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

Abstract

Sex chromosome aneuploidy (SCA) enhances risk for several psychiatric disorders associated with the limbic system, including mood and autism spectrum disorders. These patients provide a powerful genetics-first model for understanding the biological basis of psychopathology.Additionally, these disorders are frequently sex-biased in prevalence, further suggesting an etiological role for sex chromosomes. Here, to clarify how limbic anatomy varies across sex and sex chromosome complement, we characterize amygdala and hippocampus structure in a uniquely large sample of patients carrying supernumerary sex chromosomes (n = 132) and typically developing controls (n=166). After correction for sex-differences in brain size, karyotypically normal males (XY) and females (XX) did not differ in volume or shape of either structure studied.In contrast, all SCAs were associated with lowered amygdala volume relative to gonadallymatched controls. This effect was robust to three different methods for total brain volume correction, 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 correction 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 within the hippocampal surface that cuts across hippocampal subfields. These results demonstrate the power of SCA as a model to understand how genetic insults precipitate changes in brain systems relevant to psychiatric disease. SEX CHROMOSOME ANEUPLOIDY AND LIMBIC STRUCTURE Significance StatementIn approximately 1 per 500 live births, infants are born carrying extra X-or Y-chromosomes.These conditions, known as sex chromosome aneuploidies (SCA), are associated with elevated risk for psychiatric disorders such as depression, anxiety, and autism. In our study, we leverage a uniquely large dataset of brain scans from SCA patients to characterize how SCA influences the structure of the amygdala and hippocampus, which have been strongly implicated in many SCAlinked neuropsychiatric disorders. Across our different patient groups, we find converging evidence that SCA is associated with a decrease in amygdala volume, and spatially specific areal contractions in both the amygdala and hippocampus. Our findings help clarify how genetic copy number variation associated with psychiatric disease shapes brain organization.

Sex-Biased Trajectories of Amygdalo-Hippocampal Morphology Change Over Human Development

“…Our bulk volumetric analyses replicate past findings regarding sex differences in the absolute volume of both structures (males > females; Dennison et al, 2013; Herting et al, 2018; Nadig et al, 2018; Tamnes, et al, 2018; Wierenga et al, 2014). We also observed clearly non-linear trajectories of volume change for both structures which broadly replicate those detected in the other available longitudinal studies of amygdala and hippocampal volume trajectories across childhood and adolescence (Herting et al, 2018, Tamnes et al, 2018; Wierenga et al, 2014).…”

“…Murine neuroimaging data also suggest that medial amygdala volume differs as a function of chromosome complement in a manner that opposes the directional effects of gonadal sex-steroids (i.e., XY < XX, and gonadal males > gonadal females). Comparable experimental data are lacking in humans, but there is observational neuroimaging evidence for both sex steroid (Peper, Hulshoff Pol, Crone, & van Honk, 2011) and sex chromosome effects (Nadig et al, 2018) on medial amygdala organization in humans.…”

“…This region is considered to be comparable to the extreme caudal hippocampal tail in humans (Strange et al, 2014), which we also find to be larger in males than females. As for the amygdala, observational neuroimaging data suggest that human hippocampal volume may also be sensitive to sex steroid (Peper et al, 2011) and sex chromosome (Nadig et al, 2018; Satterthwaite et al, 2014) effects. Thus, existent data – though scant – are consistent with the idea that there are conserved sex-biases in regional amygdalo-hippocampal organization, and that these differences may arise through the combined effects of sex-differences in chromosomal complement and gonadal status.…”

Sex differences in Variability of Brain Structure Across the Lifespan

“…Recent work on sex-chromosome aneuploidy has indicated a dose effect of sex-chromosomes on gene expression (48) . Additional work from the same group has found effects of sex-chromosome dosage on brain structures (49,50) . These studies show sex-chromosomes influence both brain structure and gene-expression, however, further work is required to identify the underlying causes of the discrepancy in variability between males and females seen here and determine the relationship to genetic variability or gene expression.…”

Reduced mammillary body volume in individuals with a schizophrenia diagnosis: an analysis of the COBRE data set

“…Inclusion of total grey matter enabled contrasting regional changes with whole-brain atrophy. To further account for inter-individual differences, we also performed analyses following normalisations to total brain volume and gender, using three different commonly used methods: a ratio method, a covariance method and an allometric method to account for non-linearity in the scaling of sub-cortical regions (Nadig et al, 2018; see Methods for further details). Finally, we also investigated the effect of age on regional volumes.…”