Paul Patterson is an iconic figure in the field of autism.When mentioned in the context of autism his name is synonymous to the possible role of immunological mechanisms. Contrary to other researchers within the field, Paul is what is considered a scientist of «hard data» and a bench top researcher. If you are going to start an argument with him, you better come prepared. He knows both the literature as well as the methodology.
Paul graduated from the Johns Hopkins University in 1970 and went from there to build his academic career at Caltech. In 2005 he was made the Anne and Benjamin Biaginni Professor of Biological Sciences for Caltech. As of this year he is a Professor Emeritus for that academic institution. Paul is now suffering from ill-health and we are all praying for him.
A couple of years ago I approached Paul to see if he could provide some comments to a chapter from a book that I was editing (Imaging the Brain in Autism). He readily agreed and was the first author to provide a contribution to the book. I am copying a few of the paragraphs that he contributed as an opinion piece.
I am looking forwards to many scientific dialogues with my good friend Paul Patterson. We (the autism research community) are all wishing him a speedy recovery.
By Paul H. Patterson, Ph.D.
Talks and papers by geneticists working on autism frequently begin with a variant of the phrase, “autism is a genetic disease”. My understanding of the term “genetic disease” is that it applies to disorders in which a mutation invariably leads to the disease, such as in Huntington’s. Some disorders, such as Fragile X, are monogenic and include features of autism, but the overall phenotype is clearly distinct from idiopathic or sporadic autism. There are also some very rare mutations and copy number variants that cause autism, but these account for only a small fraction of the disorder. This situation has been termed, “The mystery of the missing genes”, or “Where did all the heritability go?”
The assertion that autism is a genetic disease is often justified by a statement that the concordance between monozygotic twins is 90% when one twin is diagnosed with the broader phenotype of autism spectrum disorder (ASD), while the concordance between dizygotic twins is near zero. These numbers are based primarily on older twin studies. However, a new, very large twin study used contemporary standards of diagnosis (ADOS and ADI-R) and came up with rather different numbers. For strict autism, probandwise concordance for monozygotic male twins was 58%, and 21% for dizygotic pairs. For female twins, the concordance was 60%, and 27% for dizygotic pairs. For ASD, the probandwise concordance for male twins was 77%, and 31% for dizygotic pairs. For female twins, the concordance was 50%, and 36% for dizygotic pairs (Konigsmark and Murphy 1972). Not only are the figures for monozygotic pairs considerably lower than older studies, but the concordance for dizygotic pairs is much higher than for siblings (sibling concordance values have ranged from 5% to 18%). These values agree with findings from another very large twin study (Hallmayer et al. 2011), which reported a dizygotic twin concordance of 31% for ASD. The significant discrepancy between ASD risk for siblings versus dizygotic twins leads to the hypothesis that the intrauterine environment plays a key role in the risk for autism. Indeed, recent evidence reveals an association between ASD in the offspring and the presence of inflammatory markers in maternal serum or amniotic fluid (Rosenberg et al. 2009). Moreover, maternal infection during the first trimester increases the risk for ASD in the offspring (Goines et al. 2011).
Another mental disorder that is often cited as being highly heritable is schizophrenia, and here also there is the mystery of the missing genes. Moreover, there are well-documented associations between maternal infection and schizophrenia in the offspring, as well as associations between anti-flu antibodies or cytokines in maternal serum and increased risk for schizophrenia in the offspring (Atladóttir et al. 2010). In fact, extensive epidemiologic work has shown that the effect sizes of various maternal infections are considerably larger than the most studied candidate genes for schizophrenia (Table 1-1). In fact, summing the risks for these various infections suggests that >30% of schizophrenia cases could be prevented if maternal infections were eliminated (attributable proportion calculation) (Brown and Derkits 2009). In further support of the influence of the maternal-fetal environment, indirect evidence indicates that the concordance rate for SZ appears to be much higher for monochorionic twins, which share a placenta, than for dichorionic twins, which do not share a placenta (Brown and Derkits 2009).
