Principal Investigator: Dr Derek Morris
National University of Ireland Galway, Biochemistry Room 106, Galway, H91 CF50, IrelandTags: 23739, cognition, featured, genes, neuroimaging, schizophrenia
1a: A major component of schizophrenia is problems with cognition (learning, memory, IQ, attention) that cause severe disability. Schizophrenia and cognition are both strongly genetic. New research has identified many risk genes for schizophrenia but how they cause illness and which genes affect cognition is largely unknown. Our research focuses on genes within different biological functions (epigenetics, centrosome function, immune function, neurotransmission) and explores the roles that these biological functions have in schizophrenia and cognition. These studies will seek out new knowledge about the biological basis of cognitive deficits in schizophrenia, and offer targets for development of new therapies.
1b: We aim to gain new insights into the pathophysiology of cognitive deficits in schizophrenia, which could lead to development of new treatments that are badly needed. Thus, our proposed study aligns with the UK Biobank’s stated purpose of supporting “a diverse range of research intended to improve the prevention, diagnosis and treatment of illness”.
1c: We will study known risk genes for schizophrenia for their effects on cognition. The genes that we select come from four different types of biological functions believed to be involved in increased schizophrenia risk, namely: epigenetics, centrosome function, immune function and neurotransmission. We will test these functions in two ways. Firstly, we will test individual schizophrenia risk genes with these functions. Secondly, because the effect of individual genes are small, we will calculate a schizophrenia genetic risk score test for all genes combined within a biological function, and test that score for an effect on cognitive function.
1d: We plan to include all participants for whom data is available on Genomics (n=152,727) plus Cognitive Function (up to n=498,545), Cognitive function follow-up (n= 123,671) or Brain MRI (up to n=5,822).
Project extension – 13-9-2019
De novo mutations make a substantial contribution to the aetiology of psychiatric disorders, contributing to a correlation between paternal age (the strongest determinant of the de novo mutation burden) and the risk of several major psychiatric disorders, including schizophrenia. We have previously investigated the genetic contribution to variation in germline mutation rate, uncovering a set of putative human mutator variants, which are enriched near genes involved in DNA repair and replication. Here we propose to investigate the factors that contribute to variation in somatic mutation rates and patterns in the exome sequencing data generated from UK Biobank participants, using new methods that we are developing to distinguish somatic mutations from sequencing errors and other artifacts. Given the shared pathways involved in DNA replication, damage signalling and repair between germline and somatic cells, these variants are also likely to be associated with variation in germline mutation rates and patterns, potentially shedding light on the risk of psychiatric disorders, the original goal of the project. At the same time the additional work may lead to important insights that are relevant to understanding processes that are directly impacted by somatic mutation, including in particular cancer risk and aging.
Overall, we want to extend to understanding the nature of human mutation processes, which has relevance for our original objective (genetic studies of psychiatric disorders), as well as enabling us to study cancer and aging.
Last updated Sep 16, 2019