Thomas Insel: The New Genetics of Autism – Why Environment Matters

4 Apr

Thomas Insel is the director of the National Institute of Mental Health (NIMH) and the chair of the Interagency Autism Coordinating Committee (IACC) in the U.S..

His article can be found here (The New Genetics of Autism – Why Environment Matters) and I have quoted it in full bellow. (As a government publication I feel that it is appropriate to use the entire piece):

Last week’s autism news was about prevalence. The CDC reported a 78 percent increase in autism prevalence since 2002. This week’s autism news is about genetics—three papers in Nature describe new genes associated with autism. For many people, these two stories seem contradictory or, at best, unrelated. Increasing prevalence suggests environmental factors like chemicals and microbes changing over the past decade, whereas genes change over generations. Why is anyone looking for genetic causes when there is such a rapid increase in prevalence? Shouldn’t every research dollar be invested in finding the environmental culprit rather than searching for rare gene variants?

The simple answer is that some autism is genetic. Autism, like schizophrenia and mood disorders, includes many syndromes. Indeed, we should probably speak of the “autisms.” Some of these autisms are single gene disorders, such as Fragile X, tuberous sclerosis, and Rett syndrome. While these rare genetic disorders account for less than 5 percent of children within the autism spectrum, children with any of these disorders are at high risk for autism, roughly a 30-fold higher risk than the general population and higher than any of the other known risk factors. Recent genomics research has discovered that many children diagnosed within the autism spectrum have other genetic mutations that have not yet been designated as named syndromes. Each of these mutations is rare, but in aggregate they may account for 10 – 20 percent or more of what we have been calling the autisms.1

The new papers published today in Nature use an approach called whole exome sequencing, mapping every base of DNA across the exome—the 1.5 percent of the genome known to code for protein. The three research groups are members of the Autism Sequencing Consortium (ASC), an international team of autism genetics researchers. All three look for de novo or spontaneous mutations, changes in DNA sequence that are not found in either parent. Recent sequencing studies in the general population have demonstrated that each of us diverges genomically from our parents — the process of reproduction introduces variation even beyond the random mixture of the genomes we inherit from mom and dad. People with autism and schizophrenia are far more likely to have large de novo copy number variants, sometimes a million bases of DNA that are abnormally duplicated or deleted and not found in either parent.
These new papers go beyond the previous discovery of de novo copy number variants to identify de novo single base changes associated with autism. This is tough sailing because there are so many of these changes in all of us and most of these single base changes have no impact. These studies tried to improve the odds of success by focusing on individuals from families with no one else affected (these are called “simplex” families), and sometimes comparing the individual with autism to a sibling without autism. The results are intriguing.

There is no breakthrough or single gene that is a major new cause of autism. But the role of genetics becomes even more evident when these single base changes are considered. For instance, an individual with autism is nearly 6-fold more likely to have a functional variant in genes expressed in the brain. Sanders et al. estimate as many as 14 percent of affected individuals have such a risk variant.2 This 14 percent is in addition to the 10–20 percent with a large copy number variant or identified genetic syndrome. O’Roak et al. find that 39 percent of these variants are related to a specific biochemical pathway, important for brain signaling.3 And Neale et al., while cautioning that the net effect of all of these changes still leave much of the risk for autism unexplained, note the roles of a few specific genes as genuine risk factors.4

Stepping back from this flood of genomic information, what is most important? First, these reports along with previous publications confirm that genetic risk is both complex and substantial. While individual genes appear to confer limited risk, the aggregate effect of spontaneous coding mutations across the genome is now estimated to increase the risk of autism by 5–20-fold.4 Complex genetics does not mean modest effects.

