras/MAPK pathway. These discoveries have been published in the Journal of Medical Genetics in 2014.
To figure out how these interactions might produce autism traits, she is working with collaborators at UCSF including Dr. Erik Ullian to develop induced pluripotent stem cells (iPSCs) from skin samples of patients, some with genetic mutation in the Ras/MAPK pathway, and some with 16p11.2 deletions and duplications, to generate cells of the brain. So far, the two groups have begun to compare the development of neurons and glia from patient cell lines with cell lines from healthy subjects.
Furthermore, the discoveries she has made to date have earned her grants from various sources to expand her research of genetic risk factors for autism in many ongoing directions:
- to understand differences in male vs. female genetic risk for autism. Dr. Weiss explains, “Four times as many males as females are affected with autism, for unknown reasons. If we can determine what protects females from developing autism, that information could lead not only to biological insights, but potentially to reduction of male risk.”
- to characterize the defects of neurons with autism risk variants: Dr. Weiss recently identified “a microdeletion in chromosome 16p11.2 that causes a 100-fold increase in the rate of developing autism spectrum disorders, and a 10-fold increase in the rate of other language or psychiatric disorders.” Now, she plans to study neurons generated from induced pluripotent stem cells from subjects with this genetic deletion, in order to “identify the cell biological phenotypes that lead to autism in patients with this deletion”
- to study neurodevelopmental phenotype, genetic interactors, and neurons related to Ras/MAPK disorders. In 2011, Dr. Weiss has received the high honor of an NIH New Innovator Award for this project.
Evaluating how these genetic risk factors work will yield progress toward Dr. Weiss’ long-term goals: “to improve understanding, prevention, diagnosis and treatment of autism and its related traits.”
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