Common gene variants account for most of the genetic risk for autism.

Nearly 60 percent of the risk of developing autism is genetic and most of that risk is caused by inherited variant genes that are common in the population and present in individuals without the disorder, according to a study led by researchers at the Icahn School of Medicine at Mount Sinai.

The team have shown very clearly that inherited common variants comprise the bulk of the risk that sets up susceptibility to autism. But while families can be genetically loaded for autism risk, it may take additional rare genetic factors to actually produce the disorder in a particular family member.  The Population-Based Autism Genetics and Environment Study (PAGES) Consortium conducted a rigorous analysis of DNA sequence variations from an ongoing, comprehensive study of autism in Sweden.

Although autism is thought to be caused by an interplay of genetic and other factors, there has been no consensus on their relative contributions and the nature of its genetic architecture. Recently, evidence has been mounting that genomes of people with autism are prone to harboring de novo mutations, rare, spontaneous mutations that exert strong effects and can largely account for particular cases of the disorder.  Specifically, the current study found that about 52.4 percent of autism was traced to common and rare inherited variations, with spontaneous mutations contributing a modest 2.6 percent of the total risk.

Many people have been focusing on de novo mutations, such as the ones that can occur in the sperm of an older father.  While the current study found that these mutations are also key contributors, it is important to know that there is underlying risk in the family genetic architecture itself.

Gauging the collective impact on autism risk of variations in the genetic code shared by most people, individually much subtler in effect, has proven to be even more challenging. Limitations in sample size and composition have made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited and rare, spontaneous de novo variation. Differences in methods and statistical models have also resulted in estimates of autism heritability ranging from 17 to 50 percent.

Meanwhile, recent genome-wide studies of schizophrenia have achieved large enough sample sizes to reveal involvement of well over 100 common gene variants in that disorder. These promise improved understanding of the underlying biology, and even development of risk-scores, which could help predict who might benefit from early interventions to nip psychotic episodes in the bud.

With their new study, autism genetics is beginning to catch up, say the researchers. The PAGES study was made possible by Sweden’s universal health registry, which allowed investigators to compare very large samples (n~3000 in the current study) of people with autism with matched controls. Researchers also employed new statistical methods that allowed them to more reliably sort out the heritability 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 such as age of the father at birth and parents’ psychiatric history.

This is a different kind of analysis than employed in previous studies.  Data from genome-wide association studies were used to identify a genetic model instead of focusing on just pinpointing genetic risk factors. The researchers were able to pick from all 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 in genetic material and spontaneous mutations. Even though such rare spontaneous mutations accounted for only a small fraction of autism risk, the potentially large effects of these glitches makes them important clues to understanding the molecular underpinnings of the disorder, say the researchers.

Within a given family, a de novo mutation could be a critical determinant that leads to the manifestation of autism spectrum disorder in a particular family member.  If the family has a common variation that puts it at risk, an added de novo mutation could push an individual over the edge and result in that person developing the disorder.

Source:  The National Institute of Mental Health (NIMH) 

 

Results regarding the genetic architecture of autism spectrum disorder. Variance in autism liability is determined by genetic and environmental factors. The genetic factors include additive effects (A), non-additive effects (D; dominant, recessive, epistatic) and de novo mutations (N). Environmental factors are split between common or shared environment (C) and stochastic or unique environment (E). (a) Early-autism twin studies estimate additive effects from the contrast of monozygotic (MZ) and dizygotic (DZ) correlations while assuming that non-additive effects and de novo mutations are zero. These are common assumptions for ACE (additive genetics, common environment, unique environment) heritability models but are unlikely to be appropriate for autism. (b) Applying the ACE model to the largest autism twin study thus far yields a lower estimate of additive heritability. (c) Heritability results using a more extensive set of family relationships and based on much of the population of Sweden. (d) Results from the PAGES study. (e) Contribution of the various factors to the variance in autism liability according to family relationship. De novo variation should not be shared in dizygotic twins, and, when it appears to be, it is almost surely inherited variation from a parent with gonadal mosaicism because the chance of the same mutation appearing de novo in the dizygotic twins is negligible. Most twin studies assume that common or shared environment is the same for monozygotic and dizygotic twins, although this approximation has been debated.  (f) Synthesis of results for the genetic architecture of autism (ASD).  Buxbaum et al 2014.

Results regarding the genetic architecture of autism spectrum disorder. Variance in autism liability is determined by genetic and environmental factors. The genetic factors include additive effects (A), non-additive effects (D; dominant, recessive, epistatic) and de novo mutations (N). Environmental factors are split between common or shared environment (C) and stochastic or unique environment (E). (a) Early-autism twin studies estimate additive effects from the contrast of monozygotic (MZ) and dizygotic (DZ) correlations while assuming that non-additive effects and de novo mutations are zero. These are common assumptions for ACE (additive genetics, common environment, unique environment) heritability models but are unlikely to be appropriate for autism. (b) Applying the ACE model to the largest autism twin study thus far yields a lower estimate of additive heritability. (c) Heritability results using a more extensive set of family relationships and based on much of the population of Sweden. (d) Results from the PAGES study. (e) Contribution of the various factors to the variance in autism liability according to family relationship. (f) Synthesis of results for the genetic architecture of autism (ASD). Buxbaum et al 2014.

2 comments

  • James E. Trosko, Ph.D.

    Genes, alone, do not “cause” any disease, but its interaction with specific “environmental” factors [ see the classic xeroderma pigmentosum example]. In the case of the autism spectrum diseases, it seems clear that the in utero exposure to the mother’s total environment ( her nutritional/dietary exposures; pollutant exposures, medications, stress, behavior choices-smoking, alcohol, etc.) could affect critical neurological events to the brain adult stem cells ( increase/decrease their numbers in various regions of the brain) or affect , differentially affect the gene expression of the stem cells, the progenitor and differentiated daughter cells. ( i.e. The Barker hypothesis . see Trosko, J.E. “Pre-natal Epigenetic influences on acute and chronic diseases later in lfe, such as cancer : Global health crises resulting from a collision of biological and cultural evolution.. J. Food Science & Nutrition 16: 394-407, 2011.).

    With many examples that pregnant women, when exposured to certain chemicals ( thalidomide, alcohol, retinoids, etc.), can put their embryoes/fetuses at risk to birth defects. The study of the atomic bomb survivors have indicated the risk to breast cancer can be modified by their mothers dietary/nutritional exposures during their pregnancy. Autism spectrum of diseases might be the result of a complex exposure to many “epigenetic” chemicals acting on a wide range of mutated genes that can be differentiated modifed.

    James E. Trosko, Ph.D. Professor Emeritus, Dept. Pedistrics/Human Development, College of Human Medicine., Michigan State University, East Lansing, Michigan, james.trosko@ht.msu.edu

  • Winifred Laguerre

    Keep on working, great job!

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