Copy Number Variants Increasing Risk for Schizophrenia: Shared and Distinct Effects on Brain Morphometry and...

Copy number variations (CNVs) conferring risk for mental disorders are associated with brain changes and cognitive deficits. However, whether these effects are shared or distinct across CNVs remains untested. Here we compared the effects on brain morphometry and cognitive performance across CNVs with shared psychiatric liability.

Unaffected and unrelated participants of White British and Irish ancestry were drawn from the UK Biobank. After quality control, we retained 31,941 participants not carrying any damaging CNVs and 202 participants carrying one CNV increasing risk for schizophrenia. Using regression analyses, we tested the association between brain morphometry and cognitive performance with CNV carrying status and compared these effect sizes across CNVs using z test for the equality of regression coefficients. Equation modeling was used to examine the mediation of brain phenotypes on the association between CNVs and cognitive performance.

We detected different patterns of association between CNVs and brain morphometry and cognitive abilities. Comparing across CNVs, 1q21.1 deletion showed the strongest association with surface area in frontal lobe (β = -1.03, p = 4 × 10^-8; β = -0.81, p = .00001) and performance in digit memory (β = -1.58, p = .00003), while 1q21.1 duplication showed the strongest association with volume of the putamen (β = -0.70, p = .0004) and reaction time (β = -1.14, p = .000002). We also showed that even when 2 CNVs were associated with performance in the same cognitive ability, these associations were mediated by different brain changes.

Despite sharing similar psychiatric liability, the CNVs under study appeared to have different effects on brain morphometry and on performance in cognitive abilities, suggesting the existence of distinctive neurobiological pathways into the same clinical phenotypes.