Schizophrenia-associated genomic copy number variants and subcortical brain volumes in the UK Biobank

Schizophrenia is a highly heritable disorder for which anatomical brain alterations have been repeatedly reported in clinical samples. Unaffected at-risk groups have also been studied in an attempt to identify brain changes that do not reflect reverse causation or treatment effects. However, no robust associations have been observed between neuroanatomical phenotypes and known genetic risk factors for schizophrenia. We tested subcortical brain volume differences between 49 unaffected participants carrying at least one of the 12 copy number variants associated with schizophrenia in UK Biobank and 9063 individuals who did not carry any of the 93 copy number variants reported to be pathogenic. Our results show that CNV carriers have reduced volume in some of the subcortical structures previously shown to be reduced in schizophrenia. Moreover, these associations partially accounted for the association between pathogenic copy number variants and cognitive impairment, which is one of the features of schizophrenia

Inflammation, the microcirculation and microalbuminuria

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Characterising the dynamics of repeat expansion in Huntington’s disease using single-molecule long-read DNA sequencing

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by the expansion of the CAG repeat in the huntingtin gene (HTT). The length of the CAG repeat is inversely correlated with the age at disease onset. However, onset varies considerably between individuals with the same repeat length, and other genetic variants have been identified as modifiers of age at onset of HD. These include SNPs in vicinity of FAN1, a nuclease involved in DNA repair, and changes to the sequence in and around the CAG repeat itself. Expansion of the HTT CAG tract from the inherited length is seen in both germline and somatic cells in HD. Striatal projection neurons exhibit the most somatic expansion and are also the cell type most susceptible to degeneration. Repeat expansion is recapitulated in a neuronal cell model derived from an individual with juvenile HD and 109 CAGs, however, traditional methods of quantifying the repeat have limited accuracy at this size and provide no information about the sequence of the repeat. Short-read next-generation sequencing (NGS) platforms do not span repeats of this length and thus cannot provide the repeat size. Long-read NGS platforms can generate highly accurate reads of more than 20 kilobases, which is long enough to span the repeats found in these models. In the first part of this thesis, I assess the utility of long-read PacBio sequencing in measuring the size and instability of the HTT CAG repeat in samples with various repeat lengths. In the second part of this thesis, I assess the utility of long-read PacBio sequencing in measuring the size, instability, and sequence of the HTT CAG repeat in a neuronal cell model of HD and conduct experiments looking at the effect of FAN1 genotype and cell maturity on repeat length, instability, and sequence variation