Second, the kinds of small and large genetic changes associated with autism are common in everyone. Risk is conferred not by the size of the mutation or the number of mutations (we all have many) but by the location. Increasingly, we see that interference with the genes involved in development of synapses confer risk; a similar change upstream or downstream does not.
A third point takes us back to the questions we started with. It is important to understand that de novo mutations may represent environmental effects. In other words, environmental factors can cause changes in our DNA that can raise the risk for autism and other disorders. One of these papers reports that spontaneous changes are four times more likely to show up in paternally inherited DNA and are correlated with paternal age.2 The father’s germline, his sperm cells, turn over throughout the lifespan. Presumably, with advancing paternal age, there are a greater number of spontaneous mutations and a greater likelihood that some of these will affect risk genes. Environmental factors and exposures can cause sperm cells to develop mutations that are not found in the father’s somatic, or body cell, DNA, but these new, spontaneous mutations can be passed to the next generation, raising the risk for developing autism. In the initial report of the relationship between autism and paternal age, boys with autism were 6-fold more likely to have a father in his 40s vs his 20s. In girls with autism, this difference went up to 17-fold.5 Paternal age has, of course, increased in the past few decades. This does not explain the increasing prevalence of autism, but it may contribute.

Is autism genetic or environmental? These new studies suggest it can be both. Genetics will not identify the environmental factors, but it may reveal some of the many syndromes within the autism spectrum (as in other neurodevelopmental disorders), it can define risk (as in other medical disorders), and it should yield clues to the biology of autism (revealing potential targets for new treatments). These three new papers on spontaneous mutations are an important milestone in a long journey. In parallel we need to find environmental factors, recognizing that there will be many causes for the autisms and many roads to find them.

Finally, an unavoidable insight from these new papers is that autism even when genetic may be spontaneous and not inherited in the sense that one or both parents carry some reduced form of the syndrome. Perhaps this insight will finally reduce the “blame the parents” legacy perpetuated for too long in the absence of scientific evidence.

1Geschwind DH. Genetics of autism spectrum disorders. Trends Cogn Sci. 2011 Sep;15(9):409-16. Epub 2011 Aug 18. PubMed PMID: 21855394.1
2Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. April 5, 2012. Nature.
3O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. April 5, 2012.
4Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shair K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 5, 2012.
5Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, Rabinowitz J, Shulman C, Malaspina D, Lubin G, Knobler HY, Davidson M, Susser E. Advancing paternal age and autism. Arch Gen Psychiatry. 2006 Sep;63(9):1026-32. PubMed PMID: 16953005.

10 Responses to “Thomas Insel: The New Genetics of Autism – Why Environment Matters”

  1. Dee April 8, 2012 at 00:20 #

    Love this. To add to it, the Fragile X premutation is also responsible for a genetic pathway to autism with an environmental trigger. In our family’s situation, my son’s premutation coupled with his MTHFR mutation provided the landscape for an environmental trigger to cause a regressive case of autism. Fortunately because the pathway is known, we have several treatment options and can somewhat reverse the damage caused to his RNA and neurology, which left untreated leads to seizures and Parkinson’s.

  2. McD April 8, 2012 at 01:38 #

    This is a great overview. Understanding causes has really come a long way since my boy was diagnosed. Between Insel’s overview, and Landrigan’s recent review a lot of ground has been covered:
    (Whole paper is posted here: )

  3. stanley seigler April 8, 2012 at 03:19 #

    @McD: This is a great overview. Understanding causes has really come a long way…

    has support programs come a long way as well…granted understanding is necessary and has come a long way…but has added complications…ie, spectrum v. classic kanner autism apple orange discussion…


    how has understanding causes improve acceptance of those with autism…

  4. Dee April 8, 2012 at 05:12 #

    @Stanley… I understand what you are saying… ” how has understanding causes improve acceptance of those with autism…”
    It hasn’t… Hopefully however, advocates voices are beginning to turn the tide in understanding demonstrated in the latest post on this blog.

    However understanding causes and the direct money that Autism Speaks has put into these issues has directly affected my life and my son’s life. Because of their funding of Dr. Hagerman’s work on Fragile X premutation, my son is getting treatment for his condition. This lowers his risk for seizures, Parkinson’s and FXTAS in addition to helping his GI issues (very painful for him) and his neurological dvelepment (he is three).

