Home > Science > Geri Dawson Reflects on AGP Phase 2 Results

Geri Dawson Reflects on AGP Phase 2 Results

By Geri Dawson, Chief Science Officer, Autism Speaks

Science moves so slowly and is so labor-intensive that we don’t often have moments to celebrate an achievement or breakthrough that has resulted from our investments. With this week’s announcement of Phase 2 results from the Autism Genome Project, we are celebrating such an achievement.

Several years ago, when I was a professor at the University of Washington, I remember a phone call from Andy Shih, Ph.D. (Autism Speaks VP, Scientific Affairs) who asked if he could take my colleague, Jerry Schellenberg, and me out to breakfast. Over coffee, Andy described to us an idea he had: Would we be willing to collaborate with other scientists around the world and add the genetic data we have been collecting to a combined database? While each of us at that time had been working independently to try to discover autism risk genes, we knew that ultimately we would need much larger samples to deal with the significant heterogeneity that exists in autism spectrum disorder. After a lot of discussion and questions, Andy convinced us that this would be a worthwhile effort and thus we became part of what became known as the “Autism Genome Project,” or the AGP. Eventually, Andy talked with over 50 groups worldwide and cajoled each of them to join the effort. What ensued was a series of monthly conference calls, complex negotiations and agreements that Andy helped broker, the creation of a combined database, and yearly meetings during which the goals for analysis and future data collection would be discussed. Today, the AGP is considered a driving force in autism genetic research.

Meanwhile, Clara Lajonchere, Ph.D. (Autism Speaks VP, Clinical Programs) was spearheading an effort to create a database of multiplex families called the Autism Genetic Resource Exchange (AGRE). She was leaving most of us collecting similar samples in the dust as she quickly assembled the largest private genetic individual data base that exists. Her ability to form partnerships with families, engaging them in the process of scientific discovery, was a model for us all. Not surprisingly, Clara readily agreed to join the AGP since AGRE’s basic premise was “collaboration and data sharing.”

Fast forward to this week when the AGP published the largest and most comprehensive study of copy number variations (CNV) – small deletions or duplications in our genome that can disrupt gene function – in autism families. By comparing CNVs found in 1,000 individuals with autism with those from 1,300 individuals without autism, the AGP reported the following:

  • Several novel ASD genes were discovered, and many genes previously implicated by other studies were confirmed. Some of these genes are involved with communication between neurons, while others help regulate cell growth and how they respond to environmental stimuli.
  • It was confirmed that autism risk genes are rare variants in our genome that occur very infrequently or not at all in the general population, and each person with ASD may have a unique risk gene or set of risk genes. Some of these genes are “highly penetrant” meaning that, if you carry this risk gene, you very likely will develop ASD, whereas other only raise the risk for ASD and need to combine with other genetic and/or environmental risk factors to cause ASD. Some of these are inherited, but many appear “de novo” meaning that they only exist in the child and not the parents.
  • In the not-so-distant future, we will start to see more comprehensive genetic testing being conducted in the clinic to provide parents with information about whether their child may be at risk for ASD, so they can watch for signs or better understand the cause of their child’s ASD. It will be important to consider carefully what tests are appropriate and interpret them in a manner that is responsible and helpful for parents.
  • Although the fact that so many rare genes can be related to risk for autism seems to form an overwhelmingly complex picture of autism, there is a path forward:  These genes appear to cluster around specific biochemical pathways in the brain and, thus, point to new directions for developing drugs that could potentially help recover function of these pathways. This is good news for families.

Most of all, I see the publication of this report as a celebration of the fruitful partnership between the families and the scientific community. While Autism Speaks staff like Andy and Clara helped create and implement unique and productive scientific endeavors like the AGP, ultimately, it is the families who contributed their time and literally a part of themselves that is helping us put together this puzzle called autism piece by piece.

