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The key belief of the modern antivaccine movement over the last two decades has been that vaccines either cause, contribute, or predispose children to autism. Although this particular belief is generally believed to have originated in 1998 with the publication of disgraced physician and scientist Andrew Wakefield’s case series of 12 children that reported an association between vaccination with the measles-mumps-rubella (MMR) vaccine and autism and was published in The Lancet , the idea predates Wakefield’s fraudulent publication. After all, a lawyer paid Wakefield handsomely to do “research” that he could use to sue vaccine manufacturers on behalf of parents of children with autism. Wakefield’s case series was ultimately retracted due to findings of scientific fraud and Wakefield’s medical license taken away, but it didn’t matter. The idea that vaccines cause autism is the most prevalent antivaccine misinformation that fuels the movement, and Wakefield still milks it, having produced with Del Bigtree an antivaccine propaganda movie disguised as a documentary, VAXXED .

The idea is not just limited to the MMR vaccine, either. Another strain of antivaccine belief attributes autism to the mercury in the thimerosal preservative that was used in many childhood vaccines until 2001, while others claim it’s “too many too soon,” and still others blame DNA fragments in vaccines crossing the blood-brain barrier and causing neuroinflammation. Many are the vaccines blamed for autism, and many are the bogus proposed biological mechanisms by which vaccines supposedly “cause autism”, but in the end it’s always about the vaccines. Always. Antivaxers deny that autism has a major genetic components, and, even when they do conceded a genetic component, try to divert to claiming that it’s a “genetic susceptibility” to “vaccine injury” that is responsible for autism, not primarily genetics.

All of this is why antivaxers generally lash out whenever a study comes out that reports a large genetic component to autism and autism spectrum disorders. This happened just last week, as the largest study of its kind, encompassing five countries and two million subjects was published last week and concluded that autism spectrum disorders are 80% reliant on inherited genes. Before I get to the study itself, here’s how it was reported in WebMD:

The findings could open new doors to research into the genetic causes of autism, which the U.S. Centers for Disease Control and Prevention now says affects 1 in every 59 U.S. children. It might also help ease fears that autism is caused by maternal factors — a mother’s weight, mode or timing of delivery, or nutrient intake, for example. The new study found the role of maternal factors to be “nonexistent or minimal.” Instead, “the current study results provide the strongest evidence to our knowledge to date that the majority of risk for autism spectrum disorders is from genetic factors,” said a team led by Sven Sandin, an epidemiological researcher at the Karolinska Institute in Stockholm, Sweden. The new study might help dampen public interest in supposed — but unproven — “environmental” causes of autism, such as vaccines. Long-discredited, fraudulent data linking childhood vaccination with autism is still widely cited by the “anti-vaxxer” movement.

I fear that last part is pretty much wishful thinking. Whenever a new study provides evidence for a genetic cause of autism, antivaxers tend to double down and attack the study. Will this study withstand the attacks? Scientifically, probably (as I’ll explain in a moment), but in the vaccine PR wars? Who knows?

Genes, not environment, are the primary driver of ASDs

The study under discussion, “Association of Genetic and Environmental Factors With Autism in a 5-Country Cohort“, was published online in JAMA Psychiatry on July 17 by a multinational group of researchers led by Sven Sandin, an epidemiologist at the Karolinska Institute in Stockholm, Sweden. The investigators set the stage in the introduction thusly:

Autism spectrum disorder has both genetic and environmental origins. Research into the genetic origins of ASD has consistently implicated common and rare inherited variation (heritability). However, evidence shows that there are other, noninherited, genetic influences that could be associated with variation in a trait.3 Given the prenatal origins of ASD, an important source of such genetic influences could be maternal effects.4 The term maternal effects is used to describe the association of a maternal phenotype with ASD in offspring (ie, the noninherited genetic influences originating from mothers beyond what is inherited by the offspring). Maternal effects have been associated with a substantial proportion of the variation in several traits associated with ASD, including preterm birth5 and intelligence quotient.6 Research on nongenetic origins has frequently pointed to a role for environmental exposures unique to different family members (nonshared environment), an example of which is cesarean delivery.7 In contrast, contribution from environmental exposures that make family members similar (ie, shared environment), has been uncertain.8 A meta-analysis of twin studies estimated heritability to be in the range of 64% to 91%,8 and 3 population-based studies from Sweden recently estimated the heritability of ASD to be 83%,9 80%,4 and 66%. 10 Among those earlier heritability calculations from twin and family studies (eTable 1 in the Supplement), a single study has estimated maternal effects,4 reporting modest, if any, contribution to ASD. Estimates of the contribution of shared environment range from 7% to 35%,8 but multiple studies estimate the contribution to be zero.4,9,11,12 Thus, although the origin and development of ASD has been investigated for half a century, it remains controversial.

