A review of: Losh, M., Sullivan, P.F., Trembath, D., Piven, J. (2008). Current Developments in the Genetics of Autism: From Phenome to Genome. Journal of Neuropathology and Experimental Neurology, 67(9), 829-837. DOI: 10.1097/NEN.0b013e318184482d

Dr. Molly Losh and a team at the University of North Carolina at Chapel Hill just published a comprehensive review of the scientific literature on the genetics of autism. Here I present the cliffsnotes version of the article, although I highly recommend that everyone with access to this manuscript should read it, for it is a very well crafted analysis of the status of the autism-genetics science to date.

Evidence for a genetics basis of autism: family and twin studies
- Among monozygotic twins, there is a 60% concordance rate of autism, compared to only a 3 to 5% among dizygotic twins. This means that if a monozygotic twin has autism, 60% of the time his or her twin will also have autism. In contrast, when a dizygotic twin has autism, only 3-5% of the time his or her twin will have autism.
- The recurrence rate among families (changes that more than one member of the family will have autism) is between 5 to 8%, which is 25 to 40 times greater than the rate in the general the population.

Specific Target Genes:

MET: The MET gene is associated with the receptor to tyrosine kinase, a protein associated with neural growth, organization, immunological functioning, and gastrointestinal functioning. At least one study has found that a specific variant (SNIP) of this gene is over transmitted among families with autism (Campbell et al., 2006).

SLC6A4: This is the famous serotonin transporter gene associated with depression. The data on the association between this gene and autism appears to be very inconsistent and somewhat contradictory.

RELN: Reelin is a protein that is associated with neural migration during brain development. At least five studies have found an association between variants of the RELN gene and autism (Ashley-Koch et al., 2007; Perisco et al., 2002, 2001; Zhang et al., 2002; Dutta et al., 2007). Furthermore, mutant mice that do not have a section of the RELN gene have the same atypical cortical organization that is found in post-mortem studies of autism.

PTEN: The PTEN is a tumor suppressor gene associated with the prevention of uncontrolled cell growth. Mutations in the PTEN gene is associated with macrocephaly. Four studies have documented an association between the PTEN gene and autism among children with macrocephaly (Butler et al., 2005; Buxbaum et al., 2007; Boccone et al., 2006; Herman et al., 2007).

NLGN3 and NLGN4: These genes are related to Neuroligins, molecules that are associated with cell adhesion and neural development. Four studies have identified mutations within these genes among families or individuals with autism (Jamain et al., 2006; Laumonnier et al., 2004; Yan et al., 2005; Lawson-Yuen et al., 2008).

CNTNAP2: This is another gene associated with neural development and one that has shown significant promise in the search for genetic links in autism. CNTNAP2 was associated with autism in an Amish community affected with cortical dysplasia-focal epilepsy (Strauss et al., 2006). Another three studies found an association between variants of the CNTNAP2 gene and autism, including a specific autism phenotype (Arkin et al., 2008; Bakkaloglu et al., 2008; Alarcon et al., 2008). Specifically, this gene was associated with severity of language delays among children with autism – a significant finding given that CNTNAP2 appears to be largely expressed in the language centers of the brain.

Is a gene related to CNTNAP2 also involved in brain development. One study (Durand et al., 2007) found mutations in the SHANK3 gene among 3 of 226 families affected with autism. This is significantly larger than the rate of mutations found in the general population. Another study (Moessner et al., 2007) also found increased rates of SHANK3 mutations among people with autism.

One thing to keep in mind when reading genetic studies: Although the rates of specific genetic mutations or variants may be higher in affected families than in the general population, in most studies the majority of affected families do not show such gene anomaly. That is, the proposed genetic marker identifies only a small portion of affected individuals. This is not a problem that is unique to autism, as it is a common finding when trying to link genetic variants to complex and heterogeneous disorders. Thus, the research usually progresses towards: 1) the identification of phenotypes (specific types of autism) that may be associated with specific genetic variants, and 2) the identification of specific factors (environmental exposures for example) that when interacting with specific genetic variants may lead to the development of some types of autism.


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7 Responses to Autism and Genetic Markers: A cliffsnote review

  1. A great deal of sporadic autism comes from old paternal age. Schizophrenia is also created this way. http://www.genomeweb.com/issues/news/149097-1.html

  2. Nester

    The 60% figure for identical twins both having an ASD appears to this layperson to suggest a strong genetic basis for autism.

    Does not the 40% of cases where only one of two identical twins have autism diagnoses suggest that environmental factors are also significant? Simon Baron Cohen has made a statement to that statement.

    Harold Doherty

  3. laurentius rex says:

    I would refer you to my recent blog where I introduce a weaving analogy which I hope helps to understand the complexity of the interaction of genetics and epigenetics.


  4. RAJ says:

    Twin and family studies in autism are heavily influenced by interpretations through behavioral genetics and the authors of this article are all who Sir Michael Rutter has described as 'genetic evnagelists'.

    Classical twin studies for conditions whose etiology is unknown cannot differentiate between genetic susceptability and genetic transmission. All of the genetics findings in your excellent analysis are NOT specific to autism. They are also found in conditions such as mental retardation, schizophrenia, epilepsy, language disorders with or without 'autism'. The phenotypes of these conditions is not common to all cases. This is also the case for genetic mental retardation syndromes (Fragile X, Tuberous Sclerosis, Down's Syndrome) where the phenotype is mental retardation with a minoity subgroup having enough isolated secondary symptoms to qualify for an ASD diagnosis

    The same high rates of concordance in MZ twins (60-85%) and the same rapid falloff in concordance rates in DZ twins (5-20%) are also found in research into genetic liability to leprosy, a disorder caused by exposure to myobacterium laprae.


    Leprosy also clusters within families with sib risk ratios reported from 2.9 to 8% the same sib risk ratio reported for autism.

    Genome wide scans taken from large multi incidence families have identified a number of candidate leprosy susceptability genes. Leprosy is also a spectrum disorder ranging from mild to severe.

    In the largets epidemiological study of its kind (over 400,000 patients) there is an unexplained 3:1 male female ratio. A high male:female ration that also exists in autism


  5. RAJ says:

    For some reason the link to the Nature paper truncated, I’ll try the link again:


  6. I apologize to everyone for the delay in responding to the comments. The first week of each academic year is quite challenging and I was unable to read this posts until now.

    @ Harold
    I would not focus so much on that 40% since it could be argued that the genetic marker is necessary but no sufficient – yet it may not be necessarily environmental factors that complete the picture but another factors such as interaction with a condition that only affected one twin and not the other (e.g. pneumonia etc). A stronger argument for the role of other causes (including environmental) is that only a very small number of children with autism have this genetic marker. Thus most kids with autism get the disorder without having the genetic predisposition.

    Good points, but I wanted to highlight a related concept. “Specificity” is not a required condition to establish links between a potential cause and a disorder. A factor (genetic or otherwise) can have a causative role in one condition and also be associated with other, even unrelated, conditions.

  7. [...] a recent Cliff’s Notes version of which can be found in a post by Nestor Lopez-Duran at the Child Psychology Research Blog, also linked in Kristina’s original [...]

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