  1. Mary Beth Miranda
    June 11, 2010 at 8:41 am

    Dear Geri, This is wonderful and interesting news. Thank you, Andy, and Clara and all the other
    unsung heroes that are trying to piece together this intricate puzzle. I’ve never heard of the “de novo” genes and am eager to learn what causes these to appear. Development of drugs that may help recover function of the specific biochemical pathways that autism’s rare genes cluster around is eagerly awaited. Thanks for spelling out the findings in easy to understand laymen’s terms. Mary Beth Miranda

  2. Bob
    June 11, 2010 at 10:52 am

    This is awesome news and this work should be celebrated by all in the autism community. Thank you Andy, Clara & Autism Speaks for beig true to your mission and continuing the genetic research!

  3. June 11, 2010 at 12:43 pm

    Dear Geri,

    The early research results seem to support what I’ve always thought. I’ve always thought that “a switch seems turned off” in the autistic brain. If you could just reach in “and turn the switch on” perhaps the effects would resolve along with the consequences of this disorder. The new terms “de novo” genes means more study and understanding for me. I don’t totally understand it. Are these genes mutated in some way if so by what trigger (environmental? medical?) Why are the genes considered rare when the incidence of autism appears to be rising across the board? I know the answers to these questions aren’t available yet. I had to verbalize them. I have “skin in this game” for my 18 yr old son is affected by this disorder. I’m looking forward to following this ongoing research.

  4. Katie Wright
    June 11, 2010 at 1:29 pm

    These autism families are indeed very generous to donate their time and efforts (it takes real effort to get one’s ASD child’s urine or blood samples). But none of this will stop autism and as we all know it is growing a frightening rate. Biomarkers for testing and early intervention are good things but at this rate autism will be affecting 1 in 50 kids before meaningful progress is made regarding stopping this epidemic.

    AS and the NIH are not placing significant resources in finding out which environmental triggers are causing the gene mutations. The genome route is simply taking far too long. We need to know what tips the risk factors into autism and that can only be done via intense environmental research. Has the genome project helped one child or helped prevent one case of autism? That needs to be our goal and we can only reach it by having the courage to put everything on the table and do it fast vaccine combinations, adjuvants, household toxins…

  5. Ana Maria Aldarondo
    June 11, 2010 at 7:00 pm

    The possibility of developing drugs that can recover the function of biochemical pathways in the brain is something that brings me very real hope. It’s an immense step toward true healing (on multiple levels).
    Thank you to everyone involved in this amazing research. Your work is so very important for the lives of so many.

  6. richard fauth
    June 12, 2010 at 8:11 am

    Mary Beth and Geri: It is wonderfull to hear from folks who get it. Parents and researchers. My son is one of the 1% of children with autism who has a mutation of the shank 3 gene. We are ecstatic about research conducted at Mt. Sinai hospital in NY, Toronto, Paris France, Italy, Philadephia, Germany, and at various centers in the southwest of the usa. The roadmap to real help for our children is getting clearer everyday.

    I still remain mystified by the lack of press and parental response towards these major advancements. The “vaccines and mercury cause autism” crowd continues their louder than all other screams to the world. It is therefore up to us to get the word out so that society responds appropriately and supports the tireless work of these researchers. No longer can the path forward be blocked by support siphoned by a mistaken belief. It is time to get “them” to start screaming to society about the way forward so that real help has the resources needed. Thanks for an encouraging article and Parental response.

  7. June 12, 2010 at 8:34 pm

    Any findings that lead us closer to understanding ASD is great news! I have a question though… are these abnormalities causing the Autism or is the Autism causing the abnormalities? What I mean is do we know why the variations are occuring?

  8. Sarah
    June 12, 2010 at 11:48 pm

    I’m trying really hard not to be terrified, but I’m scared we are entering the world of Gattaca (the 1997 movie).

