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Title: Common and rare genetic risk factors for schizophrenia and their associations with cognition
Author: Hubbard, Leon
ISNI:       0000 0004 5361 9085
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2014
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Individuals with schizophrenia have severe cognitive impairments that impact upon their ability to function within society. Better understanding the genetic mechanisms underlying schizophrenia and cognition provides an opportunity for targeted pharmacological intervention. This thesis investigates common and rare genetic variation in schizophrenia and their associations with cognitive ability in schizophrenia cases and healthy controls. Polygenic risk of schizophrenia and bipolar disorder predicted ability on tests of cognitive domains affected in schizophrenia, performance, verbal and full scale IQ in healthy controls. Increased polygenic risk of schizophrenia was robustly associated with lower performance IQ at different training thresholds in two independent cognition samples. There was no consistent association between bipolar polygenic risk and cognition. Common genetic differences between schizophrenia and bipolar disorder were associated with verbal and full scale IQ. I investigated the hypothesis that 155 gene-sets across six biological categories relating to cognition, brain function and structure were enriched for SNPs influencing general cognitive ability. Schizophrenia polygenic pathway scores for gene-sets were not associated with general cognitive ability in schizophrenia patients, or performance IQ in healthy individuals. Separately, neither gene-sets vi nor general categories were enriched for common SNPs showing association with general cognitive ability in schizophrenia cases. Associations between rare CNVs and general cognitive ability were tested in schizophrenia cases. Cases with a known pathogenic CNV performed approximately one standard deviation below other schizophrenia cases on the MATRICS composite score. In addition, increases in the number of genes hit by large (>100kb) and rare (frequency <1%) CNVs were associated with lower general cognitive ability. However, the number of genes hit in gene-sets previously mentioned was not associated with the MATRICS composite score. These findings indicate genetic variation in schizophrenia is associated with cognitive ability in schizophrenia cases and healthy controls, providing direction for future research.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry