NEW YORK (GenomeWeb) – Kaiser Permanente has unveiled an ambitious plan to corral 15,000 individuals into a database over the next three years that researchers can use to investigate the genetic and environmental factors involved in autism spectrum disorders.
Last week Kaiser announced that its Autism Research Program received a $4.6 million grant from the Simons Foundation to create a database of 5,000 family trios — an autistic individual under age 26 and his or her biological parents — over the next 36 months. The so-called Autism Family Research Bank will contain de-identified genetic, medical, and environmental information on these trios that researchers can use to advance their understanding of the complex condition and possibly apply to the development of treatments.
The grant from the Simons Foundation will be sufficient for enrolling the family trios in the research bank and for collecting certain types of information on them, Lisa Croen, director of the autism program within Kaiser's research division, told GenomeWeb. But, she added, additional funding will be necessary to genetically analyze the biospecimens collected from the participants.
Autism comprises a number of different neurodevelopmental disorders that cause people to have communication impairments and repetitive behavioral patterns. The US Centers for Disease Control and Prevention estimates that one out of 88 children who are eight years old have an autism spectrum disorder, and boys are four times more likely to have the condition than girls.
Parents of young autistic children often seek out behavioral training in the hopes of mitigating their kids' social and communication challenges. As an autistic child grows up, he or she may develop other symptoms, such as anxiety or obsessive-compulsive disorder, for which a doctor might prescribe drugs. Still, "currently, there are no drugs that target the core impairments of autism," Croen said.
This is where Kaiser is hoping its Autism Family Research Bank will make a difference. "The resource will facilitate research aimed at identifying genetic and non-genetic underpinnings of autism, which should facilitate the development of pharmacologic treatments for various aspects of the disorder," Croen said.
Researchers at Kaiser expect to begin enrolling families in July. They plan to take a family history, as well as blood or saliva samples from each of the family members; gather clinical information from their medical records; and give them surveys, such as the Social Reciprocity Scale, which measures the social aspects of autism spectrum disorders.
Croen explained that each study participant will have to enroll in the Autism Family Biobank. In order to be eligible for the study, the autistic individual in each family must be a member of Kaiser Permanente in Northern California, but the parents do not have to be Kaiser members.
Since the autistic participants must be Kaiser members, they will have electronic medical records through the healthcare organization, which in turn, will enable researchers to collect information on the environmental exposures that might be associated with autism. According to Croen, some of the environmental factors her team might be on the lookout for in the research cohort includes whether participants were exposed to certain types of drugs, smoking, and alcohol.
After the research bank is enrolled, Croen expects Kaiser will need additional resources to perform genetic analysis of the biospecimens, run other queries on the collected data, and pursue the different hypotheses born out of the research bank. "With additional funding, whole-genome or exome sequencing are likely possibilities," she noted.
Although it is not known precisely what causes autism spectrum disorders, studies have implicated the involvement of both genetic and environmental factors. In families with one autistic child, the risk of a second child with the condition can be as high as 20 percent. Moreover, inherited conditions like Fragile X syndrome are associated with autism. Single de novo risk variants account for 1 percent of cases, the Simons Foundation estimates, but grouped together can account for 25 percent of autism cases.
It's quite obvious that [autism] is going to be heterogenous in etiology. So, in terms of trying to understand that it's going to be a numbers game.
Environmental impacts on complex conditions are hard enough to capture, but with greater availability of advanced sequencing techniques, the genetics landscape has proven to be just as challenging as researchers have uncovered a range of variations that appear linked to the complex disorder when it occurs sporadically or in families. There are a number of diagnostics firms and academic centers that test for the genetic underpinning of autism using karyotyping, microarrays, and next-generation sequencing. In 2013, the American College of Medical Genetics and Genomics issued guidelines recommending that genetic counselors discuss genetic testing as an option for patients and families affected by autism, and included a list of genetic "hot spots."
The Simons Foundation has funded and provided key resources to researchers working to uncover the genetic complexity and diversity underlying autism spectrum disorders. According to the organization, the Simons Foundation for Autism Research Initiative (SFARI) supports 190 investigators with an annual budget of $60 million. Importantly, SFARI has built the Simons Simplex Collection, a repository of biospecimens, genetic and phenotypic data from nearly 3,000 autism simplex families, which is being readily used by researchers exploring the genetic underpinnings of the condition.
Recently, researchers led by Aravinda Chakravarti from Johns Hopkins University focused on families with more than one girl with severe autism spectrum disorder, sequenced the exomes of 13 unrelated girls, and compared the findings against data in the 1000 Genomes Project. Noting that girls are affected with autism in lesser numbers than boys, but that they tend to get it more severely, Chakravarti's team focused on families with more than one autistic girl hoping to identify genetic markers that confer a larger risk for the condition than other markers found to date.
Using this and other research techniques, researchers were able to home in on a number of variations in four genes possibly associated with a severe form of autism. Chakravarti's team believes that their analysis suggests that variations in CTNND2 in particular may be implicated in neuronal development in autism. As part of this work, researchers further explored CTNND2 variants in more than 350 autistic girls in the Simons Simplex Collection and in the 1000 Genomes Project.
A few years ago, researchers from Boston Children's Hospital, Harvard Medical School, and elsewhere also used data from the Simons Simplex Collection in their hunt for rare, highly penetrant, recessive mutations involved in causing a severe form of autism. Before that, SFARI-funded research teams from Cold Spring Harbor Laboratory and Yale University used genome-wide scans of the first 1,000 families in the Simons Simplex Collection to confirm previously identified copy number variations linked to autism and discovered previously unseen markers as well.
Given, SFARI's efforts to create the Simons Simplex Collection, a resource the foundation estimates is being used in approximately 230 projects, it's no surprise that the group is now funding Kaiser's efforts to build an even larger autism family repository and database. "Autism is clearly not a single condition," Wendy Chung, Simons Foundation director of clinical research, told GenomeWeb. "It's quite obvious that it is going to be heterogenous in etiology. So, in terms of trying to understand that it's going to be a numbers game." Chung believes Kaiser's research bank might contribute meaningfully to advancing understanding of autism because of the "robust" size of the planned cohort and the different data elements that can be collected from participants' medical records.
Another effort, the MSSNG project, being conducted by Autism Speaks, The Hospital for Sick Children in Toronto, and Google, is aiming to collect whole-genome sequencing and phenotypic data on 10,000 individuals from families affected by autism. Once it has completed enrollment of 15,000 participants from autism-affected families, Kaiser's Autism Family Research Bank could be the largest genetics resource of this type for the autism research community.
"This resource is unique in that it will be comprised of members of one large healthcare system, with extensive clinical information on the participants that can be harnessed from the electronic medical record," Croen said. She further highlighted that Kaiser has the ability to follow participants longitudinally and invite them to partake in future studies where researchers might collect more detailed data on them.
Croen noted that after the development of the Autism Family Research Bank, Kaiser is planning to collaborate with other scientists in academia and industry and make the resource available to qualified researchers.
This article has been updated with additional comments from Wendy Chung.