Effects of genomic copy number variants penetrant for schizophrenia on cortical thickness and surface area in healthy individuals: analysis of the UK Biobank

Abstract

Background: Schizophrenia is a highly heritable disorder with undetermined neurobiological causes. Understanding the impact on brain anatomy of carrying genetic risk for the disorder will contribute to uncovering its neurobiological underpinnings.

Aims: To examine the effect of rare copy number variants (CNVs) associated with schizophrenia on brain cortical anatomy in a sample of unaffected participants from the UK Biobank.

Method: We used regression analyses to compare cortical thickness and surface area (total and across gyri) between 120 unaffected carriers of rare CNVs associated with schizophrenia and 16 670 participants without any pathogenic CNV. A measure of cortical thickness and surface area covariance across gyri was also compared between groups.

Results: Carrier status was associated with reduced surface area (β = -0.020 mm2, P < 0.001) and less robustly with increased cortical thickness (β = 0.015 mm, P = 0.035), and with increased covariance in thickness (carriers z = 0.31 v. non-carriers z = 0.22, P < 0.0005). Associations were mainly present in frontal and parietal areas and driven by a limited number of rare risk alleles included in our analyses (mainly 15q11.2 deletion for surface area and 16p13.11 duplication for thickness covariance).

Conclusions: Results for surface area conformed with previous clinical findings, supporting surface area reductions as an indicator of genetic liability for schizophrenia. Results for cortical thickness, though, argued against its validity as a potential risk marker. Increased structural thickness covariance across gyri also appears related to risk for schizophrenia. The heterogeneity found across the effects of rare risk alleles suggests potential different neurobiological gateways into schizophrenia's phenotype.

Keywords: Imaging; copy number variation; cortical anatomy; genetics; schizophrenia.

Fig. 1

Differences in cortical surface area (mm²) and thickness (mm) between carriers of schizophrenia-associated copy number variants (SCZ-associated CNVs) and those not carrying CNVs, and carriers of individual SCZ-associated CNVs and those not carrying CNVs. Gyri with nominal significant associations are coloured: warm colours for positive associations (carriers larger) and cold colours for negative associations (carriers smaller). Gyri in which the association with CNV carrier status remained significant after false discovery rate (FDR) correction are marked with an asterisk (*). Only SCZ-associated CNVs that presented with FDR-corrected significant associations are included in the figure (1q21.1duplication did not present any significant association with cortical thickness even before FDR correction).

Fig. 2

Structural covariance index (averaged z-transformed correlation with all other gyri) for cortical surface area and thickness for carriers of schizophrenia-associated copy number variants (CNVs) and non-carriers, and difference between groups. In all cases the colour scheme at the bottom indicates the effect size (z-value for averaged maps, difference in z-value under ‘group difference’). Gyri with nominal significant associations are coloured: warm colours for positive associations (carriers larger) and cold colours for negative associations (carriers smaller). Gyri in which the association with CNV carrier status remained significant after false discovery rate (FDR) correction are marked with an asterisk (*).

Fig. 3

Differences in cortical surface area and thickness covariance between carriers of individual schizophrenia-associated copy number variants (SCZ-associated CNVs) and those not carrying CNVs. Gyri with nominal significant associations are coloured: warm colours for positive associations (carriers larger) and cold colours for negative associations (carriers smaller). Gyri where the association with CNV carrier status remained significant after false discovery rate (FDR) correction are marked with an asterisk (*). Only SCZ-associated CNVs that presented with FDR-corrected significant associations are included in the figure (16p13.11duplication did not present any significant association for surface area covariances even before FDR correction).