Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures

Abstract

Sex chromosome aneuploidy (SCA) increases risk for several psychiatric disorders associated with the limbic system, including mood and autism spectrum disorders. Thus, SCA offers a genetics-first model for understanding the biological basis of psychopathology. Additionally, the sex-biased prevalence of many psychiatric disorders could potentially reflect sex chromosome dosage effects on brain development. To clarify how limbic anatomy varies across sex and sex chromosome complement, we characterized amygdala and hippocampus structure in a uniquely large sample of patients carrying supernumerary sex chromosomes (n = 132) and typically developing controls (n = 166). After adjustment for sex-differences in brain size, karyotypically normal males (XY) and females (XX) did not differ in volume or shape of either structure. In contrast, all SCAs were associated with lowered amygdala volume relative to gonadally-matched controls. This effect was robust to three different methods for total brain volume adjustment, including an allometric analysis that derived normative scaling rules for these structures in a separate, typically developing population (n = 79). Hippocampal volume was insensitive to SCA after adjustment for total brain volume. However, surface-based analysis revealed that SCA, regardless of specific karyotype, was consistently associated with a spatially specific pattern of shape change in both amygdala and hippocampus. In particular, SCA was accompanied by contraction around the basomedial nucleus of the amygdala and an area crossing the hippocampal tail. These results demonstrate the power of SCA as a model to understand how copy number variation can precipitate changes in brain systems relevant to psychiatric disease.

Trial registration: ClinicalTrials.gov NCT00001246.

Keywords: CNV; amygdala; hippocampus; sex chromosome aneuploidy.

Figures

Figure 1.

Bulk volume analysis of amygdala and hippocampus. (A) Total brain volume (tbv), amygdala, and hippocampus volume across karyotype groups, relative to typically developing males (XY). (B) Scaling of amygdala and hippocampus volume in the allometric sample (amygdala β1 = 0.89; hippocampus β1 = 0.76). (C) Comparisons of regional volume across sex and sex chromosome complement. FDR-corrected log(p) values are shown. Presence of color indicates statistical significance, and color identity/sign indicates direction of effect: for contrast A-B, blue and negative values indicate smaller volume in A versus B, red and positive value indicate larger volume in A versus B.

Figure 2.

Surface-based analysis of amygdala and hippocampus shape. (A) Map of vertex-wise surface area scaling coefficients from log-log linear model with total bilateral region surface area. (B) Binarized surface maps showing areas of significant surface area contraction (blue) or expansion (red) for each patient contrast. (C) Spatial correlation of uncorrected t-statistic maps demonstrating convergence of SCA effects. AMY: Amygdala, HC: Hippocampus.