Abstract
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. We hypothesised that the extreme environmental stress of prematurity would promote neuroanatomic abnormality in individuals genetically vulnerable to psychiatric disorders. In 194 unrelated infants (104 males, 90 females), born before 33 weeks of gestation (mean gestational age 29.7 weeks), we combined Magnetic Resonance Imaging with a polygenic risk score (PRS) for five psychiatric pathologies to test the prediction that: deep grey matter abnormalities frequently seen in preterm infants are associated with increased polygenic risk for psychiatric illness. 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. Psychiatric PRS was negatively associated with lentiform volume in the full cohort (β = −0.24, p = 8 × 10−4) and a European subsample (β = −0.24, p = 8 × 10−3). Genetic variants associated with neuropsychiatric disease increase vulnerability to abnormal lentiform development after perinatal stress and are associated with neuroanatomic changes in the perinatal period.
Highlights
Preterm birth accounts for around 11% of all births and is a leading cause of infant mortality and morbidity[1]
We exploit the power of previous large genome-wide studies measuring the polygenic risk for five different psychiatric disorders[23], combining this with a large set of Magnetic Resonance Imaging (MRI) data in preterm infants to test the prediction that: the characteristic abnormalities seen in the basal ganglia and thalamus of preterm infants are associated with a greater polygenic risk for psychiatric illness
Polygenic risk scores were computed at five different P-value thresholds (PT) for our sample of 194 preterm infants from summary statistics from the meta-analysis of genome-wide single nucleotide polymorphisms (SNPs) data for five psychiatric disorders from the Cross-Disorder Group of the Psychiatric Genomics Consortium[23]
Summary
Preterm birth accounts for around 11% of all births and is a leading cause of infant mortality and morbidity[1]. Boardman et al.[6] showed the most marked morphological alteration between term and preterm infants to be a volume reduction in the thalamus and lentiform nucleus, a result confirmed by Srinivasan et al.[7] This endophenotype has been associated with poorer neurodevelopmental outcome and neurodevelopmental disability[11,12]. We hypothesized that the neuroanatomical abnormality defined by these studies might be associated with vulnerability to the environmental stress of preterm birth and this vulnerability might be greater in individuals who are at increased genetic risk for psychiatric disorders. We reasoned that if genes associated with psychiatric disease increase vulnerability to environmental effects on brain development, individuals with a greater polygenic risk for psychiatric disease who are subjected to the extreme environmental stress of preterm birth would be more likely to develop adverse consequences. We exploit the power of previous large genome-wide studies measuring the polygenic risk for five different psychiatric disorders[23], combining this with a large set of Magnetic Resonance Imaging (MRI) data in preterm infants to test the prediction that: the characteristic abnormalities seen in the basal ganglia and thalamus of preterm infants are associated with a greater polygenic risk for psychiatric illness
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