B3132 - Genetic and epigenetic variation in the newborn brain in relation to neurodevelopmental outcomes in childhood - 14/06/2018

B number: 
Principal applicant name: 
Santi Rodriguez | Integrative Epidemiology Unit, Bristol Medical School (UK)
Dr Karen Luyt, Dr David Odd, Silvia Pregnolato, Emily Jamieson
Title of project: 
Genetic and epigenetic variation in the newborn brain in relation to neurodevelopmental outcomes in childhood
Proposal summary: 

This study aims at exploring the possible influence of genetic and epigenetic variants in the newborn brain on neurologic and mental traits and outcomes. This project aims to combine research from the Bristol Neonatal Gene Study and from ALSPAC. This will represent an interesting opportunity to study in detail the effect of specific genetic and epigenetic variants both in newborns and in childhood. We specifically aim to study the main candidate pathways involved in perinatal brain injuries (glutamate signalling and inflammation) and long-term motor, cognitive and behavioural outcomes. We have produced interesting preliminary findings within the Bristol Neonatal Gene Study, which support the involvement of candidate genetic variants in the glutamate signalling and inflammation pathways. The ALSPAC cohort provides a unique opportunity to validate and add to these findings in a large sample with genetic, epigenetic and phenotypic data collected longitudinally from birth to childhood. With the availability of maternal data, it also offers the opportunity to expand the analysis to maternal-neonatal gene-gene and gene-environment interactions. We have the appropriate expertise in genetic and epigenetic research required for this project. In addition, we are coupling this approach with in vivo work on animal models of newborn brain injuries, exploring the (dys)regulation of key genes involved in glutamate transport and inflammation during perinatal insults.

Impact of research: 
Genetic and epigenetic biomarkers may provide invaluable tools to predict the risk of brain injuries at birth and potentially long before the onset of labour. They may also provide a tool to identify babies who are more likely to respond to treatment, both in the short- and long-term. Both glutamate signalling and inflammation are ideal candidates for a pharmacogenomics approach for existing and novel drugs targeting these pathways. The study may also generate hypotheses about manipulating DNA methylation to achieve neuroprotection. We expect that through a better understanding of the molecular mechanisms of injury it will be possible to improve early identification, diagnosis and treatment, ultimately providing a better prognosis for these newborns. This is likely to help mothers, families and clinicians making more informed and personalised decisions when planning pregnancy, childbirth and child follow-up, contributing to the push of neonatal care towards prediction and prevention.
Date proposal received: 
Tuesday, 12 June, 2018
Genetics, Neurodevelopmental outcomes in childhood, Gene mapping, GWAS, Statistical methods, Cognition - cognitive function, Epigenetics, Genetic epidemiology, Genetics, Genome wide association study, Mendelian randomisation, Neurology, Statistical methods