I can’t help but note here that, although there is controversy, most of the estimates cited fall within a fairly narrow range, which makes me think that how much genetics contributes to the development of ASDs is really not that controversial. Be that as it may, I do feel obligated to briefly discuss one point here before I dig into the meat of the study, and that’s to answer the question, “What do we mean by ‘genetic’?” The general public, given how these sorts of issues are reported, often tends to think that “genetic” means that there is a single gene (or a handful of genes) responsible for a trait, disease, or condition. That is, of course, very simplistic. While there are traits and diseases that can be determined by a single gene, most complex traits depend upon many genes and can be affected by many variants of those genes. What studies of this sort estimate is how much autism susceptibility is due to heritability. The other thing that you need to know is that, for purposes of this sort of model, maternal and environmental factors that impact autism risk are basically everything else that is non-heritable. We’ll come back to this point later.

So here’s what the investigators did. They examined the medical histories of more than two million children born in singleton births in Denmark, Finland, Sweden, Israel, and Western Australia between 1998 and 2012. For Sweden, Finland, and Western Australia, investigators included all births between January 1, 1998, and December 31, 2007, while for Israel they included all births between January 1, 2000 and December 31, 2011. All were tracked for a diagnosis of ASD from birth up to December 31, 2014, in Sweden; December 31, 2013, in Denmark; December 31, 2012, in Finland; December 31, 2014, in Israel; and July 1, 2011, in Western Australia. Children were followed until age 16. Denmark, Finland, Sweden, and Israel provided clinically ascertained diagnoses from national patient registers while the data from Western Australia was obtained from a government provided service and benefits register with clinically ascertained autism diagnoses. Of the cohort, 22,156 went on to be diagnosed with an autism spectrum disorder, for a prevalence in the group of 1.1%. Data were analyzed from September 23, 2016 through February 4, 2018.

As you might expect, the authors used Generalized Linear Mixed Effect Models (GLMM) to estimate genetic and environmental effects on the risk for ASD and autistic disorder (AD), using the three-generational data sources in the databases examined to construct families that vary by genetic relatedness and therefore are informative for genetic modeling. These included full siblings and cousins related through their mothers (maternal parallel cousins [mPCs]), or cousins of other relationships. To be honest, I’m not a statistician, which places the nitty-gritty of the statistics mostly beyond me. (If a statistician wants to chime in in the comments, I try never to be too proud do learn something. As Harry Callahan said in Magnum Force , “A man’s got to know his limitations.”)

The key findings of the study were as follows:

The median (95% confidence interval) ASD heritability for the whole cohort was estimated to be 80.8% (73.2%-85.5%).

For the Nordic countries combined, heritability estimates ranged from 81.2% (73.9%-85.3%) to 82.7% (79.1%-86.0%).

Country-specific heritability estimates ranged from 50.9% (25.1%-75.6%) (Finland) to 86.8% (69.8%-100.0%) (Israel).

Maternal effect was estimated to range from 0.4% to 1.6%, and in all models used the 95% CI interval included zero, meaning that the estimates for maternal effects were not distinguishable from zero, leading the authors to conclude that there was no support in their models for a significant contribution from maternal effects. (The term maternal effects is used to describe the association of a maternal phenotype with ASD in offspring; i.e., noninherited genetic influences originating from mothers beyond what is inherited by the offspring). The authors note that maternal effects have been associated with a substantial proportion of the variation in several traits associated with ASD, including preterm birth and intelligence quotient.)

Estimates of genetic, maternal, and environmental effects for autistic disorder were similar with ASD.

