Schizophrenia-risk variant rs6994992 in the neuregulin-1 gene on brain developmental trajectories in typically developing children

Abstract

The neuregulin-1 (NRG1) gene is one of the best-validated risk genes for schizophrenia, and psychotic and bipolar disorders. The rs6994992 variant in the NRG1 promoter (SNP8NRG243177) is associated with altered frontal and temporal brain macrostructures and/or altered white matter density and integrity in schizophrenic adults, as well as healthy adults and neonates. However, the ages when these changes begin and whether neuroimaging phenotypes are associated with cognitive performance are not fully understood. Therefore, we investigated the association of the rs6994992 variant on developmental trajectories of brain macro- and microstructures, and their relationship with cognitive performance. A total of 972 healthy children aged 3-20 years had the genotype available for the NRG1-rs6994992 variant, and were evaluated with magnetic resonance imaging (MRI) and neuropsychological tests. Age-by-NRG1-rs6994992 interactions and genotype effects were assessed using a general additive model regression methodology, covaried for scanner type, socioeconomic status, sex and genetic ancestry factors. Compared with the C-carriers, children with the TT-risk-alleles had subtle microscopic and macroscopic changes in brain development that emerge or reverse during adolescence, a period when many psychiatric disorders are manifested. TT-children at late adolescence showed a lower age-dependent forniceal volume and lower fractional anisotropy; however, both measures were associated with better episodic memory performance. To our knowledge, we provide the first multimodal imaging evidence that genetic variation in NRG1 is associated with age-related changes on brain development during typical childhood and adolescence, and delineated the altered patterns of development in multiple brain regions in children with the T-risk allele(s).

Figure 1

Age-related differences in DTI metrics of subcortical structures (top row) and in lateral ventricle volume (bottom row). Percentages are expressed as increases (sign +) or decreases (sign −) in values between the TT-children (green) and the CC-children (blue). Black vertical arrows indicate when the age-by-genotype interactions emerge or reverse. The bottom right panel illustrates the location of subcortical structures of interest, as well as a statistical P-value map for FA generated with the ROI-based model. DTI, diffusion tensor image; FA, fractional anisotropy; LD, longitudinal diffusivity; ROI, region of interest; TD, transverse diffusivity.

Figure 2

Summary of NRG1 genotype main effects and age-by-genotype interactions in cortical measures. (a) Statistical P-value maps showing significant interactions between smooth age and the three NRG1 genotypes (TT, TC and CC) in healthy children. The maps were generated from general additive models with cortical area and thickness as the dependent variable at each location (vertex) across the surface. Sex, device, GAF, SES were included as covariates, and findings were corrected for multiple comparisons with false discovery rate (FDR; α=0.05). The FDR threshold was obtained for left and right hemispheres combined and based on the cortical structures maps. (b) Table of NRG1-rs6994992 genotype differences and genotype-by-age interactions on cortical structures. The P-values (two-way analysis of covariance) of regions showing statistical differences with both the ROI-based and the vertex-based models are indicated in italic. The P-values that survived Holm–Bonferroni correction are in bold. GAF, genetic ancestry factor; ROI, region of interest; SES, socioeconomic status.

Figure 3

Examples illustrating the different patterns of the age-by-genotype interactions on cortical area (obtained from the ROI-based model). The graphs exemplify age-related effects of NRG1 that emerge (a) or reverse (b and c) at adolescence, and a more complex age-by genotype interaction (d). Percentages are expressed as increases (sign +) or decreases (sign −) in values between the TT-children (green) and the CC-children (blue). Black vertical arrows indicate when the age-by-genotype interactions emerge or reverse. ROI, region of interest.

Figure 4

Associations between rs6994992-NRG1 genotype and fornix measures over age. The fornix tract showed age and NRG1 genotype dependent trajectories in volume (a) and FA (b). (c) Correlation between episodic memory task performance and forniceal metrics as a function of the NRG1 genotype. The center panel illustrates the location of the fornix. Percentages in the graphs are expressed as increases (sign +) or decreases (sign −) in values between the TT-children (green) and the CC-children (blue). Black vertical arrows indicate when the age-by-genotype interactions emerge or reverse. The P-values that survived Holm–Bonferroni correction are in bold. FA, fractional anisotropy; PSMT, picture sequence memory test.