Environmental influences on autism – splashy headlines from dodgy data

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A couple of recent papers have been making headlines in relation to autism, one claiming that it is caused less by genetics than previously believed and more by the environment and the other specifically claiming that antidepressant use by expectant mothers increases the risk of autism in the child. But are these conclusions really supported by the data? Are they strongly enough supported to warrant being splashed across newspapers worldwide, where most readers will remember only the headline as the take-away message? The legacy of the MMR vaccination hoax shows how difficult it can be to counter overblown claims and the negative consequences that can arise as a result.

So, do these papers really make a strong case for their major conclusions? The first gives results from a study of twins in California. Twin studies are a classic method to determine whether something is caused by genetic or environmental factors. The method asks, if one twin in a pair is affected by some disorder (autism in this case), with what frequency is the other twin also affected? The logic is very simple: if something is caused by environmental factors, particularly those within a family, then it should not matter whether the twins in question are identical or fraternal – their risk should be the same because their exposure is the same. On the other hand, if something is caused by genetic mutations, and if one twin has the disorder, then the rate of occurrence of the disorder in the other twin should be much higher if they are genetically identical than if they only share half their genes, as fraternal twins do.

Working backwards, if the rate of twin concordance for affected status are about the same for identical and fraternal twins, this is strong evidence for environmental factors. If the rate is much higher in monozygotic twins, this is strong evidence for genetic factors. Now to the new study. What they found was that the rate of concordance for monozygotic (identical) twins was indeed much higher than for dizyogotic (fraternal) twins – about twice as high on average.

For males: MZ: 0.58, DZ: 0.21
For females: MZ: 0.60, DZ: 0.27

Those numbers are for the diagnosis of strict autism. The rate of “autism spectrum disorder”, which encompasses a broader range of disability, showed similar results:

Males: MZ: 0.77, DZ: 0.31
Females: MZ: 0.50, DZ: 0.36.

These numbers fit pretty well with a number of other recent twin studies, all of which have concluded that they provide evidence for strong heritability of the disorder – i.e., that whether or not someone develops autism is largely (though not exclusively) down to genetics.

So, why did these authors reach a different conclusion and should their study carry any more weight than others? On the latter point, the study is significantly larger than many that have preceded it. This study looked at 192 twin pairs, each with at least one affected twin. However, some recent studies have been comparable or even larger: Lichtenstein and colleagues looked at 117 twin pairs and Rosenberg and colleagues looked at 277 twin pairs. These studies found eveidence for very high heritability and negligible shared environmental effects.

Another potentially important difference is in how the sample was ascertained. Hallmayer and colleagues claim that their assessment of affected status was more rigorous than for other studies and this may be true. However, it has previously been found that less rigorous assessments correlate extremely well with the more standardised assessments, so this is unlikely to be a major factor. In addition, there is very strong evidence that disorders like autism, ADHD, epilepsy, intellectual disability, tic disorders and others all share common etiology – having a broader diagnosis is therefore probably more appropriate.

In any case, the numbers they came up with for concordance rates were pretty similar across these studies. So, why did they end up with a different conclusion? That’s not a rhetorical question – I actually don’t know the answer and if anyone else does I would love to hear it. Given the data, I don’t know how they conclude that they provide evidence for shared environmental effects.

The methodology involves some statistical modeling that tries to tease out the sources of variance. However, this modeling is based completely on a multifactorial threshold model for the disorder – the idea that autism arises when the collective burden of individually minor genetic or environmental insults passes some putative threshold. Sounds plausible, but there is in fact no evidence – at all – that this model applies to autism. In fact, it seems most likely that autism really is an umbrella term for a collection of distinct genetic disorders caused by mutations in separate genes, but which happen to cause common phenotypes (or symptoms).

If that is the case, then what the twin concordance rates actually measure is the penetrance of such mutations – if one inherits mutation X, how often does that actually lead to autism? For monozygotic twins, let us assume that the affected proband (the first twin diagnosed) has such a mutation. Because they are genetically identical, the other one must too. The chance that the other twin will develop autism thus depends on the penetrance of the mutation – some mutations are more highly penetrant than others, giving a much higher probability of developing a specific phenotype. If we average across all MZ twin pairs we therefore get an average penetrance across all such putative mutations. Now, if such mutations are dominant, as many of the known ones are, then the chance that a dizygotic twin will inherit it is 50%, while the penetrance should remain the same. So, this model would predict that the rate of co-occurrence in DZ twins should be about half that of MZ twins, exactly as observed. (No stats required).