    I know this is not what you and others want to hear, but autism is not simply a social disability. It’s also a medical condition and science is beginning to understand cause and pathways in a manner that relieves suffering. The idea of acceptance should not be incompatible with understanding, science, and treatment… If it continues to be represented in a manner that excludes discussion about cause, treatment, prevention and recovery for all of the autisms… It will be a movement based on conviction, righteousness, and ignorance.

    I don’t mean for these words to be that strong… I’m trying to get my point across without offending… Truly…

    But my son deserves treatment for his condition. It is toxic and progressive. Because of autism advocacy I have learned much about accepting who my son is as he is treated… At the same time the idea that autism is one thing, one locked, in-born, neurological pattern, predetermined and defined and any treatment of this neurological difference is not accepting the person…this is simply a false ideal of autism. This post above demonstrates this.

  5. McD April 8, 2012 at 10:33 #

    @stanley I agree with you. Completely. I feel like I am banging my head against a brick wall as I try to get services for my boy.

    I don’t see what that has to do with the science. The people who allocate services in my country appear to be completely resistant to evidence in any area. Short-term cost-cutting seems to be their guiding principle. False economy, as they look at costs to the Ministry of Education, but do not consider the much greater costs across the life span incurred by the Ministry of Social Welfare when potential taxpayers are left as life-long beneficiaries in the absence of early behavioural intervention.

    I certainly do not rely on the validation of these people as part of any assessment of new studies.

    As much as I am personally pleased at the new findings, I have not seen any great improvement in services, and I don’t think anyone has claimed anything of this nature, or even that this would happen. I may be autistic, but I am not Pollyanna.

    * On re-reading I have replaced the term ‘dickheads/those dickheads’ which appeared at some points, with the more neutral terms ‘people’ and ‘they’.

  6. stanley seigler April 8, 2012 at 18:50 #

    @Dee, McD

    i agree with you…to repeat, maybe clarify, my concern.

    i see a disproportional allocation of funds (tho neither, research/support funding, is adequate)…advocates (eg, AS) seems to perseverate on cause/cures…guess the scientist writes better grant proposals than the support program provider…

    BTW is there still research re the VAX link to autism…funding for some scientific research better spent on quality, effective, support programs.

    my comments are mostly based on my understanding of funding by, eg, AS and M.I.N.D

  7. Dee April 9, 2012 at 23:25 #

    @Stanley- all you say is too true. Thanks for clarifying and I’m sorry for my defensiveness.

  8. Roger Kulp April 17, 2012 at 03:53 #

    I hate to revisit the old argument from the Hannah Ploing kerfluffle,but is metabolic disease counted as a “cause” of autism.I am particularly talking about my recent diagnoses of a combined cerebral folate deficiency,like the one described here

    Click to access mp2011175a.pdf

    and a form of folate transport based autoimmunity.(Autism AND autoimmune disease that responds to high dose Leucovorin.)

    Or is something like this so rare,it is barely a blip on the radar? My diagnosis was a combination of a more severe PDD-NOS,or “atypical autism”,and a severe NVLD.

    Even in cases like this,where you work and work,and finally find a main cause,there are all kinds of hits on multiple genes.Multiple polymorphisms,partial mutations that you need to look into,to see what is the cause,and what is just distracting “noise”.

    • Sullivan April 17, 2012 at 18:10 #

      Roger Kulp,

      here is an article you might be interested in Workshop report: Regression in autism

      This quote in particular:

      Metabolic disorders can also be associated with autism and present as a regression of abilities. Cerebral folate deficiency and mitochondrial disorders both have symptoms similar to autism, but are treatable.

      I expect that quote to generate some negative discussion, by the way.

  9. usethebrainsgodgiveyou June 25, 2013 at 15:24 #

    Genetic testing is now often covered by insurance. Against my husbands wishes, I may be taking Ben here:” Dr. John Shoffner recognized as a Leader in Neurogenetics Disease Research;” Ten years ago, some birth marks concerned the R.N. who evaluated Ben at the USC CARE center in Columbia, SC. We were sent for genetic testing…we could only afford Fragile X as it was out of pocket at that time.

    This post is helpful. As much as I try to see the possibilities of woo, I hope for the possibility of science.

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