Translating genetic findings on chromosome 10q24 into an understanding of neurobiological risk mechanisms for schizophrenia

Student thesis: Doctoral ThesisDoctor of Philosophy


Schizophrenia is a poorly understood mental disorder, for which treatment options show variable efficacy and serious side effects. The aetiology of schizophrenia remains unclear, but genetics are known to make a large contribution to risk. It is expected that a third to half of the genetic variation contributing to risk is accounted for by common genetic variants. So far, large-scale genome-wide association studies (GWAS) have implicated 108 common genome-wide significant loci in susceptibility to schizophrenia. While analysis of larger cohorts will likely identify more common variants involved in susceptibility, the functional characterisation of individual risk loci is necessary to identify the risk genes and the functional effects associated with risk variation, potentially exposing novel drug targets. The functional characterisation of a risk locus, on chromosome 10q24, is presented in this thesis. As the best supported risk variants at the locus (rs11191419 and chr10_104957618_I) are noncoding, risk alleles were hypothesised to alter the regulation of one or more genes in the region. Measures of allele-specific expression were used to investigate cisregulatory effects associated with the risk variants on the primary positional candidates BORCS7, AS3MT, CNNM2, and NT5C2 in the human brain. The risk allele of rs11191419 was found to be associated with increased allelic expression of BORCS7 and AS3MT, and with decreased expression of NT5C2. The risk allele of chr10_104957618_I was associated with decreased expression of BORCS7, AS3MT, and NT5C2. A RNA-sequencing pilot study was performed to identify transcripts produced by these genes in brain tissues where cis-regulatory effects associated with risk alleles were observed. This revealed RNA expression of RefSeq transcripts of BORCS7, AS3MT, and NT5C2, as well as of novel transcripts of AS3MT and NT5C2. Using immunohistochemistry, the cytosolic 5'-nucleotidase II, produced by NT5C2, was found to co-localise with neurons, glial cells and neuropil in the adult dorsolateral prefrontal cortex (DLPFC). Knockdown of NT5C2 in neural progenitor cells was found to alter expression of genes involved in the regulation of the cytoskeleton, cellular metabolism and AMPK signalling. These results suggest neurobiological mechanisms through which genetic variation on chromosome 10q24 confers risk to schizophrenia.
Date of Award2017
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorDeepak Srivastava (Supervisor), Robin Murray (Supervisor) & Nick Bray (Supervisor)

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