Endophenotypes are measurable components (e.g., neurophysiological, biochemical, neuroanatomical, cognitive or neuropsychological) that exist between the behavioral symptoms of a disease and distal genotype1.

The purpose of the psychiatric concept is to divide behavioral symptoms into more stable phenotypes with a clear genetic connection. The rationale holds that a smaller number of genes will be associated with a less complex phenotype than the behavioral manifestation of a complex neuropsychiatric disorder. A true endophenotype must meet the following criteria:

  • associated with illness in the population.
  • heritable.
  • primarily state-independent (seen in individuals with and without the active illness/diagnosis).
  • co-segregates with the illness within families.
  • found in affected individuals, is present in unaffected family members at a higher rate than in the general population.

Relevance to autism:

Although a heritable component has been demonstrated in autism etiology, researchers have yet to identify putative risk genes. Given the complex genetics of the disorder, they have made efforts to identify endophenotypes in recent years.

A 2010 study identified a potential ‘neuroendophenotype’ of autism in a functional magnetic resonance imaging (fMRI) study of children with autism and their unaffected siblings2,3. In a social perception task, these two groups showed common brain regions of decreased activity compared with typically developing children.

In 2011, Spencer and colleagues applied a similar approach in an fMRI study of the brain response to facial expressions4.

The identification of endophenotypes of autism has great potential to inform the search for genetic mechanisms.

  1. Gottesman I.I. and T.D. Gould Am. J. Psych. 160, 636-645 (2003)
  2. Kaiser M.D. et al. Proc. Natl. Acad. Sci. USA 107, 21223-21228 (2010)
  3. Kaiser M.D. and K.A. Pelphrey Dev. Cog. Neurosci. Epub ahead of print (2011)
  4. Spencer M.D. et al. Transl. Psych. 1, e19 (2011)