Analysis of Diffusion Tensor Imaging Data From the UK Biobank Confirms Dosage Effect of 15q11.2 Copy Number Variation on White Matter and Shows Association With Cognition

Biol Psychiatry. 2021 Sep 1;90(5):307-316. doi: 10.1016/j.biopsych.2021.02.969. Epub 2021 Mar 3.


Background: Copy number variations at the 15q11.2 BP1-BP2 locus are present in 0.5%-1.0% of the population, and the deletion is associated with several neurodevelopmental disorders. Previously, we showed a reciprocal effect of 15q11.2 copy number variation on fractional anisotropy, with widespread increases in deletion carriers. We aim to expand these findings using a larger sample of participants (N = 29,166) and higher resolution imaging and by examining the implications for cognitive performance.

Methods: Diffusion tensor imaging measures from participants with no neurological or psychiatric diagnoses were obtained from the UK Biobank database. We compared 15q11.2 BP1-BP2 deletion (n = 102) and duplication (n = 113) carriers to a large cohort of control individuals with no neuropsychiatric copy number variants (n = 28,951). Additionally, we assessed how changes in white matter mediated the association between carrier status and cognitive performance.

Results: Deletion carriers showed increases in fractional anisotropy in the internal capsule and cingulum and decreases in the posterior thalamic radiation compared with both duplication carriers and control subjects (who had intermediate values). Compared with control subjects, deletion carriers had lower scores across cognitive tasks, which were partly influenced by white matter. Reduced fractional anisotropy in the posterior thalamic radiation partially contributed to worse cognitive performance in deletion carriers.

Conclusions: These results, together with our previous findings, provide convergent evidence for an effect of 15q11.2 BP1-BP2 on white matter microstructure, this being more pronounced in deletion carriers. Additionally, changes in white matter were found to partially mediate cognitive ability in deletion carriers, providing a link between white matter changes in 15q11.2 BP1-BP2 carriers and cognitive function.

Keywords: 15q11.2 BP1-BP2; CYFIP1; Cognition; Copy number variant; Diffusion tensor imaging; Genetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Specimen Banks
  • Cognition
  • DNA Copy Number Variations*
  • Diffusion Tensor Imaging
  • Humans
  • United Kingdom
  • White Matter* / diagnostic imaging