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These results provide support for the Kraepelinian dichotomy of psychosisto the extent that we have demonstrated markedly different gray matter endophenotypesassociated with the genetic risks for schizophrenia and psychotic bipolardisorder. Genetic risk for schizophrenia was associated with a relativelyextensive system of frontal, temporal, and subcortical gray matter deficits.These regions are compatible with regions of structural deficit identifiedby prior case-control studies of patients with schizophrenia.^{12- 14} However,interregionally correlated anatomical variation in this gray matter systemwas associated with variable genetic risk in relatives without psychosisas well as patients with schizophrenia (suggesting that anatomical variationin this system is a marker for genetic risk rather than for caseness) butwas not significantly associated with genetic risk among unaffected relativesof patients with bipolar disorder (suggesting that this endophenotypic brainsystem is indicative of genetic risk specifically for schizophrenia).

In contrast, risk for bipolar disorder was associated with more localgray matter deficits in the right anterior cingulate gyrus and ventral striatum,both of which are components of brain circuits for emotional processing³⁸ and have been identified as exhibiting abnormalitiesin previous case-control studies of patients with familial bipolar disorderusing structural and functional neuroimaging.³⁹ However,in this article we have clarified that anatomical variation in these regionsis a marker for genetic risk even among relatives without psychosis, not merelya marker for the presence of bipolar disorder in patients, and we have shownthat this endophenotypic brain system is indicative of genetic risk specificallyfor bipolar disorder.

Studies examining unaffected relatives or discordant twins of patientswith schizophrenia have previously linked genetic risk to volumetric reductionof the thalamus^40,41 and prefrontaland temporal cortical gray matter,^42,43 especiallythe dorsolateral prefrontal cortex,⁴³ but therewas no evidence of gray matter reduction with genetic risk in a recent twinstudy of bipolar disorder.⁴⁴ Some studies comparingunaffected relatives of patients with schizophrenia with controls have reportedthat genetic risk is related to volume reduction of the hippocampus,^41,45,46 which did not emergein this study. However, the effect of genetic risk on this structure remainsto be fully elucidated because other studies failed to find hippocampal volumereduction in unaffected relatives^47,48;evidence also suggests that hypoxic birth complications and the transitionto psychosis influence medial temporal lobe volume deficits in schizophrenia.^{46,48- 50} Inrelation to these prior data, the distinctive value of our results is thatthey provide a more comprehensive map of the gray matter endophenotype inschizophrenia throughout the brain, and they allow an unprecedented directcomparison with the gray matter endophenotype in bipolar disorder.

The unique comparative design of this study also draws attention toaspects of the brain phenotype that are expressed in common between the 2forms of psychosis. Genetic risk for both disorders was associated with distributedwhite matter volume deficits that were anatomically coincident in the leftprefrontal and temporoparietal regions. White matter abnormalities have beenreported in case-control studies of both schizophrenia^14,51,52 andbipolar disorder.^16,17,53 Studiesof discordant twins have reported a genetic effect on global white mattervolume reduction in schizophrenia⁵⁴ and lefthemispheric white matter volume reduction in bipolar disorder,⁴⁴ althoughother studies assessing unaffected relatives of subjects with schizophreniahave failed to find a genetic effect on global white matter volume.^42,55,56 Our data map thewhite matter endophenotype for psychosis more precisely to territories normallyoccupied by major intrahemispheric tracts: the left superior longitudinalfasciculus, which connects the frontal lobe to the temporal, parietal, andoccipital lobes; and the left inferior longitudinal fasciculus, which connectsthe temporal pole to the occipital lobe.

We surmise that risk for psychosis in general is associated with a patternof white matter abnormality that is likely to compromise intrahemisphericanatomical connectivity between the left prefrontal and temporoparietal cortex.This conjecture is compatible with a substantial body of case-control dataand theory implicating disintegration or disconnectivity of large-scale neurocognitivenetworks, especially frontotemporal disconnectivity, as a critical substratefor the generation of psychotic symptoms.^{57- 60} Weacknowledge that the neuropathological substrate of these white matter changesis incompletely determined by the magnetic resonance signal changes reportedin this article. For example, it is possible that the white matter changeswe have described as deficits could reflect changes in the magnetic resonancesignal owing to abnormal myelination rather than reduction in the number ofaxons. There is prior evidence from case-control studies of gene expressionin the frontal cortex for the down-regulation of genes related to myelinationand oligodendrocyte function in both schizophrenia and bipolar disorder.^61,62 In future studies, we will directlyinvestigate associations between allelic variation in candidate genes andstructural variation in the gray and white matter endophenotypes defined inthis article. Such studies are expected to improve the power to detect pathogeneticallyrelevant genes for psychotic disorders and to enhance understanding of thecellular substrates of MRI endophenotypes.

Some methodological aspects of our study deserve comment. The patientsparticipating in this study were carefully diagnosed according to operationalizedcriteria and were drawn exclusively from multiply affected families. We treatedgenetic risk as continuously variable among relatives without psychosis ratherthan assuming that all relatives shared the same level of risk. We suggestthat this is a more realistic assumption, in light of the likely variationbetween families in their exposure to multiple susceptibility genes, thatmay have conferred greater statistical power to detect brain endophenotypeswith our regression analysis of anatomical variation and continuous geneticliability scores than would have been attainable by, for example, an analysisof variance treating patients and relatives as 2 discrete levels of geneticrisk. We also used a customized, computerized “pipeline” for computationalmorphometry of the whole brain structure that incorporated software sourcedfrom several laboratories for optimized nonlinear image registration and nonparametrichypothesis testing of spatially informed cluster-level statistics. All imageswere registered to a single template image constructed for this purpose fromMRI studies acquired using the same scanner and pulse sequence of a groupof healthy comparison subjects demographically matched to the patient andrelative groups.

Enduring controversy often indicates that more than one view is reasonablytenable. We suggest that the long-standing dialectic between categorical anddimensional accounts of major mental illness is related to the main implicationof these data: genetic risks for schizophrenia and bipolar disorder are associatedwith both specific and generic brain structural endophenotypes. The anatomicallysegregated expression of specific and generic genetic effects that, to ourknowledge, we have demonstrated for the first time is consistent with morphometricdeviations linked to the clinical phenotypes of schizophrenia and bipolardisorder. These results also provide an important basis for future studiesseeking to more powerfully identify susceptibility genes for psychosis byassociation with neuroimaging endophenotypes. We conclude that Kraepelin’spivotal distinction was neither wholly right nor wholly wrong.It is more apt, perhaps, to think of psychosis as a sibling pair of neurogeneticsyndromes than as 1 or 2 discrete disease entities.

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