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Genetic risk for autism stems mostly from common genes

Discussion in 'Other Health News and Research' started by Ecoclimber, Jul 23, 2014.

  1. Ecoclimber

    Ecoclimber Senior Member

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    Genetic risk for autism stems mostly from common genes
    Date:July 20, 2014 Source:Carnegie Mellon University
    Summary:
    Using new statistical tools, scientists have discovered that most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches.

    Using new statistical tools, Carnegie Mellon University's Kathryn Roeder has led an international team of researchers to discover that most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches.

    Published in the July 20 issue of the journal Nature Genetics, the study found that about 52 percent of autism was traced to common genes and rarely inherited variations, with spontaneous mutations contributing a modest 2.6 percent of the total risk. The research team -- from the Population-Based-Autism Genetics and Environment Study (PAGES) Consortium -- used data from Sweden's universal health registry to compare roughly 3,000 subjects, including autistic individuals and a control group. The largest study of its kind to date, the team also showed that inheritability outweighs environmental risk.

    "From this study, we can see that genetics plays a major role in the development of autism compared to environmental risk factors, making autism more like height than we thought -- many small risk factors add up, each pushing a person further out on the spectrum," said Roeder, professor of statistics and computational biology at Carnegie Mellon and a leading expert on statistical genomics and the genetic basis of complex disease. "These findings could not have happened without statistics, and now we must build off of what we learned and use statistical approaches to determine where to put future resources, and decide what is the most beneficial direction to pursue to further pinpoint what causes autism."

    Although autism is thought to be caused by an interplay of genetic and other factors, including environmental forces, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive, until now. With this new study, the researchers believe that autism genetics is beginning to catch up.

    Led by Roeder, the researchers used new statistical methods -- such as machine learning techniques and dimension reduction tools -- that allowed them to more reliably sort out the inheritability of the disorder. In addition, they were able to compare their results with a parallel family-based study in the Swedish population, which took into account data from twins, cousins, and factors like age of the father at birth and parents' psychiatric history. A best-fit statistical model took form, based mostly on additive genetic and non-shared environmental effects.

    "Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now see the forest for the trees," said Thomas R. Insel, director of the National Institute of Mental Health (NIMH). "Knowing the nature of the genetic risk will help focus the search for clues to the molecular roots of the disorder."

    Thomas Lehner, chief of the NIMH's Genomics Research Branch, agreed and added, "This is a different kind of analysis than employed in previous studies. Data from genome-wide association studies was used to identify a genetic model instead of focusing just on pinpointing genetic risk factors. The researchers were able to pick from all of the cases of illness within a population-based registry."

    Now that the genetic architecture is better understood, the researchers are identifying specific genetic risk factors detected in the sample, such as deletions and duplications of genetic material and spontaneous mutations. The researchers said even though such rare spontaneous mutations accounted for only a small fraction of autism risk, the potentially large effects of these glitches make them important clues to understanding the molecular underpinnings of the disorder.

    "Within a given family, the mutations could be a critical determinant that leads to the manifestation of ASD in a particular family member," said Joseph Buxbaum, the study's first author and professor of psychiatry, neuroscience, genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai (ISMMS). "The family may have common variation that puts it at risk, but if there is also a 'de novo' mutation on top of that, it could push an individual over the edge. So for many families, the interplay between common and spontaneous genetic factors could be the underlying genetic architecture of the disorder."

    Current studies have not been large enough to reveal the many common genetic variants that increase the risk of autism. On their own, none of these common variants will have sufficient impact to cause autism.

    "Our group in Pittsburgh is working to develop a model that predicts the genetic risk for a family based on a myriad of small effects. Such a score could provide clinical benefit to families," Roeder said.


    Journal Reference:

    1. Trent Gaugler, Lambertus Klei, Stephan J Sanders, Corneliu A Bodea, Arthur P Goldberg, Ann B Lee, Milind Mahajan, Dina Manaa, Yudi Pawitan, Jennifer Reichert, Stephan Ripke, Sven Sandin, Pamela Sklar, Oscar Svantesson, Abraham Reichenberg, Christina M Hultman, Bernie Devlin, Kathryn Roeder, Joseph D Buxbaum. Most genetic risk for autism resides with common variation. Nature Genetics, 2014; DOI: 10.1038/ng.3039
     
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  2. xchocoholic

    xchocoholic Senior Member

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    "On their own none of these common variants will have sufficient impact to cause autism".

    (From the bottom of this report. )

    It's great that they're looking at genes but aren't they restating what was already suspected.

    What's turning these genes on ? Tc . X
     
  3. natasa778

    natasa778 Senior Member

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    Absolutely. And whatever happened to that old "corellation does not equal causation..." ;)

    I.e. one can only speculate that these variations raise the risk, let alone be causative of anything - we could simply be looking at a situation where those gene changes reflect levels of environmental insults (and are happening in parallel to other pathogenic processes).
    http://scienceoveracuppa.com/2013/06/30/all-roads-once-led-to-rome-but-do-all-roads-lead-to-autism/ is an essential read for anyone (genuinely) interested in the topic.
    (I'm esp interested in the subject of mobile retroelements activating in response to envir signals and causing gene changes - discussed elsewhere on the blog)



    As ancientdaze just said on genes-schizophrenia thread:

    Same true for autism - when the 'risk' gene clusters are analysed turns out most are linked to immune function...
     
    Last edited: Jul 24, 2014
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  4. natasa778

    natasa778 Senior Member

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    this is what you get when such findings are analysed:



    http://www.massgeneral.org/about/pressrelease.aspx?id=1531
     
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  5. natasa778

    natasa778 Senior Member

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    Or they could simply be false positives (in short, genetic changes such as deletions and duplications could simply be reflective of cellular pathology and not related to/involved in pathogenesis)
     
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