Image of NLM Family Foundation banner
Image of stained glass
 
 
 
 
 
 
 
 

GENETICS

Below are descriptions of the Genetics grants that are currently active. To view a list of past grants in this area, please click on the link below.

Genetics - Past Grants



Beth Israel Deaconess Medical Center, Boston, MA
2010-2012

Principal Investigator: Matthew Anderson, MD, Ph.D.

Genetic Mouse Models of Autism

Recent studies of autism patients’ DNA revealed decreases or increases in the number of copies of specific genes. Two of these genes are unique in that they do not encode proteins, but instead only make strings of ribonucleic acid (non-coding RNA). The function of these recently discovered non-coding RNA molecules are completely unknown. Interestingly, protein coding sequences are highly homologous (80-90%) between mouse and man and most genes are shared between these two mammalian species. However, these two non-coding RNA genes cannot be found anywhere within the complete DNA sequence of the mouse genome. They are only found in humans and other primates, suggesting they might have a unique role in the primate brain. Dr. Anderson will explore the function of these two novel genes in human neuronal cells and will also introduce them into the mouse brain to assess their impact on autism-related behaviors and neuronal circuit function. These studies will discover the function of these two novel genes. The studies will also determine whether these genes can alter the behavior and neuronal circuit function to help establish an etiologic role in human autism.

Matthew Anderson Laboratory



Children’s Hospital Boston, Boston, MA
2014

Principal Investigator: Isaac Kohane, MD, PhD

Delineating autism subtypes by phenotype-wide scan across genome-wide genotypes in a patient centric information commons

This grant is for a one-year study that would result in a phenome-wide scan across all genotypes measured by SNP array. This will likely generate novel insights about the substructure of the different autisms. The involvement of genetic factors in ASD is demonstrated. Several genome-wide association studies (GWAS) of common single nucleotide polymorphisms have been performed but the effect sizes remained modest. New approaches, with a better integration of phenotypes and genotypes, such as pathway and network analyses could help to unravel the genetic mechanisms of ASD.  Stessman et al. suggested a “genotype-first” approach. In this approach, the selection criterion is no more phenotypic but genotypic: the variants of an identified gene of interest. Then, systematic associations of phenotypes with the variants of this gene are assessed. This new approach could allow the discovery of new subtypes of ASD. This genotype-first approach is similar to another method described by Denny et al: Phenome-wide association studies (PheWAS). Dr. Kohane’s group demonstrated in a previous work on thiopurine methyl-transferase enzymatic activity in the field of thiopurine therapy that this method could help to describe new subgroups of patients with specific characteristics. The PheWAS approach might allow the linkage of genes variants to specific sub-phenotypes of ASD. Some of these subgroups could benefit of a specific therapy, given that an earlier treatment can improve the situation. This kind of study requires large amounts of genotypic and phenotypic data. Big cohorts of ASD patients and families exist. They gather genetic and phenotypic data from thousands of patients, representing a promising source of data. One of the issues preventing wide research programs over these cohorts is the heterogeneity of the assessment tools for ASD phenotyping. Dr. Kohane argues that integrating genotypic and phenotypic data these cohorts into a single patient centric information platform enabling the unification of the different sources of data would allow a more effective use of their data for research purposes. One of the challenges preventing an effective use of this knowledge gold mine is the fragmentation of the data. Indeed, it is difficult to analyze phenotypic data fragmented over several different tools, representing thousands of questions and answers that may or may not overlap between the tools. Dr. Kohane’s group thinks that the unification and the harmonization of all these phenotypic data into single concept based ontology might enable its effective use in research. Collecting phenotypic data is expensive and time consuming. Lots of phenotypic data are collected on a daily basis but are difficult to access for research purposes. Therefore, clinical data warehouses (CDW), like i2b2, were designed to enable second use of data collected for health care for research purposes. The Children’s Hospital Boston (CHB) is equipped with such CDW and a significant part of ASD children from SSC are also treated in this hospital. With this grant, Dr. Kohane’s group will integrate anonymized data from CHB CDW to SSC phenotypic data, augmenting the number of phenotypic data available for analyses by performing a phenotypic expansion.

