Linking Lysosomal Enzyme Targeting Genes and Energy Metabolism with Altered Gray Matter Volume in Children with Persistent Stuttering

Abstract

Developmental stuttering is a childhood onset neurodevelopmental disorder with an unclear etiology. Subtle changes in brain structure and function are present in both children and adults who stutter. It is a highly heritable disorder, and 12-20% of stuttering cases may carry a mutation in one of four genes involved in intracellular trafficking. To better understand the relationship between genetics and neuroanatomical changes, we used gene expression data from the Allen Institute for Brain Science and voxel-based morphometry to investigate the spatial correspondence between gene expression patterns and differences in gray matter volume between children with persistent stuttering (n = 26, and 87 scans) and their fluent peers (n = 44, and 139 scans). We found that the expression patterns of two stuttering-related genes (GNPTG and NAGPA) from the Allen Institute data exhibited a strong positive spatial correlation with the magnitude of between-group gray matter volume differences. Additional gene set enrichment analyses revealed that genes whose expression was highly correlated with the gray matter volume differences were enriched for glycolysis and oxidative metabolism in mitochondria. Because our current study did not examine the participants' genomes, these results cannot establish the direct association between genetic mutations and gray matter volume differences in stuttering. However, our results support further study of the involvement of lysosomal enzyme targeting genes, as well as energy metabolism in stuttering. Future studies assessing variations of these genes in the participants' genomes may lead to increased understanding of the biological mechanisms of the observed spatial relationship between gene expression and gray matter volume.

Keywords: longitudinal; lysosome; metabolism; stuttering; voxel-based morphometry.

Figure 1.

Spatial relationship between gene expression and between-groups differences in gray matter volume (GMV). (A) Voxel-wise differences between children with persistent stuttering (pCWS) and controls in GMV. Color-coded t values of group differences are overlaid on an anatomical image. Areas exhibiting a significant between-group difference in GMV (corrected p < 0.05) are outlined by black lines. The other colored areas are subthreshold (uncorrected p < 0.1). (B) Parcellated gene expression of GNPTG and NAGPA and absolute GMV differences in t statistics (|t stat|) in 45 left hemispheric regions and the right cerebellum (which anatomically connects to the left hemisphere) were overlaid on a single-subject anatomical image. The parcellation of the brain was based on a standard atlas with automated anatomical labeling (AAL). Gene expression and |t stat| of the right cerebellum were displayed in the left cerebellum to save space. (C) Frequency plot of Spearman’s correlation coefficients between GMV group differences and each of the 19,174 genes expressed across the regions. The red dashed lines indicate the levels of correlation at the 2.5th and 97.5th percentiles. The probability of obtaining a correlation >0.474 or <−0.360 is less than 5% if a gene is randomly selected. (D) Scatter plots between gene expression and group differences in GMV in the sensorimotor areas (red dots), the parietal lobe (purple dots), the cingulate cortex (orange dots), the middle frontal gyrus (green dots) and the rest of the regions (blue dots). Regions in which gene expression is 2.5 standard deviations above or below the mean are labeled.