The authors did a variety of sensitivity analyses to determine if changing their inputs had a major effect on the estimates, and the estimates remained pretty solid. The authors note the following strengths in their study:

The major strength of this study is the use of multiple large population-based samples with individual-level data in 3-generation pedigrees. Our data were based on prospective follow-up and health systems with equal access. This approach, following all participants from birth using population registers, avoids bias owing to self-report and retrospective collection of data and reduces selection biases owing to disease status or factors such as parental education. In addition to providing exceptional statistical power, the study directly addresses the concern of lack of replication in research findings31,32 replicating results across 5 countries and health systems.

And limitations:

Our study has several limitations. Despite its large overall sample size, the effective sample size for individual countries was limited by the low prevalence of ASD. Misspecification is another potential limitation. The first potential misspecification arises from the possible violation of the assumption of independence between genetic and environment. If this correlation is not specifically included in the model, its components will mostly be incorporated into the estimate of genetic variance component, potentially biasing the heritability estimate. The direction of the bias will depend on the sign of the covariance between genetic and environmental factors.36 The second misspecification arises from plausible gene-environment interactions that were not modeled and could also bias the heritability estimate. The direction of bias will depend on whether the environmental component is familial and whether the trait is multifactorial.36

Of course, in the case of autism and ASDs, what those “plausible gene-environment interactions” might be is rather unclear. Of course, predictably, antivaxers latched on to that one issue, as you will see. Before I get to that, though, let’s look at the accompanying editorial, “The Architecture of Autism Spectrum Disorder Risk: What Do We Know, and Where Do We Go From Here?” by Amandeep Jutla, Hannah Reed, and Jeremy Veenstra-VanderWeele, which notes:

The study by Bai et al1 elegantly summarizes and confirms, using the largest data set to date, a key truth about ASD’s risk architecture: the disorder is strongly heritable, with environmental factors, although important, contributing relatively less to its variance than genetic factors. Where do we go from here? One clear next step is to disentangle ASD’s heritability into components that can be identified in ever-growing molecular genetic data sets. The most robust data in ASD implicate de novo copy number variants and rare, de novo single-nucleotide variants in at least 99 genes,6 many of which are involved either in synaptic signaling or regulating expression of other genes, which suggests convergent pathways. Importantly, in a twin study, these noninherited (de novo) variants would be shared by a monozygotic twin pair but not dizygotic twins and would therefore contribute to an estimate of genetic risk. In a family study such as this one,1 these de novo variants are not captured in the estimate of genetic risk because they are not shared between nontwin family members. These rare mutations would instead land in the remaining variance not accounted for by either inherited genetic or shared environmental risk.

Of course, if it is true that de novo (new noninherited) gene variants play a significant role in the pathogenesis of autism and ASDs and, in this analysis, would show up in the nonshared environmental risk component, then it’s possible, even probable, that the genetic contribution to ASD was actually underestimated in this study. Jutla et al also note:

The contribution of the environment to ASD risk appears to be much smaller than the contribution of genetics, yet potential environmental risk factors often receive disproportionate attention from the public and the media, even when (as in the case of vaccine fears) they are debunked. Perhaps this is because environmental risk factors, at least in principle, are modifiable. Even with a smaller contribution to risk, it is worthwhile to enrich understanding of environmental risk factors, which remain relatively understudied.10 Some identified risk factors, such as preterm birth or birth complications,4 are already targets of public health efforts for other reasons. Others, such as a shortened interpregnancy interval or an infection during pregnancy,4 may also be modifiable if the underlying risk mechanisms can be better understood.

Ironically, one of those potentially modifiable environmental factors is congenital infection with rubella, which greatly increases the risk of autism in the child and is, ironically enough, preventable with vaccination of the mother with MMR. In any event, here’s the problem with the assertions above. To antivaxers, the top “environmental risk factors for autism” = vaccines, vaccines, vaccines, vaccines, vaccines, and then everything else. (Actually, perhaps I should have repeated “vaccines” ten times instead of five.) Indeed, I’ve said in the past that one additional harm caused by the antivaccine movement other than depressing vaccine uptake and thus making various populations susceptible to outbreaks of vaccine-preventable diseases, is that their fanatical belief that vaccines cause autism (1) has diverted funding and research effort to repetitive studies looking at correlations between vaccines and autism and (2) might have made researchers more reluctant to study potentially plausible environmental risk factors for autism because of the association with antivaccine pseudoscience and, of course, the inevitable attacks on them when they find potential environmental risk factors for autism that antivaxers don’t like (anything not vaccines).

