Deciphering the Genetic Complexity of Schizophrenia

Studiesusinggenetic epidemiologicmethods toprobe thegenetic architectureof schizophrenia are increasinglygivingway to those using genome-wide association approaches. In this issueof JAMAPsychiatry, Bohlkenetal1 report thatgenetic epidemiologic methods, in particular structural equation modeling of twin and family correlations on intermediate traits of interest, can yield important insights into the genetic underpinnings of the disorder, results that in turn could help to organize associations at the molecular level. Bohlken et al evaluated sets of twin pairs discordant for schizophrenia and healthy twinpairswith2neuroimaging techniques, diffusionweighted and T1-weighted imaging, to determine the extent towhichgenetic susceptibility to schizophrenia overlapswith measures sensitive to the integrity of white matter and gray matter, respectively. Both white matter integrity (as indexed by fractional anisotropy [FA]) and cortical gray matter thickness were found to be heritable traits that were significantly reduced in people with schizophrenia. In both cases, genetic influences shared with schizophrenia were found to account for a high proportion of these phenotypic correlations. However, the genetic factors that influenced the correlation between schizophrenia and reduced FA were found to be independent of the genetic factors that influenced the correlation between schizophrenia and reduced cortical gray matter thickness.1 Because schizophrenia is clinicallyheterogeneousandhas acomplexgeneticarchitecture that involves thousandsofcommonandraregeneticvariants,2 it is generallyaccepted thatdifferent sets of risk-relatedpolymorphismswill be related todifferent aspects of the pathophysiologic mechanisms and expressionof thedisorder.Oneway to conceptualize the complex territory thatmediates between specific genetic risk factors and syndromal schizophrenia is by way of a watershed analogy.3 In this approach, individual genetic risk factors represent the “headwaters”or originpoints for phenotypic effects that get aggregated together as they flow downstream. The specific phenotypic effects are determined by aggregations in contiguous territories, such that the effects of genes with commonmechanisms (ie, operating on the same signaling cascades) flow together to form rivulets that affect specificprocessesat thecellularor systems level (eg, synapticplasticity,myelination). In turn, theeffectsofmultiple suchrivulets flow together to form streams that have an impact at the level of specific cognitive operations (eg, multimodal integration, memory), andmultiple such streams flow together into tributaries that affect particular symptoms. Finally, the effects of multiple such tributaries flow together, reaching their broadest effect at the delta, representing the syndromal phenotype (schizophrenia). This kind of model is able to account for heterogeneity in the sense that theprofile of risk variants (relevant headwaters) will be at least partially different in different patients, resulting in different degrees of mixtures from various rivulets, streams, and tributaries in the intermediate zones. With this model in mind, the results of the study by Bohlken et al appear to reveal a topography such thatwith respect to the genetics of schizophrenia, the genetic inputs to disruptedwhitematter integrity operate in a different rivulet from those contributing to reduced cortical graymatter thickness.One implicationof this result forgeneticassociationstudies is that the inheritedvariants that contribute to lowerFAwill be different from those contributing to graymatter reduction in schizophrenia.A strong test of this hypothesis couldbeperformed by training and validating genome-wide risk scores2 associated with measures of tract integrity and gray matter thinning in large samples of patients with schizophrenia and determining the overlap (or, as the case may be, nonoverlap) in the 2 sets of risk variants, both of which should nevertheless be represented within the larger set of variants associated with risk for syndromal schizophrenia. DecreasedFA is thought to reflect lower integrity ofwhite matter tracts that link different parts of the brain, making it relevant tomodels that specify disconnection as a key pathophysiologic mechanism in schizophrenia. Decreased cortical thickness in schizophrenia is generally viewedas reflecting reductions in dendritic spines,4 which would also be expected to have an effect on neuronal connectivity. Thus, in a broader (more downstream) sense, both the white matter and gray matter rivulets are likely to affect a stream, representing interneuronal communicationand functional connectivity,with their effects flowing together into tributaries and increasing the risk of symptom formation, in combination with other genetically regulated streams (eg, neurotransmitter release, neuroreceptors). Although reduced FA and reduced cortical thickness are correlatedwith eachother in patientswith schizophrenia, according to the results of Bohlken et al,1 this is not because of shared genetic causes. Thus, their phenotypic correlation in schizophrenia may reflect an additional degree of effect over and above that associatedwith their respective inherited substrates, as in a secondary effect. In this case, it remains ambiguous whether reduced dendritic spine density is primary, driving some further degree of reduction in FA in tracts that link the affected pyramidal cells (ie, beyond the reduced FA associatedwith schizophrenia-related susceptibility genes) or, conversely,whetherdisruptedwhitematterdevelopment leads Related article page 11 Opinion