Sex Chromosome Dosage Effects on White Matter Structure in the Human Brain

Abstract

Sex chromosome aneuploidies, a group of neurogenetic conditions characterized by aberrant sex chromosome dosage (SCD), are associated with increased risks for psychopathology as well as alterations in gray matter structure. However, we still lack a comprehensive understanding of potential SCD-associated changes in white matter structure, or knowledge of how these changes might relate to known alterations in gray matter anatomy. Thus, here, we use voxel-based morphometry on structural neuroimaging data to provide the first comprehensive maps of regional white matter volume (WMV) changes across individuals with varying SCD (n = 306). We show that mounting X- and Y-chromosome dosage are both associated with widespread WMV decreases, including in cortical, subcortical, and cerebellar tracts, as well as WMV increases in the genu of the corpus callosum and posterior thalamic radiation. We also correlate X- and Y-chromosome-linked WMV changes in certain regions to measures of internalizing and externalizing psychopathology. Finally, we demonstrate that SCD-driven WMV changes show a coordinated coupling with SCD-driven gray matter volume changes. These findings represent the most complete maps of X- and Y-chromosome effects on human white matter to date, and show how such changes connect to psychopathological symptoms and gray matter anatomy.

Sex differences in the human brain: a roadmap for more careful analysis and interpretation of a biological reality

“…Evidence for sex chromosome dosage effects on the human brain comes from observational research in groups with differing X and/or Y chromosome doses due to sex chromosome aneuploidy. Specifically, increasing X- and/or Y- chromosome dosage induces highly reproducible changes in diverse aspects of regional brain anatomy, including parieto-occipital cortical surface area (increased), lateral temporal cortical thickness (decreased), and volume of the cerebellum and globus pallidus (both decreased) [ 58 – 61 ].…”

“…Second, newer tools for brain-wide analyses of cell counts in mice show that many foci with sex-biased cellular compositions are also regions that show sex-biased volumes by sMRI [ 100 , 101 ]. Third, gonadal and sex chromosome factors that tend to differ between typical males and females have been shown to modulate sMRI measures of regional brain volume using experimental methods in mice [ 42 , 43 ] and observational data in humans [ 47 , 48 , 58 – 61 ].…”

The pivotal role of the X-chromosome in the genetic architecture of the human brain

“…This heightened influence of the X-chromosome-coupled with its comparatively lower total heritability to other tracts-complements existing knowledge about significant sex differences in the development of the corticospinal tract 50,51 . Further evidence suggests that increased X-chromosome dosage can notably decrease the white matter volume of the corticospinal tract 14 . This unique heritability of the corticospinal tract might stem from the additional dosage of X-escapee genes.…”

“…The X-chromosome is home to a wealth of genes predominantly expressed in brain tissues 10,13 as the chromosome-X to autosome expression ratio exceeds one 10 , underscoring the pronounced influence of the X-chromosome on brain anatomy, connection, and functions [14][15][16][17] . Mounting evidence has shown that the X-chromosome significantly impacts a myriad of neurological diseases and psychiatric disorders from both genetic and epigenetic viewpoints 5,[18][19][20] .…”

“…Chromosome mutations, such as sex chromosome aneuploidy, can have profound implications on brain structures 14,22 , cognitive capacities 23,24 , behaviors 24 , and both neurological 24,25 and psychiatric disorders 26,27 . A combination of factors -including the dense presence of associated genes, varying gene expression between sexes, and the influence of epigenetic processes steered by sex steroid hormonesestablishes the X-chromosome as a nexus for sex differences in the human brain across various age groups 4,7,8,[28][29][30][31][32][33] .…”