A final issue noted in the editorial is that, although the population studied was geographically diverse, it was not as ethnically diverse as one would like. In addition, the smaller sizes of the Israeli and Australian populations studied hamper a clear understanding of whether contributions to ASD risk may differ geographically, leading as they did to higher variability in the estimate of the genetic contribution to ASDs and autism in those countries. I thus agree that it’s unlikely that the estimates for genetic risk will become much more precise with additional family studies, but I also agree that it “would be useful for the findings to be replicated in non-Western or more ethnically diverse countries”.

Antivaxers counterattack

Not surprisingly, antivaxers do not like this study. The reason they don’t like it is because it is practically gospel among them that autism and ASDs are not primarily genetic conditions, but rather caused mainly by environment, specifically vaccines, although they frequently obfuscate by attributing the conditions to vaccines and “other environmental influences” and “toxins”. Also not surprisingly, first out of the gate (that I could find, anyway) to attack the study was James Lyons-Weiler. We’ve met him before when he tried to attribute the death of a teenage boy to Gardasil. The sad thing is that Lyons-Weiler was once an actual reputable scientist (or at least not, to my knowledge, a disreputable one) who during his pre-antivaccine career directed two different bioinformatics cores, one at the University of Massachusetts in Amherst and the other at the University of Pittsburgh, the latter of which closed in 2014. Since then, he’s gone all-in on antivaccine pseudoscience, even going so far as to form an institute he dubbed the Institute for Pure and Applied Knowledge (IPAK), which is about as arrogant-sounding a name for an institute as I’ve ever heard. IPAK isn’t just into antivaccine “science”, but that does seem to be its primary focus compared to others. Since then, Lyon-Weiler’s been battling it out with Leslie Manookian for the title of Most Antivaccine, appearing on antivaccine panels with Del Bigtree, Gayle DeLong, Sherri Tenpenny, and Toni Bark, and, it appears, helping antivaccine pediatrician Paul Thomas carry out a “vaxxed vs. unvaxxed” study.

Lyons-Weiler thus knows a lot, and he really should know enough to know that the complaints he has about the study are mostly irrelevant, save one, which was explicitly and openly acknowledged by the study’s authors. However, something about going antivaccine leads once competent scientists to embrace analyses that in their past lives they would have recognized immediately as nonsense. None of that stopped Lyons-Weiler from entitling his blog post “Yet Another Highly Unethical and Socially Irresponsible “Genes-Only” Study Fails to Show that Autism is 80% “Genetic”” and run with it. Oddly enough, he harps mainly on the WebMD article that I discussed above, rather than the actual study:

The article skips over the fact that the newest, latest study, like the prior studies, fails to actually measure the contribution of a single environmental factor. While the article rails against “anti-vaxxers”, the study ignores the vaccination status of those involved in the study. The mantra of so many studies never showing association has be tempered with a mature, responsible and realstic interpretation in the context of how those studies were conducted: restricted to one vaccine (MMR), and then there is this:

I found it amusing that he repeated one of his criticisms of autism-gene studies twice. As for the Bonferroni correction, I’m not sure why he’s harping on that in the context of the Generalized Linear Mixed Effect Models. The Bonferroni correction is used for much simpler models than this. Actually, the whole thing is rather confused, a list of things that he thinks studies should do (Bonferroni correction) and that they do that he doesn’t like (analyze the data repeatedly until the effect “goes away”). Of course the latter of those two examples reveals shocking statistical ignorance, as quite frequently, raw data reveal an effect that turns out to have been spurious when adjustments are appropriately made for confounding factors. Apparently, like Brian Hooker, Lyons-Weiler prefers the simplicity of the raw, unadjusted analysis that doesn’t control for confounders and provides false positive associations between vaccines and autism.

Next up, Lyons-Weiler asks a question all scientists love: “Why didn’t you study and measure what I think you should have studied and measured?” Here’s what I mean:

Their entire methodology is based on familial correlations. In the current study under consideration, no exposure levels to pesticides, medical exposures in utero, smoking history, nothing environmental was measured. And yet somehow the study authors pretend they can estimate the % liability from environmental factors. How do they pretend to achieve such a feat?

