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.

Keywords: catechol-O-methyltransferase; cortex; disrupted-in-schizophrenia-1; neonate; neuroimaging.

Figures

Figure 1.

The effect of DISC1 (rs821616) genotype on brain structure. Upper images show the locations of significant GM decreases (blue) in Ser/Ser homozygotes when compared with Cys carriers projected onto surface-rendered views of the left and right hemispheres; lateral view (top) and medial view (middle). Bottom images are selected 2-dimensional (2-D) slices (axial and sagittal) with significant clusters displayed on the T2 atlas of the neonate brain. Color bar gives the t-value at each voxel. Blue/green indicates Ser/Ser <Cys carrier.

Figure 2.

The effect of COMT (rs4680) genotype on brain structure. Upper images show the locations of GM increases (red) and decreases (blue) in Val/Val homozygotes when compared with Met carriers projected onto surface-rendered views of the left and right hemispheres; lateral view (top) and medial view (middle). Bottom images are selected 2D slices (1 coronal and 2 sagittal) with significant clusters displayed on the atlas of the neonate brain. Color bar gives the t-value at each voxel. Red/yellow indicates Val/Val > other. Blue/green indicates Val/Val < other.

Figure 3.

The effect of NRG1 (rs35753505 and rs6994992) genotype on brain structure. (a) rs35753505. Upper images show the locations of GM decreases (blue) in TT homozygotes when compared with C carriers projected onto surface-rendered views of the left lateral and right medial hemispheres, and a selected 2D axial slice with significant clusters displayed on the atlas of the neonate brain. Color bar gives the t-value at each voxel. Blue/green indicates TT < Other. (b) rs6994992. Upper images show the locations of GM increases (red) and decreases (blue) in TT homozygotes when compared with C carriers projected onto surface-rendered views of the left and right hemispheres; lateral view (top) and medial view (middle). Bottom images are selected 2D slices (axial and coronal) with significant clusters displayed on the atlas of the neonate brain. Color bar gives the t-value at each voxel. Red/yellow indicates TT > other. Blue/green indicates TT < Other.

Figure 4.

The effect of APOE genotype on brain structure. Upper images show the locations of GM increases (red) and decreases (blue) in ɛ3ɛ4 heterozygotes when compared with ɛ3ɛ3 homozygotes projected onto surface-rendered views of the left and right hemispheres; lateral view (top) and medial view (middle). Bottom images are selected 2D slices (coronal and sagittal) with significant clusters displayed on the atlas of the neonate brain. Color bar gives the t-value at each voxel. Red/yellow indicates ɛ3ɛ4 > ɛ3ɛ3. Blue/green indicates ɛ3ɛ4 < ɛ3ɛ3.

Figure 5.

The effect of ESR1 (rs9340799) genotype on brain structure. Upper images show the locations of GM increases (red) and decreases (blue) in AA homozygotes when compared with G carriers projected onto surface-rendered views of the left and right hemispheres; lateral view (top) and medial view (middle). Bottom image is a selected 2D axial slice with significant clusters displayed on the atlas of the neonate brain. Color bar gives the t-value at each voxel. Red/yellow indicates AA homozygotes > G carriers. Blue/green indicates AA homozygotes < G carriers.

Figure 6.

The effect of BDNF genotype on brain structure. Upper images show the locations of GM increases (red) and decreases (blue) in Val/Val homozygotes when compared with Met carriers projected onto surface-rendered views of the left and right hemispheres, lateral view. Bottom images are selected 2D sagittal slices with significant clusters displayed on the atlas of the neonate brain. Color bar gives the t-value at each voxel. Red/yellow indicates Val/Val > other. Blue/green indicates Val/Val < other.