Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era

Abstract

Schizophrenia is a complex neuropsychiatric disease with documented clinical and genetic heterogeneity, and evidence for neurodevelopmental origins. Driven by new genetic technologies and advances in molecular medicine, there has recently been concrete progress in understanding some of the specific genetic causes of this serious psychiatric illness. In particular, several large rare structural variants have been convincingly associated with schizophrenia, in targeted studies over two decades with respect to 22q11.2 microdeletions, and more recently in large-scale, genome-wide case-control studies. These advances promise to help many families afflicted with this disease. In this review, we critically appraise recent developments in the field of schizophrenia genetics through the lens of immediate clinical applicability. Much work remains in translating the recent surge of genetic research discoveries into the clinic. The epidemiology and basic genetic parameters (such as penetrance and expression) of most genomic disorders associated with schizophrenia are not yet well characterized. To date, 22q11.2 deletion syndrome is the only established genetic subtype of schizophrenia of proven clinical relevance. We use this well-established association as a model to chart the pathway for translating emerging genetic discoveries into clinical practice. We also propose new directions for research involving general genetic risk prediction and counseling in schizophrenia.

Figure 1

Neurodevelopmental model of schizophrenia, informed by new molecular genetic discoveries. One or more transmitted or de novo sequence or structural mutations, involving one or more genes, and acting individually or interactively, is proposed as the initial causal event. The pathway from genotype to phenotype is formulated as a dynamic process beginning at or before conception, and involving gene expression (including, but not limited to, protein activity) and interaction with normal brain development and neuronal plasticity mechanisms, and likely multiple other genetic and non-genetic factors. Different phenotypic endpoints are possible, and specific factors that dictate variable expression of ostensibly the same genetic loading are largely unknown and may be variant-specific. These resulting phenotypes could include clinically diagnosable schizophrenia, other psychiatric illnesses, other conditions including disorders of development, or no detectable expression. For example, a 22q11.2 deletion (yellow structural variant) may be expressed as schizophrenia and/or a related psychiatric disorder and/or another developmental disorder (yellow stars). Note: Adapted from AS Bassett, EW Chow, S O’Neill, LM Brzustowicz, Genetic insights into the neurodevelopmental hypothesis of schizophrenia, Schizophrenia Bulletin, 2001, 27, 3, pp. 417–430, by permission of Oxford University Press. Abbreviation: CNV, copy number variation.