This is just a diversion. Remember, if you accurately estimate the percentage of risk that is genetic, then whatever’s left over must include the environmental risk factors. You don’t have to measure exposure to each and every potential environmental risk factor.

Lyons-Weiler does make one valid criticism, but, as is his wont, he drives off the cliff of ridiculousness with it and fails to note that the authors themselves listed this as a limitation of their study, namely that there could be interactions between genetics and environment. Naturally, he assumes that these interactions would overwhelm the genetics component:

And if the interaction term “(Genetics + Environment)” is more highly significant than “Genetics” or “Environment“, a reasonable interpretation would be that we cannot interpret genetics in a vacuum, that the significance of many ADK risk alleles must be modified by environmental factors. If during model selection, G or E is significant, but then in the full model G x E is significant, we attribute liability to both G and E working together.

Of course, the problem is that we don’t know the size of this term, and it would have to be pretty darned large to push the genetics-only risk factor down to the second or third most important risk factor. We have no good evidence that this is likely, and, if you click on the review article cited, you’ll find that the examples cited by Lyons-Weiler are all supported by small studies, the largest of which had only 408 subjects. It’s wishful thinking to believe that these potential examples are going to overshadow the contribution of genetics to overall risk of autism and ASDs.

Lyons-Weiler then continues:

There are over 850 genes that have been determined to contribute to ASD risk – and not one of them explain >1% of ASD risk individually. Most of these are Common Variants – meaning they are ancient – as in, they pre-date both the ASD epidemic (and yes, there is an epidemic) and vaccination.

Here, he appears to be either falling prey to the simplistic idea that there must be “a” gene for autism or counting on the likelihood that antivaxers reading his screed won’t know that complex conditions and traits are often impacted by many genes, any one of which has little effect. Surely he knows this if he ran bioinformatics cores until 2014, and if he didn’t then he shouldn’t have been running those cores.

Now here’s the part that made me laugh out loud:

The study ignores the fact that environmental factors can impact genes, proteins and biological pathways in a manner that is identical to the effects of genetic variation. This is called Phenomimicry – a term so cool I wish I had invented it. Examples of Phenomimicry are known in science relevant to ASD.

Phenomimicry, if it exists, would indeed be a cool biological phenomenon, but basically here Lyons-Weiler is speculating wildly, pulling something out of his nether regions and using its lack in the study as a cudgel without telling us any plausible scientific rationale why the study authors should have even considered phenomimicry. It’s also a term that, as far as I can tell from Pubmed and Google, is only used by one person, Dorothy V.M. Bishop and is not a generally accepted concept. A PubMed search turns up only one article by Bishop using the term and Googling only turns up mainly articles referring to Bishop’s article.

Lyons-Weiler gives up the game not long after that:

It is highly unethical – and socially irresponsible – for “Genes-only” studies to be conducted that claim to rule out environmental factors. All “Yet Another Highly Unethical Genes-only Study”s – YAHUGS – should be replaced with fully and correctly specified models – that means measuring and studying both vaccination patterns and genetics.

See what I mean? To antivaxers “environmental risk factors” = vaccines, first and always. Whatever the strengths and weaknesses of the current study, the reason Lyons-Weiler doesn’t like it is because it doesn’t consider vaccines (why should it, given the mountains of epidemiological evidence that show no association between vaccination and autism risk?) and concentrated on genetics. Remember that.

The genetics of autism

None of this is to say that this and all the other studies examining the genetics of autism are without problems. Autism and ASDs represent a spectrum of neurodevelopmental disorder impacted by many genes. Teasing out which genes and combinations of genes are most important in determining autism risk is incredibly difficult, as is the case for any complex multigene condition. I’ll even concede that sometimes scientists go too far in touting gene association studies. However, this study was not a gene association study, but rather the largest study to date to estimate how much of the risk of autism is genetic. As such, it produced an estimate that is in line with previous estimates and strengthens the scientific conclusion that autism is mainly heritable, with an effect on risk due to environment that is much smaller and, however large it actually is, not due to vaccines.