Common Variants in Psychiatric Risk Genes Predict Brain Structure at Birth

Abstract

Studies in adolescents and adults have demonstrated that polymorphisms in putative psychiatric risk genes are associated with differences in brain structure, but cannot address when in development these relationships arise. To determine if common genetic variants in disrupted-in-schizophrenia-1 (DISC1; rs821616 and rs6675281), catechol-O-methyltransferase (COMT; rs4680), neuregulin 1 (NRG1; rs35753505 and rs6994992), apolipoprotein E (APOE; ε3ε4 vs. ε3ε3), estrogen receptor alpha (ESR1; rs9340799 and rs2234693), brain-derived neurotrophic factor (BDNF; rs6265), and glutamate decarboxylase 1 (GAD1; rs2270335) are associated with individual differences in brain tissue volumes in neonates, we applied both automated region-of-interest volumetry and tensor-based morphometry to a sample of 272 neonates who had received high-resolution magnetic resonance imaging scans. ESR1 (rs9340799) predicted intracranial volume. Local variation in gray matter (GM) volume was significantly associated with polymorphisms in DISC1 (rs821616), COMT, NRG1, APOE, ESR1 (rs9340799), and BDNF. No associations were identified for DISC1 (rs6675281), ESR1 (rs2234693), or GAD1. Of note, neonates homozygous for the DISC1 (rs821616) serine allele exhibited numerous large clusters of reduced GM in the frontal lobes, and neonates homozygous for the COMT valine allele exhibited reduced GM in the temporal cortex and hippocampus, mirroring findings in adults. The results highlight the importance of prenatal brain development in mediating psychiatric risk.

Gray matter maturation and cognition in children with different APOE ε genotypes

“…5 However, larger cortical areas in our e3e4 children resemble larger parietal volumes in e3e4 infants (ages 8.5-14 months) 7 relative to e3e3 participants. Moreover, consistent with our results, prior studies found similar IQ or cognitive performance between e3e4 and e3e3 children.…”

“…[1][2][3][4] In addition, APOE e4 may influence brain development. [5][6][7] However, the APOE e4 allele demonstrates antagonistic pleiotropy, with deleterious effects on cognition, brain morphometry, and activation primarily after 55 years of age, but no negative 8 or even beneficial effects in adults younger than 50 years 9,10 and children aged 6 to 15 years. [11][12][13] Compared to non-e4 carriers, healthy children carrying e4 (8-20 years) tended to have thinner entorhinal cortex, 5 while healthy infants carrying e4 showed altered brain measures in regions affected by AD.…”

“…[11][12][13] Compared to non-e4 carriers, healthy children carrying e4 (8-20 years) tended to have thinner entorhinal cortex, 5 while healthy infants carrying e4 showed altered brain measures in regions affected by AD. 6,7 Whether these structural differences influence cognitive performance in children with e4 remains controversial.…”

“…Image processing included verification of protocol compliance and quality assurance. Automated morphometry using a modified FreeSurfer software was performed on the whole brain, and 7 subcortical and 20 cortical regions of interest (ROIs) from the standard FreeSurfer atlas were selected based on reported APOE e effects in children 5 and neonates, 6,7 or patients with AD. 4 Fractional anisotropy (FA) (corrected for B 0 inhomogeneities) in the same 7 subcortical ROIs was also assessed, since FA in these regions often increases during neurodevelopment.…”

“…Similarly, cortical surface areas were smallest in e2e4 but largest in e3e4 or e4e4. Hence, combining all e4 carriers might have attenuated or abolished group differences compared to non-e4 carriers, [5][6][7]12,14,40 and the larger parietal volumes in the youngest e2e4 children or the thinnest isthmus gyrus and temporal poles in the youngest e4e4 children might have been missed. In fact, our e4 carriers collectively had nonsignificantly thicker temporal lobes, contrasting with thinner entorhinal cortices in a prior study of healthy e4 children.…”