Isaac Kohane


Children's Hospital, Boston, MA
2012-2013

Principal Investigator: Isaac Kohane, M.D, Ph.D. and Alal Eran

Synaptic A-to-I RNA Editing in Autism Spectrum Disorders

Autism spectrum disorder (ASD) is likely caused by a combination of genetic and environmental factors acting at a sensitive period of neuronal development. Recent studies show that in many cases ASD is a disorder of abnormal synaptic function. To better understand the interactions between genes and the environment that modulate synaptic function, this research will investigate the role of adenosine-to-inosine (A-to-I) RNA editing in ASD. A-to-I RNA editing is a regulatory mechanism that takes place mostly in the brain, in which the sequence of RNA molecules, especially those making synaptic proteins, changes in response to environmental stimuli. Because tweaking the levels of A-to-I editing in model organisms (such as mice and flies) alters their behavior, it is thought that A-to-I RNA editing is one of the molecular mechanisms connecting environmental stimuli and behavioral outputs. Several lines of evidence suggest that A-to-I editing could be important in ASD, including findings of differential editing of synaptic candidate genes between postmortem cerebella of individuals with ASD and neurotypical controls. Investigators will validate and expand these findings by examining many more genes in more brain regions and more individuals. Using targeted capture and ultradeep sequencing of RNA and DNA, they will compare the patterns of neurodevelopmentally-regulated editing between brain regions, individuals, and groups. This will provide a comprehensive view of the potential extent of A-to-I editing alterations in ASD, and their contribution to the synaptic abnormalities underlying the disorder. This research will shed more light on environment-dependent epigenetic mechanisms involved in ASD, and more generally, complex human behavior in health and disease.

Isaac Kohane



Children’s Hospital of Philadelphia, Philadelphia, PA
2012-2014

Principal Investigator: Robert T. Schultz, Ph.D.

Characterizing IQ Impairments in ASD and Testing Their Genetic Foundations (Co-funded with the Simons Foundation)

Half or more of all persons with an autism spectrum disorders (ASD) have an intellectual disability (ID). IQ is one of the best predictors of which individuals will respond well to current interventions. It also is a good predictor of adult outcomes.  Thus, it is important to try to understand the biological mechanisms that cause ID in order to reveal new avenues for devising effective treatments.  Dr. Schultz and colleagues recently published the first genetics paper using the Simons Simplex Collection (SSC) focused on the relationship between genes that confirm risk for ASD and ID (Sanders et al, 2011).  Contrary to the field’s expectation, they did not find any relationship between large genetic defects in persons with ASD and ID. In fact, the degree of ID was a poor predictor of overall genetic risk for autism.  In the current project, Dr. Schultz’s group will collect additional data to make a re-analysis of their initial findings more powerful.  In particular, they will collect IQ data on other family members, including both parents and other siblings.  Family IQ data will help give much more precise estimates of the degree of ID in the youth with ASD. Including these data in their statistical analyses should yield much more powerful statistical analyses aimed at understanding the origins of ID in ASD.  Dr. Schultz’s group expects that a better understanding of the genetics of ID in those with ASD will reveal important clues as to biological mechanisms that can lead to innovative treatments.  Moreover, all of the new IQ data collected in this study will become part of the SSC and will be available for future use to all investigators, greatly enhancing the value of the important resource.

Robert Schultz, Developmental Neuroimaging Laboratory at Children’s Hospital of Philadelphia Research Institute


Massachusetts General Hospital, Boston, MA
2012-2014

Principal Investigator: James F. Gusella, Ph.D.

Molecular Signatures of Strong-effect ASD Genes and 16p11.2 Deletion (Co-funded with the Simons Foundation)

Understanding how the genetic defects that cause autism lead to abnormal neurodevelopment is critical both to understanding the disorder and to developing effective treatments. One particularly important question is whether different genetic defects produce autism in completely different ways, or alternatively, whether alterations in quite different genes might trigger a cascade of cellular changes that overlap with each other and ultimately produce autism by the same biochemical mechanism.  Recently a number of autism genes have been discovered whose normal function is to help in the regulation of the timing and level of expression of genes throughout the human genome.  Using new sequencing techniques to simultaneously measure the regulation of all genes in the genome, Dr. Gusella’s group will explore the consequences on gene expression of each of these new autism genes and determine whether these effects are distinct or shared.  They will also compare these changes in gene expression with the effects of the common autism-associated chromosome 16p deletion.  Importantly, these comparisons will be done in authentic human cells at the immature nerve cell precursor stage and throughout their development into mature nerve cells, a process of fundamental relevance to the neurodevelopment in autism.  The results of their analysis will test whether the different autism genes produce the disorder by leading to the same kinds of changes in nerve cell development and whether that biochemical mechanism is also triggered by the 16p deletion mutation.  Identification of a shared disease process despite different initial triggering genes would allow that shared process to be targeted for development of interventions that would apply broadly in autism.

