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Next Generation Sequencing to Identify Genes Underlying Extreme Psychiatric Illness and Extraordinary Cognition

Final Report Summary - GACPD (Next Generation Sequencing to Identify Genes Underlying Extreme Psychiatric Illness and Extraordinary Cognition)

This project was designed to identify rare genetic variants underlying exceptional human cognition, extreme personality disorder, and childhood onset psychosis (COP). Pilot projects were conducted investigating exceptional human cognition and extreme personality disorder, and it was determined that alternative populations would have to be identified to have a good chance of identifying relevant genes. The rest of the project was focused on COP.

COP is a difficult condition to study because it is exceptionally rare, but there is evidence that it is likely to be the most heritable (i.e. genetic) of psychiatric illnesses. As there is evidence of considerable genetic overlap between almost all neurological and psychiatric illnesses, it is likely that genes identified in this study would be relevant to more common forms of psychosis, and other disorders of the brain. In addition to identifying novel genes underlying psychosis, we were able to pilot the use of genetics as a diagnostic tool for psychiatric disorders with a likely genetic basis. This is relevant as psychiatric disorders are often excluded from clinical genetics due to assumed complex etiology.

During the project, we set up over 20 study sites in NHS Trusts across England, to identify patients. I and my study team visited each of these sites to recruit patients and have recruited a total of 100 participants from 35 families. The DNA from these patients and their relatives was extracted and qualitatively and quantitatively assessed and was found to be of sufficient abundance and quality for sequencing. We have sequenced and performed genetic analysis on 25 of these families so far. We have performed analysis on the genomes, looking at de novo, compound heterozygous, newly homozygous and newly hemizygous variants as well as very damaging variants inherited from affected parents. These have been reported at national and international conferences. Through collaboration with international colleagues, we have identified at least one probably new disease gene which we are in the process of confirming and publishing. Other strong candidates are being followed up.

Additionally, we have so far identified three probably causal variants (in a sample of 25) and have reported these back to the clinician. Although the sample size is small, this suggests that sequencing the genomes of people with very early onset severe psychiatry illness may yield a diagnosis for 10-15% of patients, and should be investigated further. We will strengthen this estimate by combining these results with those from “schizophrenia-plus” samples from the 100,000 Genomes Project, and from the Nigerian samples collected by our collaborator, Dr. Okewole.

The study website is and further enquiries should be directed to