Table 1-1 Comparison of the effect sizes for schizophrenia for various maternal infections and candidate genes. Data courtesy of Alan Brown
Maternal infection Odds Genes Odds
Influenza—1st half of pregnancy 3.0 NRG1 1.1–1.2
Toxoplasmosis 2.6 DISC1 1.1–1.2
Genital/Reproductive—periconception 5.3 DTNBP1 0.9–2.7
Respiratory—2nd trimester 2.1 COMT 1.1
MHC class I sequences— SNPs 1.1–1.3
It is important to take these epidemiological findings into account in order to more accurately balance the relative importance of genes and environment in autism. For instance, overstating the importance of genetics has implications for understanding the developmental origins of this disorder. A great deal has been made of findings that many of the genes suggested to be involved in autism code for proteins that function at synapses, and that the excitatory-inhibitory balance is important. How could synapses not be relevant for mental illness? Emphasizing genetics relative to environmental influences has also influenced research funding. Enormous expenditures have been (and are still being) made in the search for the ever-elusive candidate genes, while far less is being spent on the epidemiology of a variety of environmental risk factors and the pathophysiologies underlying them using animal models.
Is it not simply a truism that genes and environment (both surrounding the fetus and encountered later by the offspring) must interact to yield the autism phenotype(s)? This should be reflected in correcting the balance of funding as well as the mislabeling of autism as a “genetic disorder”. Heritability estimates based on out-of-date twin studies should also be revised.
Note: I think that most scientists within the field readily agree with Paul about the overstated importance that genetics has had in autism research. We hope that sometime in the future NIH and other funding organizations realize that their current path of funding is not yielding the desired results.
Addendum: Unfortunately I just found out that Paul passed away at the end of June this year (bit.ly/1qHeyEQ). Truly a remarkable person and a dear friend. He will be missed. I am extremely sad. –I feel incredibly honored that one of the last things he penned in academics, even when sick, was the opinion piece published in this blog.
Cortical Chauvinism 
Hi Manuel Casanova –
Sad news regarding PHP. He was always very quick to send a simple Internet Drone one of his papers when asked.
Heritability estimates based on out-of-date twin studies should also be revised.
Similarly, using twin studies from the 80s and 90s introduces an insidiously subtle confounder; the *assumption* that the past autism was the same thing as today’s autism. Perhaps the older twin studies were valid because *at the time*, the small volume, high penetrant genetic changes were causing most of the autism. Maybe so, but maybe not.
It has occurred to me that *if* the alarming prevalence values we see today are (at least in part), the reflection of a ‘true’ increase, we might need to reconsider some of the basic underpinnings of the ‘improved diagnostic capability’ line of thought, in particular, the idea that what used to be diagnosed as MR three decades ago, was, in fact, autism with another label; i.e., the diagnosticians of the time before got it wrong and we are just now starting to get it correct..
But what if that isn’t exactly right? What if, instead, there have been both reductions in MR, and increases in autism, but it wasn’t an issue of DSM shifts, but rather,of actual physiological differences at brain development time?
For example, there have been some exploratory studies indicating that exposure to car exhaust during gestation could be a risk factor for autism; our existing data in humans is based on where you live(d) in relationship to pollution and is by no means conclusive. But, playing along, we’ve made some pretty big changes in the composition of fuel and the resultant exhaust in the past few decades, most well known is the reduction in leaded gasoline with associated gains in IQ. But we’ve also changed *other* things coming out of tailpipes.
If we have *replaced* an agent known to lower IQ with *different* agents with *different* neurodevelopmental characteristics, how could we tell the difference if our analysis begins and ends by looking at MR diagnosis and autism diagnosis, noting the differing slopes of each over time, and assigning the blame on the failings of psychiatrists from the past? What if the psychiatrists of days gone past weren’t as wrong as we thought they were?
End rant.
RIP PHP
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I answered your comment from the office. I have no idea what happened with my response. My initial comment was meant to say that older physicians were probably more clinically adept than present day practitioners. We presently rely on neuroimaging modalities and sophisticated laboratories to make a diagnosis. Several decades ago the only thing available was clinical acumen. Making a diagnosis based on behavioral traits was an art form. The clinical notes were spectacular back then. I do not believe that diagnostic substitution is adequate to explain the prevalence. I am very interested in your proposal about a see saw phenomenon between MR and ASD. What could account for the same, it is something to ponder.
