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Common mutations account for half of autism risk

by  /  21 July 2014
Genetic risk: Using multiple statistical models, researchers have attributed 59 percent of the risk of developing autism to genetics.

Genetic risk: Using multiple statistical models, researchers have attributed 59 percent of the risk of developing autism to genetics.

Common gene variants that have minor effects may contribute about half the risk of developing autism, according to a study published Sunday in Nature Genetics1. Identifying these variants would require tens of thousands of samples.

Much of autism research so far has focused on rare, de novo mutations, which appear spontaneously in individuals with autism. These mutations often have strong effects and so can be straightforward to find — for example, by comparing the genomes of the affected individuals with those of their unaffected family members.

By contrast, common variants are present in 5 percent or more of the population. Alone, each variant may have little effect on an individual, but taken together they can tip the scales toward a particular condition, such as autism.

Because of their prevalence, definitively linking a particular variant to a disorder requires tens of thousands of samples.

Rather than pinpoint individual variants, the new study looked at how much common variants contribute to autism risk overall. The results suggest that roughly 49 percent of the risk of developing autism can be attributed to common variants, versus 3 percent for rare, de novo variants.

De novo mutations are extraordinarily important, but we need to consider this other kind of inherited risk as a critical part of the [genetic] architecture,” says lead researcher Joseph Buxbaum, director of the Seaver Autism Center at the Icahn School of Medicine at Mount Sinai in New York City.

Family ties:

Several studies have tried to define exactly how much of autism risk can be attributed to inheritance. These studies often analyze the genomes of twins because identical twins share the same DNA. However, they don’t always adequately account for the fact that twins also share other factors — such as the in utero environment, their homes or pediatricians.

“In the world of heritability, which is something of a dark art, twin studies are the darkest of the arts,” says Stephan Sanders, assistant professor of psychiatry at the University of California, San Francisco.

Perhaps as a result, estimates from twin studies of genetics’ contribution vary widely — ranging from 90 percent in twin studies in the 1980s to only 37 percent in a controversial 2011 twin study.

The new study falls in the middle, estimating the contribution of genetics overall at around 59 percent.

The researchers looked at autism risk across all children born in Sweden between 1982 and 2007, including 5,689 diagnosed with autism, in a total of 1.6 million families.

The researchers pieced together pedigrees of extended families to an unprecedented level, from first-degree relatives (parents, siblings) to ninth-degree distant cousins. By looking at autism recurrence across these families, they calculated that about 52 percent of autism risk is inherited.

In the world of heritability, which is something of a dark art, twin studies are the darkest of the arts.

The “magic” of this analysis is that the distant relatives — many of whom don’t even know each other — are less likely to share a home or other environmental confounds than siblings are, says Kathryn Roeder, professor of statistics 
at Carnegie Mellon University in Pittsburgh.

To identify the role of common variants, the researchers looked at more than 500,000 variants shared among 3,046 unrelated individuals in the population. From this, they estimated that common variants contribute about 49 percent of autism risk overall. That suggests that only the remaining 3 percent of risk comes from rare, inherited mutations.

These calculations are estimates, with sizable error rates. A study of Swedish twins published earlier this month similarly pegged the risk from inherited genetics at 54 percent, however, boosting the numbers’ credibility2.

“By using a variety of different analytical approaches, the researchers still come up with the same figure of around 54 percent,” says Louise Gallagher, professor of child and adolescent psychiatry at Trinity College, Dublin, who was not involved in the study. “The strength [of the new study] is the large population sample.”

Spontaneous risk:

The new study also calculated the contribution of de novo mutations — which are not included in estimates of inherited risk — at about 3 percent. This calculation may be an underestimate, say experts. For example, the analysis includes only mutations found in the coding portion of the genome.

Still, the relatively low contribution from de novo variants belies the importance the field has given to them so far, says Dan Arking, associate professor at the Institute of Genetic Medicine at John Hopkins University in Baltimore, who was not involved in the study. “This is bringing people back to the reality that common variation is explaining most of autism risk,” he says.

Together, all these genetic factors (along with a previously published estimate of recessive mutations) add up to 59 percent of autism risk.

Although other studies have designated the remainder as ‘environmental’ risk, the researchers say this category should be considered “unaccounted.” This is because the analysis does not account for interactions between risk factors — between common and rare variants, for example, or the influence of environment on gene expression.

De novo mutations may in fact act as a ‘second hit’ that pushes a set of common variants toward autism, says Buxbaum.

“The inter-relationship between common and rare variation and inherited and de novo variation is going to be the big thing for the next few years,” he says.

In any case, it’s clear that large numbers of samples can transform autism research — as they have in work on schizophrenia.

Just five years ago, schizophrenia researchers had access to only a few thousand genomes — enough to show that common variants are important in the disorder, but not enough to identify any particular variant — says Benjamin Neale, assistant professor of analytic and translational genetics at Massachusetts General Hospital.

But after analyzing nearly 40,000 schizophrenia genomes, an international consortium of researchers identified more than 100 common variants associated with schizophrenia — 83 of which are new links to the disorder.The researchers published their results yesterday in Nature3.

“The kind of trajectory we’ve seen in schizophrenia suggests what the future of autism genetics may hold — if we make a strong commitment as a community to increasing sample sizes,” says Neale.


