Subcortical Signatures of Hemizygosity and Psychosis in 22q11.2 Deletion Syndrome: Finding Common Ground in Rare Genetic Variation

For decades, the heritability of common and debilitating psychiatric conditions, such as schizophrenia and bipolar spectrum illnesses, has been appreciated not just as evidence that there are specific molecular foundations of clinical neurobehavioral phenomena, but also as a promise that were these foundations to be identified and mechanistically understood, novel and life-changing targeted therapeutics would follow (1). Increasingly large-scale genome-wide association efforts to identify common risk polymorphisms have made it clear that the clinical intricacies of psychiatric diagnoses are paralleled by genetic architectures that are complex, and despite accelerating innovation and accumulating findings, much of the path from genes to illness remains unknown. When available, a “genotype-first” approach (2) can offer an important alternative with which to understand these complexities where molecular causality may be more easily inferred. In this approach, a selected study population might harbor a rare, well-characterized, and well-bounded genetic variant with an associated large phenotypic risk, such as is the case of many clinically apparent copy number variants (CNVs). A CNV is a type of genetic alteration in which an individual has fewer (i.e., deletion) or more (e.g., duplication, triplication, etc.) copies of a gene or set of genes as a result of nonallelic homologous recombination events introducing errors across a stretch of DNA during cell division.

One important example is the case of 22q11.2 deletion syndrome (22q11DS), a CNV associated with a host of multiorgan manifestations, where current efforts in this vein are largely rooted in a clinical observation nearly 30 years ago of markedly increased risk of schizophrenia (3). This finding, later buttressed by larger-scale quantification (4), has seeded field-wide interest and encouraged the growth of vigorous, multifaceted research initiatives aimed at understanding how hemideletion at this site on the long arm of chromosome 22 might confer neuropsychiatric disability. Advances along these lines from pooled neuroimaging data sets have begun to afford the field a more detailed view of the 22q11DS neurostructural landscape than previously available (5, 6). Drawing from the largest 22q11DS multisite neuroimaging cohort assembled to date, in this issue of the Journal Ching and colleagues (6) illustrate this well by identifying robust subcortical structural patterns present in individuals with the deletion and by additionally reporting on within-cohort effects of psychosis and deletion size subgroups. This work offers important new insights and raises intriguing questions about the neurogenetic mechanisms underlying neuropsychiatric disease states both within and outside of copy number variation contexts.

In this study, reduced intracranial, thalamus, putamen, hippocampus, and amygdala volumes, along with increased lateral ventricle, caudate, and accumbens volumes, were identified in 22q11DS, with generally consistent but more complex (e.g., an anterior-posterior shift in local caudate thickness) shape analysis findings. Whereas overall lateral ventricle, thalamus, and medial temporal lobe structure findings align quite well with observations reported in idiopathic schizophrenia, the striatal findings differ. Because the typical 22q11.2 deletion includes multiple CNS-expressed genes and results in multiple neuropsychiatric outcomes aside from schizophrenia, this CNV would not necessarily be expected to result in a neuroanatomical profile identical to that found in non-CNV-associated schizophrenia. On the other hand, a framework for establishing the circumstances under which any phenotype concordances reflect meaningful shared mechanisms between 22q11DS psychosis and non-22q11DS psychosis merits explicit articulation. Because discovery of shared mechanisms is a fundamental goal of this brand of “genotype-first” molecular medicine approach, such a framework is critical, particularly when the studied genetic variation is incompletely penetrant or pleiotropic in its sequelae, as in the case of 22q11DS. In the special situation of characterizing the biology of such a variant and making homology inferences about the relevance of that biology when observed in other contexts (i.e., idiopathic illness), several principles merit consideration.