Researchers from Cardiff University found the potential for multiple neurobiological pathways to lead to schizophrenia, with a complex relationship between structural thickness of brain regions and rare risk variants, according to study results published in The British Journal of Psychiatry.

There is limited data on the effect of carrying genetic risk for schizophrenia on brain anatomy, as well as the disorder’s neurobiological basis. Study researchers sought to analyze the effect of rare copy number variants (CNV) associated with the disorder on brain cortical anatomy in healthy individuals.

Study researchers utilized data from the United Kingdom (UK) Biobank for this regression analysis. Magnetic resonance imaging (MRI) T1 images of brains from 18,534 individuals were included. Participants also provided genetic samples and had no prior history of neuropsychiatric disorders or neurological conditions that could impact cortical anatomy.

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All participants were of White, British or Irish descent (53%, women; mean age, 55 [standard deviation [SD], 7.46 years]). Gender was equally distributed across carriers of known schizophrenia variants and noncarriers among the study population (c2[1], 0.78; P >.1). Among carriers, 49% had the most common CNV deletion 15q11.2.

Reduction of total brain surface area (b, -0.020 mm2; P <.001) and thicker cortex (b, 0.015 mm; P =.035) were associated with carrying any established schizophrenia-associated CNV.

Within specific CNVs, the 1q21.1 (n=9; b, -0.011 mm2; P =.006) and 15q11.2 (n=59; b, -0.016 mm2; P <.001) deletions were significantly associated with surface area reductions. The 15q11.2 deletion was also significantly associated with a thicker cortex (b, 0.020 mm; P =.006).

Overall structural surface area covariance did not differ between carriers and non-carries of schizophrenia-associated CNVs (z, 0.16 vs 0.14, respectively; P =.239). The structural cortical thickness covariance was significantly increased among carriers compared with non-carriers (z, 0.31 vs 0.22, respectively; P <.0005); this was observed widespread across gyri.

Despite the large sample size, the penetrance of schizophrenia-associated CNVs limited the sample size and power. The study investigators noted that further studies should try to replicate these findings in the future release of the UK Biobank which is projected to include MRI data from 100,000 individuals.

The study authors concluded individuals who carry schizophrenia-associated variants were predicted to have reduced cortical surface areas and increased cortical thicknesses when compared with non-carriers. However, they added that “the heterogeneity found across the effects of rare risk alleles suggests potential different neurobiological gateways into schizophrenia’s phenotype.”


Caseras X, Kirov G, Kendall KM, et al. Effects of genomic copy number variants penetrant for schizophrenia on cortical thickness and surface area in healthy individuals: Analysis of the UK Biobank. Br J Psychiatry. 2020;1-8. doi: 10.1192/bjp.2020.139