    I’m convinced that my child wouldn’t have autism if, if, if (very long story deleted – starting at his first trimester, his birth, his food, his chemical exposures, add in where we live, etc., etc.) – If, if, if. All of these ifs combined wrote a terrible story (and continue to write it). Not one trigger, but multiple, multiple, triggers – many of them, on-going.

    You can never convince me that if all these ‘ifs’ weren’t in place – this wouldn’t have happened.

    He is not one of the 10% with chromosome deletions/duplications, he doesn’t have fragile-x or anything else they would have tested for 7 years ago. He has perfectly normal genes that have been sent spiraling by his very polluted “environment,” every step of the way.

    But, for the crime of being born in these decades, in this society (and add in whatever happened to me – e.g., raised on antibiotics, as if they were candy) – his genome won’t be welcomed on earth any longer (or me, my husband, my other child – or all of our relatives)?

    Rachel Carson (“Silent Spring”) was right: we are killing not only the insects, but everyone animal on earth – including ourselves (via a whole host of autoimmune diseases/cancers). And, our society will nail the coffin shut on our genes through genetic testing (and taking out a future version of my husband/other child/nephews/brother-in-law/parents-in-law while your at it. All of whom, the potential future genetic testing would probably whack. Hint: one of the immediate relations has a theorem named after him – and, they all would, if they were all in the exact same field). Does our society really want to kill off these genes? Temple Grandin is right – these genes made the wheel (or something in that vein).

    Please, please, please Autism Speaks – please funnel everything you have to the EARLI study. We, as a society, are not ready to identify the genes. We need to identify the trigger(s). The cart is before the horse, please, please slow down the cart.

    And, while your at it, forget Autism Insurance reform (lobbying dollars spent) – spend that lobbying stream of dollars fighting Monsanto, DuPont, the coal industry, etc., etc. Okay, I’m dreaming on that one. But, it’s a lovely dream.

  9. Christina Glynn
    June 13, 2010 at 12:48 am

    Dear Geri, Thank you for sharing the latest news on the Genome Project. As a parent with a child on the spectrum I have been concerned about the outcome of your research in the area of genetic counseling. Will it lead parents toward the same outcome as the tests for Trisomy 21 (Down’s Syndrome)? Result… Marking risks not for any viable intervention but for elective abortion (or E.T., embryonic termination as the current o.b. lingo goes). Fear would lead many parents in that direction. As you state, “in the not-so-distant future” genetic testing will be a reality in the standard clinic but it may easily become a diservice. You hint at the need to be careful in the application and interpretation of these genetic tests. Hope you can clarify more directly regarding this in future columns or we may be impoverished of many wonderfully unique, gifted people who have ASD. Thank you.

  10. K. Castellanos
    June 14, 2010 at 7:51 am

    Dear Geri,
    As a teacher of ASD children I am jumping for joy because for once I feel hope. I can’t wait for the day my classroom has little or no ASD children. I know it’s a long road ahead for everyone but keep up the great work. God Bless. Thank You

  11. Katie Wright
    June 14, 2010 at 11:16 am

    It is wonderful if this work benefits that 2% of ASD children w/ the gene mutations. In total 4% was found, but the genes were all present of the 2% controls, so the real result is 2%.

    For those of us whose children have nothing unusual about their genes it is hard to feel hope. Yesterday’s NYT had a long front page article on how and why genome science has been a big disappointment for those suffering w/ diseases. Genome science has yet to yield one useful medical intervention over 10 years and a billion dollar investment. The article stressed that we need to find out what is the environment causing the mutations.

