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Functional consequences of Setd1a haploinsufficiency: from gestation to behaviour

Bosworth, Matthew 2019. Functional consequences of Setd1a haploinsufficiency: from gestation to behaviour. PhD Thesis, Cardiff University.
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Abstract

Advances in psychiatric genetics are providing opportunities to investigate underlying pathogenic mechanisms. Rare loss of function (LoF) variants that have large effects on risk are of particular interest because they unequivocally implicate LoF of a single gene and are expected to have prominent phenotypic effects. The first LoF variants to be identified for schizophrenia were in the SETD1A gene. SETD1A catalyses methylation of lysine residue 4 on histone 3 (H3K4) and its pathogenic role is consistent with convergent evidence implicating disrupted H3K4 methylation in schizophrenia and other neurodevelopmental disorders. However, understanding of the biological mechanisms underlying the association between SETD1A LoF and psychopathology is lacking. This thesis investigated the functional consequences of Setd1a haploinsufficiency using a mouse model. Setd1a haploinsufficiency resulted in modest transcriptomic changes in the developing mouse brain that were enriched for mitochondrial annotations (Chapter 3). However, there was no enrichment for schizophrenia common variant association. Additionally, placental weight was reduced in Setd1a+/- mice and sexually dimorphic changes in placental gene expression and postnatal growth were observed in Setd1a+/- males but not females (Chapter 4). Behavioural phenotyping revealed that constitutive Setd1a haploinsufficiency caused heightened emotional reactivity and aberrant sensorimotor gating (Chapter 5). The effects on sensorimotor gating were robust and could not be rescued by established antipsychotics (haloperidol and risperidone) (Chapter 6). However, male (but not female) Setd1a+/- mice showed an insensitivity to the startle-inhibiting effects of risperidone, potentially indicating 5-HT2A receptor dysfunction. Finally, behavioural phenotyping of a conditional knockout with Setd1a haploinsufficiency constrained to the nervous system revealed evidence for a degree of convergence with the constitutive model (Chapter 7). In conclusion, this thesis provides novel insights into the diverse effects of Setd1a haploinsufficiency. These findings warrant further investigation to establish the pathophysiological relevance of effects on the developing brain, placenta, and adult brain function.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Psychology
Subjects: B Philosophy. Psychology. Religion > BF Psychology
Funders: Wellcome Trust
Date of First Compliant Deposit: 15 November 2019
Date of Acceptance: 15 November 2019
Last Modified: 19 Nov 2019 11:00
URI: http://orca.cf.ac.uk/id/eprint/126862

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