As an aside, I used to meet with Paul each year at IMFAR and catch up with his more recent experimental results. He never force fed them to you. I shot him down on a couple of occasions (regarding the pathology of his animal model). He was completely open minded and took criticisms and new findings in stride. His only concern was science not egos. A rare individual in today’s marketable research environment.
Well now I end my own rant. Thank you for posting.
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As far as twin studies are concerned, no autism twin study had ever investigated the concordance rate for autism of MZ twins segregated by chorion type, monochorionic (single placenta, same prenatal environment) vs dichorionic (separate placenta, different prenatal environment). Studies have shown that MZ concordance rates for personality features and schizophrenia vary significantly by chorion type:
http://www.ncbi.nlm.nih.gov/pubmed/7481567
http://www.ncbi.nlm.nih.gov/pubmed/7487842
As far the missing heritability is concerned the problem is the current thinking that autism is dimensional rather than being categorical. I view the genetic influences underlying autistic-like traits as being dimensional, common and widely distributed throughout the general population but strict autism is categorical. The genes underlying autistic traits are a background genetic effect that is always reliant on other genetic, environmental and/or epigenetic risk factors that cumulatively increase total risk in any individual case. Find the genes underlying autistic traits and you will find the ‘missing’ heritability.
http://www.ncbi.nlm.nih.gov/pubmed/11079353
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Thank you for the comments. Would you like to expand on your comments and make them into a full blog? I would be happy to post them along with some biographical information about yourself.
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Thanks Dr. Casanova,
I have been working on this for some time and in a few months may have something worth publishing. One of the first so-called ‘autism’ genes discovered are polymorphisms in the serotonin transporter gene. The human serotonin transporter gene is located on the long arm of chromosome 17 (17q11.2) and encodes for the serotonin transporter that is involved in the communication between neurons. In the human population, the frequency of the long allele (LL) of 5-HTT is approximately 57%, while that of the short allele is 43% (Danielle et al 2011). The short allele is the most referenced polymorphism that has been described as an ‘autism’ gene. The problem with autism researchers is that they are only looking at patients with autism and draw a false conclusion. The polymorphisms in the serotonin gene can be more robustly described as a polymorphism associated with increased rates of autistic traits or the broad autism phenotype, not strictly diagnosed autism. The SS serotonin transporter gene, SLC6A4, has been associated with social and nonsocial phenotypes typically described in broad autism phenotype symptom array including high rates of autistic personality traits, depression, obsessive compulsive traits, rigid behavioral traits, irritable bowel syndrome and eating disorders.
The short allele in the serotonin transporter gene can’t be an ‘autism’ gene since it is present in 43% of the general population. Conceptually it is a broad autism phenotype common polymorphism that runs straight through the general population in affected and unaffected populations. The SLC6A4 polymorphism is a background genetic effect that is always reliant on other genetic influences, environmental risk factors and/or epigenetic events that cumulatively increase total risk for strictly defined autism
http://iv.iiarjournals.org/content/25/6/895.full.
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You have already acquired a lot of knowledge and could write quite a sophisticated book on the subject (seriously consider Jessica Kingsley publishers). For the purpose of the blog I would recommend toning it down and focusing on one or two issues that you may think of importance.I am looking forwards to your blog.
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I think we may be wasting our time looking for a cause for most causes of autism.It’s «autisms» not «autism». I think my case is kind of interesting.It has taken me five years of tests and going from one doctor to another to get to where I can find an underlying cause or two for my autism.As of right now,I am looking at a dual diagnosis of a type of Severe MTHFR or Severe 5-MTHF Deficiency,and Complex I and Complex IV mitochondrial disease.I am able to document problems in my mother’s family related to folate metabolism,and mitochondrial disease over four generations.Disorders of folate transport and metabolism,in particular,are very heritable,and can span generations in families.Perhaps you could tell me why mutations in folate cycle genes is not considered more as a genetic cause for both autism and schizophrenia?
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Thank you for your personal observations. As always very insightful.
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