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Objective: Schizophrenia has one of the highest heritability estimates in psychiatry, but the geneticallybased underlying neuropathology has mainly remained unclear. We conducted a multimodal coordinatebased meta-analysis (CBMA) to investigate brain structural and functional alterations in individuals with high familial risk for schizophrenia, i.e. in first-degree relatives of schizophrenia patients (FRs). Methods:We conducted a systematic literature search from two electronic databases to find studies that examined differences between FRs and healthy controls using whole-brain functional magnetic resonance imaging (fMRI) or voxel-based morphometry (VBM). A CBMA of 30 fMRI (754 FRs; 959 controls) and 11 VBM (885 FRs; 775 controls) datasets were conducted using the anisotropic effect-size version of signed differential mapping. Further, we conducted separate meta-analyses about functional alterations in different cognitive tasks: social cognition, executive functioning, working memory, and inhibitory control. Results:When compared to healthy controls, FRs showed higher fMRI activation in the right frontal gyrus during cognitive tasks. In VBM studies, there were no differences in grey matter density between FRs and healthy controls. Furthermore, multi-modal meta-analysis obtained no differences between FRs and healthy controls. Finally, by utilizing the BrainMap database, we showed that the brain region which showed functional alterations in FRs (i) overlapped only slightly with the brain regions that were affected in the meta-analysis of schizophrenia patients and (ii) correlated positively with the brain regions that exhibited increased activity during cognitive tasks in healthy individuals. Conclusions: Based on this meta-analysis, FRs may exhibit only minor functional alterations in the brain during cognitive tasks, and the alterations are much more restricted and only slightly overlapping with the regions that are affected in schizophrenia patients. The familial risk did not relate to structural alterations in the grey matter.

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