# White matter microstructure differences between 15q11.2 copy number variation carriers and non-carriers in mid-to-late life

## TL;DR

The study finds that people with a specific genetic variation in mid-to-late life show differences in brain white matter structure, particularly in the corpus callosum.

## Contribution

This study is the first to examine white matter microstructure differences in 15q11.2 CNV carriers in mid-to-late adulthood.

## Key findings

- 15q11.2 deletion carriers showed altered white matter microstructure in the corpus callosum, cingulum, and hippocampus.
- Lower diffusivity and higher fractional anisotropy suggest microstructural changes in deletion carriers.
- Findings suggest possible axonal overgrowth and myelination abnormalities in deletion carriers.

## Abstract

The 15q11.2 BP1-BP2 copy number variant (CNV) has been associated with neurodevelopmental and psychiatric conditions and brain grey matter structure, but its effects on white matter microstructure (WMM) in mid-to-late adulthood to assess long-term neurobiological effects remain unclear. Understanding these effects is important for evaluating long-term neurobiological impacts across the lifespan. WMM parameters were extracted from UK Biobank diffusion magnetic resonance imaging data for 15q11.2 BP1-BP2 deletion (n = 126, mean age: 66 ± 8) and duplication (n = 131, mean age: 64 ± 7) carriers, as well as age- and sex-matched non-carriers (n = 1260 and n = 1310). We used multiple advanced diffusion approaches, extending beyond DTI, providing metrics on various spatial levels comparing the CNV carriers and non-carriers. All metrics were projected on the WM skeleton for further group comparisons. We present various atlas-derived region-level differences between 15q11.2 BP1-BP2 deletion carriers and non-carriers. These differences suggest altered microstructural organization in the corpus callosum, cingulum and hippocampus, uncinate fasciculus, indicated by lower diffusivity and higher fractional anisotropy, kurtosis, axonal water fraction, and intra-neurite volume fraction (absolute standardized effects > 0.22). Most significant differences across multiple diffusion approaches were detected in the corpus callosum. Our findings suggest that during mid- to-late life, WMM in the corpus callosum is affected by 15q11.2 deletion. Different diffusion approaches allowing for microscopic assessments of WM, beyond previous non-microscopic diffusion MRI based assessments, suggest altered axonal density or microstructural organization, potentially reflecting pathological axonal overgrowth and myelination abnormalities, adding explanations for observable developmental and psychiatric differences between deletion carriers and healthy controls.