THE IMPACT OF RARE GENETIC VARIANTS ON BRAIN STRUCTURE AND RISK FOR NEUROPSYCHIATRIC DISORDERS

Abstract

Background

Rare recurrent copy number variants (CNVs) have been implicated in atypical neurodevelopment and elevated risk for neuropsychiatric disorders. Among these, CNVs at the 22q11.2 locus (i.e., deletions or duplications on the long arm of chromosome 22) represent one of the most robust genetic risk factors for developmental neuropsychiatric conditions. The 22q11.2 deletion, occurring in ∼1 in 3,600 live births, is associated with markedly increased risk for autism spectrum disorder and schizophrenia. In contrast, the reciprocal 22q11.2 duplication, found in ∼1 in 1,200 live births, confers elevated risk for autism spectrum disorder but is associated with a reduced risk of schizophrenia relative to the general population. These reciprocal CNVs thus provide a unique model to investigate the neurobiological mechanisms underlying vulnerability and resilience to neuropsychiatric disorders. This presentation will highlight preliminary results showing that 22q11.2 CNVs are associated with substantial distribution shifts and regional brain structural variability beyond mean differences, as measured by magnetic resonance imaging, compared to controls. A novel neurodevelopmental model of the mechanisms underlying these alterations will also be discussed.

Methods

Magnetic resonance imaging data of 22q11.2 CNV carriers and unrelated, typically developing controls were derived from an ongoing longitudinal study (111 22q11.2 deletion carriers, 109 controls and 38 22q11.2 duplication carriers) and the world’s largest multi-site study on 22qDel (438 22q11.2 deletion carriers and 412 controls). Brain structural measures include cortical thickness, cortical surface area, cortical folding, intracranial volume, white matter volume and gray matter volume.

Results

22q11.2 deletion carriers show widespread increased cortical thickness and lower cortical surface area, characterized by a complete distribution shift in these measures compared to controls. The 22q11.2 deletion carriers also showed greater gray matter volume relative to white matter volume, which was related to individual differences in cortical surface area. In addition, there was a significant dosage effect (i.e., linear association between brain measures and copies of the 22q11.2 locus) on cortical folding (positive association) and cortical thickness (negative association).

Discussion and Conclusion

The 22q11.2 CNVs yield large effects on brain structure, resulting in a distribution shift in brain phenotypes among 22q11.2 deletion carriers. We posit that the consistently observed increased cortical thickness and lower cortical surface area in 22q11.2 deletion may represent increased neuronal density in deep cortical layers and reduced neuronal density in upper cortical layers. In contrast, 22q11.2 duplication may yield increased neuronal density in upper cortical layers, resulting in a thinner cortex and increased axonal tension. This may, in part, be driven by trans-effects of the 22q11.2 CNVs on genes implicated in thalamocortical axonal overgrowth (i.e., FOXP2 and ROBO2) and cortical expansion (i.e., PAX6). The relationship between lower and upper cortical layers may underlie vulnerability to schizophrenia and autism spectrum disorders.