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Genes associated with neuropsychiatric disease increase vulnerability to abnormal deep grey matter development

Presented at the Neonatal Society 2018 Summer Meeting.

Cullen H1, Krishnan ML1, Selzam S2, Ball G1, Visconti A3, Saxena A4, Counsell SJ1, Hajnal J1, Breen G2, Plomin R2, Edwards AD1

1 Centre for the Developing Brain, Kings College, London
2 Institute of Psychiatry, Psychology and Neuroscience, Kings College, London
3 Department of Twin Research and Genetic Epidemiology, King’s College London
4 NIHR Biomedical Research Centre, Guy’s and St Thomas’ NHS Foundation Trust, London

Background: Brain injury in preterm infants is not completely explained by clinical variables, however genome-wide studies have largely failed to uncover genetic vulnerabilities, probably because of underpowered studies and highly variable outcome measures. We hypothesised that inherited vulnerability is polygenic and that genes conferring risk for neuropsychiatric disease would be associated with the characteristic endophenotype of abnormal deep grey matter development.

Methods: We combined Magnetic Resonance Imaging (MRI) and genome-wide single nucleotide polymorphism (SNP) data from 194 infants, born before 33 weeks of gestation, to test whether the characteristic deep grey matter abnormalities seen in preterm infants are associated with polygenic risk for psychiatric illness. Summary statistics from a meta-analysis of SNP data for five psychiatric disorders (1) were used to compute individual polygenic risk scores (PRS). The variance explained by the PRS in the relative volumes of four deep grey matter structures (caudate nucleus, thalamus, subthalamic nucleus and lentiform nucleus) was estimated using linear regression both for the full, mixed-ancestral, cohort (European, Asian and African) and a subsample of European infants.

Results: For the full, mixed-ancestry cohort the psychiatric PRS was negatively associated with lentiform nuclear volume (β=-0.24, p=8×10-4, R2 = 0.057) and showed a modest negative association with subthalamic nuclear volume (β=-0.18, p=0.01, R2 = 0.032) that did not survive multiple-testing correction. In the sub-sample of European infants, the psychiatric PRS was negatively associated with lentiform nuclear volume (β=-0.24, p=8×10-3, R2 = 0.056) and subthalamic nuclear volume (β=-0.26, p=3×10-3, R2=0.069). No association was found between the psychiatric PRS and caudate or thalamic volume for either the full mixed-ancestral sample or the sub-sample of European infants.

Conclusion: Genes associated with neuropsychiatric disease increase vulnerability to abnormal deep grey matter development in the perinatal period. This may allow discovery of biologic mechanisms for abnormal brain development in preterm infants.

Corresponding author: Harriet.cullen@kcl.ac.uk

References
1. Smoller, J.W., 2013. Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis. The Lancet, 381(9875), pp.1371–1379.

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