The conclusions from this study that the heritability is only modest and that a larger fraction of variance (55%!) is caused by shared environment thus seem extremely shaky. This is reinforced by the fact that the confidence intervals for these estimates are extremely wide (for the effect of shared environment the 95% confidence interval ranges from 9% to 81%). Certainly not enough to overturn all the other data from other studies.

What about epidemiological studies that have shown statistical evidence of increased risk of autism associated with a variety of other factors, including maternal diabetes, antidepressant use, season and place of brith? All of these factors have been linked with modest increases in the risk of autism. Don’t these prove there are important environmental factors? Well, first, they don’t prove causation, they provide a statistical evidence for an association between the two factors, which is not at all the same thing. Second, the increase in risk is usually on the order of about two-fold. Twice the risk may sound like a lot, but it’s only a 1% increase (from 1 to 2%), compared with some known mutations, which increase risk by 50-fold or more.

The main problem with these kinds of studies (and especially with how they are portrayed in the media) is that they are correlational and so you cannot establish a causal link directly from them. In some cases, two different correlated parameters (like red hair and freckles, for example) may actually be caused by an unmeasured third parameter. For example, in the recently published study, the use of antidepressants of the SSRI (selective serotonin reuptake inhibitor) class in mothers was associated with modestly increased risk of autism in the progeny. This association could be because SSRIs disrupt neural development in the fetus (perfectly plausible) but could alternatively be due to the known genetic link between risk of depression and risk of autism. Rates of depression are known to be higher in relatives of autistic people, so SSRI use could just be a proxy for that condition. The authors claim to have corrected for that by comparing rates of autism in the progeny of depressed mothers who were not prescribed SSRIs versus those who were but one might imagine that the severity of depression would be higher among those prescribed an antidpressant. In addition, the authors are careful to note that their findings were based on a small number of children exposed and that “Further studies are needed to replicate and extend these findings”. As with many such findings, this association may or may not hold up with additional study.

As for season and place of birth, those findings are better replicated and, interestingly, also found for schizophrenia. There is a theory that these effects may relate to maternal vitamin D levels, which can also affect neural development. This also seems plausible enough. However, the problem in really having confidence in these findings and in knowing how to interpret them is that they are population averages with small effect sizes. Overall, it seems quite possible that the environment – especially the prenatal environment – can play a part in the etiology of autism. At the moment, splashy headlines notwithstanding, genetic factors look much more important and genetic studies much more likely to give us the crucial entry points to the underlying biology.

Mirrored from Wiring the Brain.

Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, & Risch N (2011). Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Archives of general psychiatry PMID: 21727249

Lichtenstein P, Carlström E, Råstam M, Gillberg C, & Anckarsäter H (2010). The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. The American journal of psychiatry, 167 (11), 1357-63 PMID: 20686188

Rosenberg, R., Law, J., Yenokyan, G., McGready, J., Kaufmann, W., & Law, P. (2009). Characteristics and Concordance of Autism Spectrum Disorders Among 277 Twin Pairs Archives of Pediatrics and Adolescent Medicine, 163 (10), 907-914 DOI: 10.1001/archpediatrics.2009.98

Croen LA, Grether JK, Yoshida CK, Odouli R, & Hendrick V (2011). Antidepressant Use During Pregnancy and Childhood Autism Spectrum Disorders. Archives of general psychiatry PMID: 21727247

One Comments

  1. If Autism is caused by heredity the genes involved must be spreading parabolically.

    A 2009 study published in the journal Epidemiology found that…

    “A study by researchers at the UC Davis M.I.N.D. Institute has found that the seven- to eight-fold increase in the number of children born in California with autism since 1990 cannot be explained by either changes in how the condition is diagnosed or counted — and the trend shows no sign of abating.”

    “The incidence of autism by age six in California has increased from fewer than 9 in 10,000 for children born in 1990 to more than 44 in 10,000 for children born in 2000.”

    http://www.sciencedaily.com/releases/2009/01/090108095429.htm

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