James Gusella, Massachusetts General Hospital


Massachusetts General Hospital, Boston, MA
2012-2014

Principal Investigator: Michael Talkowski, Ph.D.

Cryptic Chromosomal Aberrations Contributing to Autism (Co-funded with the Simons Foundation)

Half a century ago, the introduction of karyotyping transformed human genetics and clinical diagnostics by opening access to gross changes in the chromosomes, revealing an entire class of previously undetectable genetic lesions. More recently, microarrays revealed that DNA gains and losses can cause genetic disease; however, the rate of return of significant findings from genomic microarray is quite low, with over 80% of clinical referrals yielding unremarkable or inconclusive genomic profiles. Similarly, even in extensively studied common complex diseases such as autism, the fraction of genetic contribution not explained by conventional association methods remains quite large. This project brings together leading experts in genomics, statistics, clinical diagnostics, and computational genetics to open access to another potentially critical class of genomic variation that remains unseen to all current methods of gene discovery in autism: chromosomal rearrangements that do not involve gains and losses of DNA. Previous research suggests this class of 'cryptic' alterations (or not visible at microscopic resolution) can have a profound impact in autism, ranging from small microinversions that directly inactivate the message of a single gene to highly complicated shattering and reorganization of chromosomes in autism cases that went completely unnoticed by current gold standards in clinical diagnostics. Dr. Talkowski’s group will perform an innovative form of whole-genome sequencing to identify all classes of structural variations at an order of magnitude lower cost than standard whole-genome sequencing, enabling access to a large number of cases at modest overall cost. This study will thus rapidly fill this glaring knowledge void in autism genetics and identify individually causal genes.

Michael Talkowski




University of California, Davis, Davis, CA
2015-2018

Principal Investigator: Judy Van de Water, Ph.D.

Concerted Impact of Genetic Susceptibility and Maternal Autoantibodies in a Rat Model of Autism (In partnership with the Robert E Landreth and Donna Landreth Family Fund)

Current literature estimates the genetic heritability of ASD to be approximately 50% and the remaining risk is thought to be due to environmental factors. The majority of this genetic risk is found in common genetic variants, not rare inherited or de novo mutations. To promote the development of safe, effective interventions and treatments to reduce symptoms of ASD, animal models that truly represent the human clinical profile are needed.  Such a model can be achieved through the incorporation of genes that are found to be associated with ASD combined with ASD-specific biologic profiles. This will aid in the development and testing of relevant therapeutic strategies in the future.

Recent advances in genetic technology have made possible the development of rats with autism-associated genes to be inserted or deleted into the rat genome. However, of the rats generated thus far, only the Met knockout rat represents a common genetic variant that is susceptible to environmental challenges; this rat has yet to be utilized for ASD research. It is therefore the goal of the investigators to develop a gene x environment ASD rat model by first validating that the heterozygous Met knockout in rats results in decreased MET receptor expression akin to the human mutation. They will then test a specific gene x environment interaction in this newly created rat model.  They have chosen the MET-heterozygous rat because MET controls how strong the immune response is after stimulation. Thus, the researchers will take advantage of their previous work that described the presence of maternal autoantibodies to proteins in the fetal brain that are highly associated with ASD, and combine this biologic condition with the reduced production of MET (which reduces immune regulation), to recreate what they have seen in the human clinical population in a subset of mothers whose children have ASD.  The investigators hypothesize that a genetic risk factor, represented by reduced MET production, when combined with an environmental challenge (immune challenge with MAR autoantigens) will result in an animal model that clinically represents MAR autism. Thus, they will measure the susceptibility to development of maternal anti-brain antibodies in the context of the Met heterozygous genotype to determine how this environmental insult affects behavior in the offspring. Lastly, they will define the consequences of Met x autoantibody interaction in the brains of the offspring. The researchers hypothesize that there will be a decrease in MET receptor expression that will in turn increase the susceptibility of the female rats for developing maternal anti-fetal brain antibodies. Furthermore, the combination of the Met mutation and maternally derived autoantibodies in the brain of offspring will result in more severe autism related behaviors and neuroanatomical differences compared to controls. 

 



 
Copyright © 2011 Nancy Lurie Marks Family Foundation
Link to homepage Link to links Link to contact page Link to search page