PT  - JOURNAL ARTICLE
AU  - Harriet Cullen
AU  - Michelle L Krishnan
AU  - Saskia Selzam
AU  - Gareth Ball
AU  - Alessia Visconti
AU  - Alka Saxena
AU  - Serena J Counsell
AU  - Jo Hajnal
AU  - Gerome Breen
AU  - Robert Plomin
AU  - A David Edwards
TI  - Genes associated with neuropsychiatric disease increase vulnerability to abnormal deep grey matter development
AID  - 10.1101/342394
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 342394
4099  - http://biorxiv.org/content/early/2018/06/12/342394.short
4100  - http://biorxiv.org/content/early/2018/06/12/342394.full
AB  - Background Neuropsychiatric disease has polygenic determinants but is often precipitated by environmental pressures, including adverse perinatal events. However, the way in which genetic vulnerability and early-life adversity interact remains obscure. Preterm birth is associated with abnormal brain development and psychiatric disease. We hypothesised that the extreme environmental stress of premature extra-uterine life could contribute to neuroanatomic abnormality in genetically vulnerable individuals.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 the prediction that: 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 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 and a subsample of European infants.Results The PRS was negatively associated with: lentiform volume in the full cohort (β=−0.24, p=8×10−4) and the European subsample (β=−0.24, p=8×10−3); and with subthalamic nuclear volume in the full cohort (β=−0.18, p=0.01) and the European subsample (β=−0.26, p=3×10−3).Conclusions Genetic variants associated with neuropsychiatric disease increase vulnerability to abnormal deep grey matter development and are associated with neuroanatomic changes in the perinatal period. This suggests a mechanism by which perinatal adversity leads to later neuropsychiatric disease in genetically predisposed individuals.