  12. richard fauth
    June 14, 2010 at 11:07 pm

    Dear Katie: Your quote “for those of us whose children have nothing unusual about their genes” is the source of your losing hope. “Yet” is the word which is missing. Please re-read what is being found here- dozens of genes in which statistical proof has been established with more being found literally every month. New technology is emerging at an incredible rate which is allowing new discoveries of these mutations, cnv’s and monogene associations. It is the real deal. Look at what is going on with fragile x syndrom-4 completely unrelated drugs in trials-this means a major amount of work is coming to fruition. 22q13 deletion syndrom (now called Phelan Mcdermid Syndrom) wasnt even discovered until 1998- less than three years ago mutations in one of the genes deleted, SHANK 3, were proven to cause autism. 1 month ago it was announced that a drug has been proven to eliminate symptoms of autism in mice with shank 3 mutations. These discoveries prove not only that autism has heritable and de novo genetic roots but the proteins that many of thes genes code for are proteins that make synapses. Autism is now being considered a disease of the synapse. Drugs are being developed that are not only likely to improve the outcomes for children with currently discovered genetic causes but children who have undiscovered causes that affect the same synaptic pathways.

    The test which showed my son has a mutation of the shank 3 gene wasnt even commercially available last year at this time-We currently believe but have not yet even gotten the results to prove it is de novo-yet the real possibility that drugs for treating this disorder may be available in the next few years is happening. Nothing unusual? everybodies genes are differant-we all have 70 to 90 mutations. I note- well over 100 drugs have been discovered over the past decade using one genetic technique alone- the ny times sells papers but the price of the paper does not require losing hope.

    • Christine
      October 17, 2010 at 2:31 pm

      Hi Richard: How did you go about having your child tested? My son is 19 and I would be very interested to see the results of a genetic test. He has Asperger’s Syn., and my hope is that someday, with the right medication, I will see him going out with friends and doing the things that the “average” young man would do. I know the test will not “cure” him, but just knowing a little more of the “why” picture would be nice.
      Thanks for any suggestions you may pass on.

      Christine

  13. RA Jensen
    June 18, 2010 at 1:27 pm

    This study did not use a representative control group. The supplementary data shows that the SAGE control group (N=1880) was comprised of 31% males and 69% females, the complete opposite of the ASD group 4:1 male female ratio. The study did not control for age (as admitted by the authors) nor by IQ.

    http://www.nature.com/nature/journal/vaop/ncurrent/extref/nature09146-s1.pdf

    “1. SAGE cohort: 1,880 control subjects from the larger SAGE case-control study5 were made
    available. The consented sample included 31% males and 69% of females, with mean age of 39.2
    (SD 9.1) and 73% of subjects self-identified as European-American, 26% as African-American
    and 1% as other”

    Males may have a higher rate of risk for germline de novo mutations than females:

    http://www.bioone.org/doi/abs/10.1111/j.1558-5646.2007.00250.x?journalCode=evol

    “In many instances, there are large sex differences in mutation rates, recombination rates, selection, rates of gene flow, and genetic drift. Mutation rates are often higher in males, a difference that has been estimated both directly and indirectly. The higher male mutation rate appears related to the larger number of cell divisions in male lineages but mutation rates also appear gene- and organism-specific”.

    The authors never explain why in heritable cases the parents are unaffected.

    The controls used in this study would be unacceptable if they were used in autopsy studies.

    It is time for the AGP to employ meaningful control groups that control for age, IQ and gender, this study did not meet any acceptable standards for meaningful control groups. Until they do this type of study screams out for invoking the old bromide of “correlation does not imply causation”.

    Aids researchers have identified a single gene CCL31 as representing risk for infection after exposure to HIV. Lower Copy number variations substantially increase the risk for infections after exposure to HIV:

    http://www.sciencemag.org/cgi/content/abstract/1101160v1

    The authors of the Nature study claiming CNV’s ’cause’ autism is as big a stretch as an Aids researchers who would claim that lower CNV’s in the CCL31 gene ’causes’ AIDS.

    • dugmaze
      June 23, 2010 at 10:05 pm

      I don’t think you was supposed to ask real questions. Good job.

    • Sergio
      December 6, 2010 at 2:34 am

      I Do agree.

  1. June 15, 2010 at 4:39 pm
  2. September 13, 2010 at 9:19 am

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