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. SHANK3: 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.