July 3, 2014

expert reaction to genetics of psychiatric illnesses

Investigators reporting in the journal Cell Stem Cell describe a method that may help reveal how genetic variants that may increase risk of psychiatric disorders, but are insufficient to cause disease, interact with other risk factors or environmental exposures to affect the development of the nervous system.

Dr Mandy Johnstone, Wellcome Trust Clinical Research Fellow, University of Edinburgh & Honorary Consultant Psychiatrist, said:

“This is a lovely paper and very timely given that we really need to look for subtle cellular differences in the neural precursor cells as they develop into neurons.

“The study by Yoon et al published in Cell Stem Cell has taken a multi-faceted approach to begin to unravel the underlying molecular and cellular mechanisms underpinning the development of neuropsychiatric disorders by focusing on a particular genetic risk variant. Taking human induced pluripotent stem cell-derived neural progenitors with deletions in the 15q11.2 chromosomal region, they have demonstrated that these cells have specific cytoskeletal abnormalities. They also showed that it was possible to engineer a similar deficit in mice who subsequently demonstrated abnormalities in the development of the cortex.

“We were looking at this in Edinburgh too, but there are so many risk genes to investigate that the particular ones from this study went onto the back burner as we pursue other risk factors also thought to be important in the development of neuropsychiatric disorders such as schizophrenia, autism and intellectual disability. This study ties in neatly with recent work published in Nature that looked at imaging and cognition because it shows that carrying the 15q11.2 copy number variant not only correlates with some of the detectable differences seen by brain scanning but also with the cognitive differences often seen clinically in these conditions.

“I am intrigued also at their complementary mouse studies showing that reducing the expression of one of the genes expressed in the 15q11.2 region resulted in abnormalities of development of the cerebral cortex in these animals. Overall, a very impressive body of work and a good example of how induced pluripotent stem cell technology (iPSC) can be exploited to thoroughly interrogate the cell biology of neuro-developmental disorders. It also shows how hiPSC technology allows us to probe how the genetic risk factors identified in these complex disorders is manifest at a cellular level.”

‘Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity’ by Yoon et al. published in Cell Stem Cell on Thursday 3^rd July.

Declared interests

None declared