1: Gaugler T. et al. Nat. Genetics Epub ahead of print (2014) PubMed

2: Sandin S. et al. JAMA 311, 1770-1777 (2014) PubMed

3: Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature Epub ahead of print (2014) Abstract

13 responses to “Common mutations account for half of autism risk”

  1. ASDgenome says:

    I would also mention that heritability “dark arts” are only dark insofar as methods are made opaque or oversimplified. Important note from the Gaugler et al paper:

    “For small samples, however, the correct model, the one truly generating the data, can be quite different in structure from the selected model, and yet the two can have only small differences in likelihood. It is possible that the different conclusion of the California study in comparison to others of its design is due to a modest stochastic difference that altered model selection. In this regard, a cautionary note for all such studies, including ours, is worthwhile: although we assume here a simple model structure, ours is but one of many possible models that could underlie trait covariance (for example, see ref. 31). The assumed model can alter inference, sometimes substantially, and many of these models can fit the data almost equally well.”

    Which in simpler terms basically says, “Don’t hang your hat on these numbers just yet.”

  2. ASD Dad says:

    It will be interesting to see if this study is replicated in other population cohorts outside of Sweden. Within this population a 41% association with environmental factors underlines the importance of both aspects and their interplay in autism.

  3. brian says:

    Note that “41% unaccounted” does not equal “a 41% association with environmental factors.” The “missing heritability” problem is seen in other polygenic traits, such as human adult stature. An honest attempt to address this issue was made in this paper:

  4. Eileen Nicole Simon says:

    I don’t see what this research accomplishes??? Can it explain evolutionary development of language in the brain? Or, how maturation of the language areas is disrupted in children who become autistic?

    Why are concussions due to sports injuries of such great concern? Wouldn’t research on brain damage in autism be of greater value? Of all of autism’s many causes, complications at birth have been reported more than any other. What happens to the brain during a brief period of oxygen insufficiency was described decades ago (see the research of WF Windle), and is relevant to language development and repetitive movements.

    Genetics research like this one is useless, and a huge waste of money that could be better spent elsewhere.

    • Steve White says:

      I think you are off base here. The research in fact to some extent suggests looking for the “unaccounted” causes — and so actually encourages research into non-genetic causes, if I understand the article.
      Also, complications at birth == even if your claim this is the most common known cause = can you do anything about it? I don’t think you are going to find many obstetricians who think oxygen deprivation is not dangerous to a baby — and yet, it still goes on. “Environmental” causes are not necessarily more preventable than genetic – in THEORY they may be – in the real world, stuff happens.

      • Eileen Nicole Simon says:

        Clamping the umbilical cord immediately after birth was adopted as a protocol in the mid 1980s. Textbooks of obstetrics up to that point in time all taught that the cord should not be tied or clamped until placental circulation had ceased. Until the fetal valves in the heart close, blood continues to be pumped to the placenta.

        Even in uncomplicated deliveries, a lapse in respiration occurs if the cord is clamped before the first breath. Blood may then be drained from other organs (including the brain) to fill the capillaries surrounding the alveoli. Clamping the cord at birth is viewed as natural, but there are NO health benefits from clamping the cord. It is a dangerous procedure, and should be stopped.

  5. RAJensen says:

    The first genetic studies implicating genetic variants were found on chromosome 7 but how strong are these risk factors? Not very much .
    rs1858830 C variant in the promoter region of the MET gene has been the most replicated common gene variation associated with autism. 47% of the general population has this common genetic variation. The MET promoter variant rs1858830 allele “C”, found at increased rates in autism, is associated with neuronal growth and development, but also is involved in immune function and gastrointestinal repair. making the strength of this genetic variation autism risk about the same as the genetic risk for autism as the possession of a ‘Y’ chromosome.

  6. Autismmom says:

    According to the article below seems mutations are common and that even healthy people carry genetic mutations that carry disease risk so what’s the trigger???? What is tipping the genome over the edge into dysfunction? Genetics alone does not explain the enormous increase in autism not 1 in 68.

  7. Reader says:

    We did a controversial, publicly known gene test since the renowned geneticist we consulted wouldn’t provide us our child’s gene information. We just wanted to know about mutations. The gene test showed VDR, MAO, MTHFR, COMT, BHMT issues. What will we do with this info? At least it now helps me understand why my child has always had a vitamin D problem despite the pediatrician telling me he’s not getting enough sunlight or cow’s milk. Thank you SFARI for putting the pieces together. I can’t wait to have a doctor open and unafraid to discuss this with me.

  8. Reader says:

    Afterthought….Plus a CBS mutation. If SFARI would like to start an open forum for families to discuss gene mutations, I’d love that. There are autism forums elsewhere discussing them but having SFARI involved, being open-minded and conversational, would send quite a positive message.

  9. RAJensen says:

    CLassical twin studies are a dark art. Classicical twin studies fail to note the contribution of de novo gene mutations in twins. Nearly 100% of Down syndrome identical pairs are concordant for Down Syndroma and nearly 100% of fraternal twins are discordant for Down Syndrome. Same goes for many genetic syndromes such as Klinefelter Syndrome, Rett Syndrome, Williams Syndrome and 22Q1 deletion syndrome. Classical twin studies do not segregate type of indentical twins. Monochorionic MZ twins (single placenta) share the same prenatal environment while dichorionic MZ twins twins do not share the same prenatal environment (seperate placenta). 60-66% of MZ twins are monochorionic. Heritiability estimates using classical twin studies inflate heritability estimates. Down syndrome using classical twin study design has the highest hertibility estimates (nearly 100%). The only population based study found that leprosy is 57% heritable and the sib recurrance rate is 6.4% The same heritabily estimates reported by Hallmayer’s autism twin study and the same sibling recurrance risk reported in Scandinavian studies. The data in twin and family studies are not wrong. The interpreation of the meaning of the data is entirely reliant on the biases and beliefs of the interpretor.

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