Genes 2 Brains 2 Mind 2 Me

It has long been known that complex neuropsychiatric and neurodevelopmental illnesses have familial patterns of inheritance and that concordance in identical twins is greater than in fraternal twins. The genetic influences of mental illness – whilst apparent – do not, however, provide clues about which genes, of the 20,000 or so to choose from, confer risk. Hallucinations, mania, mood-swings, paranoia, disorganized thinking – to describe some of the difficulties that patients experience – do not immediately suggest specific candidate molecules. In an effort then, to pinpoint the specific neural processes that go awry in one particular complex mental illness, the The Consortium on the Genetics of Schizophrenia has published a landmark analysis of 183 nuclear families consisting of affected and unaffected siblings to address this problem. In their paper, “Initial Heritability Analyses of Endophenotypic Measures for Schizophrenia” (Arch Gen Psychiatry. 2007;64(11):1242-1250) the team examine so-called endophenotypes, often consisting of cognitive assessments designed to engage discrete, anatomically characterized neural networks in order to zero-in on where in the brain the genetic risk exerts an effect. The critical point the authors make is that these endophenotypes must be shown to be reliable, stable, and, most importantly, heritable. In other words, while many neural proceeses may go awry in schizophrenia, not all of these processes will have been influenced by genetic factors. Hence the analogy to carving up the complex system (turkey) along the proper genetic lines (joints). Their analysis showed that a great many of their candidate endophenotypes are indeed heritable, such as pre-pulse inhibition of the startle response, the antisaccade task for eye movements, Continuous Performance Test, California Verbal Learning Test, Letter-Number Sequencing test, Abstraction and Mental Flexibility, Face Memory, Spatial Memory, Spatial Processing, Sensorimotor Dexterity, and Emotion Recognition. Other processes such as suppression of the P50 ERP was not found to be heritable, and thus may not be a process that is affected by genetic risk. Interestingly, as reported by the authors, “The genetic correlations observed between the CVLT and LNS, between Abstraction and Mental Flexibility and Spatial Memory, and between Spatial Processing and the antisaccade task, CPT, LNS, and Abstraction and Mental Flexibility were significant at the P .001 level and remained significant after correction for multiple testing. These results suggest that overlapping genetic architecture (pleiotropy) underlies some of these endophenotypes”. Further dissection of these validated endophenotypes may therefore yield more specific neural processes, and perhaps specific synaptic connections, that would more readily provide clues to the molecular players in these complex developmental disabilities.

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