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Maternal factors, birth order up autism risk

by  /  17 July 2014


Having one child with autism raises the odds of having a second child with the disorder 20-fold, according to one of the largest epidemiological studies so far to address the inheritance of autism risk1.

The study, published 27 June in the American Journal of Psychiatry, found that this effect is greater for full siblings than it is for half-siblings, supporting genetics as a key factor in autism risk.

However, the study also hints at the importance of environmental factors. For example, the shorter the time between the birth of the child with autism and the birth of the sibling, the more likely the sibling is to have autism.

Half-siblings who share a mother also have a higher risk of having autism than those who share a father. This suggests that the uterine environment and other factors may contribute to autism risk.

“These kinds of results suggest to me that it’s probably a genetic-environmental interaction going on here,” says lead researcher Neil Risch, professor of biostatistics at the University of California, San Francisco.

The environmental component may be the most useful information for trying to reduce autism risk, Risch adds. “While the genetics provides important leads, it doesn’t provide immediate solutions.”

The new study is particularly valuable because it takes into account the fact that parents often refrain from having more children after having one with autism — a phenomenon called stoppage. A study published last year, which did not take stoppage into account, found only a sevenfold increase in autism risk for children who have a sibling with the disorder.

“The study benefits from the very large sample size and the ability to meaningfully contrast between different siblings and birth order without being hindered by stoppage,” says Elise Robinson, instructor in medicine at Harvard University, who was not involved in the study.

Sibling status:

The researchers looked at children who had received benefits through the California Department of Developmental Services. This approach is powerful because it involves all children with autism in a large geographical area rather than those at a certain clinic, says Aravinda Chakravarti, professor of molecular biology and genetics at Johns Hopkins University School of Medicine in Baltimore.

The researchers used birth certificates to link families and identify siblings. To account for stoppage, they looked only at siblings born after a child with autism. They began with 6,616 children with autism who have at least one full sibling, 644 who have a maternal half-sibling and 299 who have a paternal half-sibling. They directly compared these children with 29,384 typically developing children with at least one sibling.

About 10 percent of siblings of children with autism have the disorder, compared with 0.52 percent of siblings of controls, the study found. A 2011 study followed the outcome of infant siblings of children with autism and found that roughly 20 percent of the infants developed autism.

The new study’s estimate may be lower because it looked only at children who received services, and so may be skewed toward the more severely affected end of the autism spectrum, says Lonnie Zwaigenbaum, professor of pediatrics at the University of Alberta in Canada, who was not involved in the study. Severe symptoms are often the result of spontaneous mutations and are less likely to be inherited than are mutations with mild effects.

The study found that the risk is higher for the sibling born immediately following a child with autism than it is for those later in the birth order. The timing of birth is also important: “If the next child is born within a year or 18 months of the prior child [with autism], the risk is dramatically higher than if the couple waits, say, three or four years,” says Risch.

The reason for this trend is unclear, but it is consistent with evidence that exposure to byproducts of the immune system during gestation — which fade over time — may add to autism risk.

Two children born close together may also have other things in common, such as a pediatrician with a particular awareness of autism, so the explanation may be more straightforward than a complex environmental risk.

The fact that children who share a mother have about double the risk of those who share a father also points to environmental factors. (The study found only seven children with autism among the paternal half-siblings, but the difference is still significant.)

Still, genetic factors could explain this observation, researchers say. For example, females may need more genetic hits to develop autism than males do. That suggests that mothers who don’t have autism may carry some autism-linked mutations — the so-called female protective effect.

“The observations fit very well instead with protective effects in females,” says Kevin Mitchell, associate professor of genetics at Trinity College, Dublin, who was not involved with the study.

In fact, data from the new study may support this theory: The siblings of girls with autism (who presumably carry more mutations than do boys with autism) are 1.18 times more likely to have autism than the siblings of boys are — although this difference is not statistically significant. Risch says this effect is not large enough to account for the difference in risk between maternal and paternal half-siblings.

The debate is testament to the fact that autism risk lies in a foggy middle ground between genetics and environment.

“I have a hard time imagining a world in which one is true and the other is not,” says Robinson.


1: Risch N. et al. Am. J. Psychiatry Epub ahead of print (2014) PubMed



4 responses to “Maternal factors, birth order up autism risk”

  1. Autism mom says:

    For a completely differnet take on why multiple siblings in a family develop autism and what is happening to our kids that causes regression, follow the microbiome, gut-brain research by Dr. Sydney Fiengold, Dr. Derrick MacFabe and Dr. Richard Frye. Feingold’s team analyzed the micro flora in the gut of children with regressive autism and compared it to typical controls. The researchers found clear evidence of gut dysbiosis as well as high levels of a pathogen called Desulfovibri, a gram negative bacteria that robs the body of sulfur. He says this bacteria can be transmitted child to child because it can adhere to surfaces which children come intocontact with. He says this is likely the reason why multiple siblings in the same family have autism -the children are passing around this pathogen. The severity if autism is connected to the amount of the pathogen. Feingolds work is tremendous. He gave a lecture at the autim-microbiome. Com web site. He also co authored a study called “Gastrointestinal flora and gastrointestinal status in children with autism — comparisons to typical children and correlation with autism severity
    James B Adams1*, Leah J Johansen1, Linda D Powell1, David Quig2 and Robert A Rubin3

  2. Richard Griffin says:

    Jessica, the first line is quite misleading. Sfari should be above using the devices common to “shock” journalism. Recurrence risk of 20% is too often reported, based on a smaller study that reported recurrence risk of 18.7%. Larger, more recent, studies, including this one, find the recurrence risk to be around 10%. The authors write “The overall sibling recurrence risk was 10.1%, compared with a prevalence of 0.52% in siblings of controls”as you mention later in the piece. Note also that 0.52 is lower than current baseline prevalence estimates. It looks to me like recurrence risk is actually lower than is commonly being reported.

    • Stephan Sanders says:

      The first line says ’20-fold’ not ‘20%’. This is based on 10.1% / 0.52% which is 19.42-fold; I think 20-fold is a fair description. The 0.52% prevalence is lower than the current CDC estimate, however this publication is based on data from 2010. The most important consideration is that the calculation of ASD prevalence was applied equally to the population and the siblings so that the numbers are comparable.

  3. Richard Griffin says:

    Hi Stephan. Thanks for engaging.I realize how the 20-fold increase was calculated. That’s why I mentioned the 0.52% prevalence in the comparison group. I think that the Risch et al paper is quite good. But it’s important that we get our baseline prevalence and recurrence estimates as close to the mark as possible. This is particularly important in research with infant sibs. How many infants (out of 100, say) can we expect to be diagnosed with ASD? 10, 20? That’s a big difference! If we assume baseline prevalence to be 1%, a 20-fold increase = 20%, but the quality recurrence risk studies (like this one) indicate that 10% is closer to the mark. Finally, regarding journalism (and baseline neglect), the claim that x “raises the odds” whatever-fold is only interpretable when the reader knows what the odds are to begin with.

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