Abstract
First‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs (d = −0.42, p = 3 × 10−5), with weak evidence of IQ reductions among BD‐FDRs (d = −0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Highlights
Schizophrenia and bipolar disorder are highly heritable disorders with a shared genetic architecture (Anttila et al, 2018; Lee et al, 2013; Lichtenstein et al, 2009)
Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for intelligence quotient (IQ) or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment
That study found that first-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) had a larger intracranial volume (ICV) which was not present in first-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs)
Summary
Schizophrenia and bipolar disorder are highly heritable disorders with a shared genetic architecture (Anttila et al, 2018; Lee et al, 2013; Lichtenstein et al, 2009). When we adjusted for ICV, no differences were found between BD-FDRs and controls but SZ-FDRs still showed significantly smaller brain volumes, diminished cortical thickness and larger ventricle volume compared to controls These findings suggest that individuals at familial risk for either bipolar disorder or schizophrenia may show diseasespecific deviations during early brain development. We extended our findings of group differences in global brain measures between relatives and controls (and patients) for both disorders (de Zwarte, Brouwer, Agartz, et al, 2019) by adding local cortical measures. Linear mixed model analyses were performed within each cohort for bipolar disorder and schizophrenia separately, comparing relatives (per relative type) with controls and, if present, patients with controls, while taking family relatedness into account
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