Abstract
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. 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. 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. 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). 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.
Highlights
Schizophrenia is a highly heritable disorder with undetermined neurobiological causes
Schizophrenia is a highly heritable (h2 ∼ 80%),[1] severe and chronic psychiatric disorder for which we have greatly advanced our understanding of the genetic risk factors;[2,3] this has not been followed by a significant improvement in our understanding of its neurobiological underpinnings
Most of these studies have suffered from low statistical power and/or have included participants with severe psychopathology, adding the confounding effect of variables related to the presence of mental illness known to have an impact on brain anatomy.[4,5,6]
Summary
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 compared between groups. This study used a subsample of participants from the UK Biobank (www.ukbiobank.ac.uk) for which brain magnetic resonance. A. β-values were assigned to CNV carrier status after regressing out the effect of gender, age, intracranial volume and scanning centre. All participants have consented to take part in genetic and imaging studies. The UK Biobank was granted ethical approval by the North West Multi-Centre Research Ethics Committee.
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