Summary: First-degree relatives of people with schizophrenia and bipolar disorder show distinct patterns of brain structure compared with individuals without a family history. Relatives of bipolar disorder patients tend to have larger intracranial volume, while relatives of schizophrenia patients show smaller brain volumes and specific regional reductions.
Source: Elsevier
Overview
A large international meta-analysis published in Biological Psychiatry reveals that familial risk for schizophrenia and bipolar disorder affects brain structure in different ways. Although the two disorders share some genetic liability and overlapping symptoms, this study found disorder-specific patterns of brain differences in first-degree relatives, suggesting divergent neurodevelopmental trajectories associated with familial risk.
Study purpose
Researchers aimed to determine how being a first-degree relative of someone with schizophrenia or bipolar disorder relates to brain development. By studying relatives rather than patients, the investigators sought to isolate effects of inherited and environmental risk without the confounding influences of illness progression or medication.
Methods and dataset
The analysis was performed by the ENIGMA consortium and combined standardized imaging measures from 34 family cohorts. In total, the meta-analysis included 6,008 individuals: 1,228 first-degree relatives of schizophrenia patients (FDRs-SZ), 852 first-degree relatives of bipolar disorder patients (FDRs-BD), 2,246 control subjects without family history, 1,016 people diagnosed with schizophrenia, and 666 people diagnosed with bipolar disorder. Global and subcortical brain measures were analyzed, and results were tested both with and without correction for intracranial volume (ICV) and for the presence of any psychopathology in relatives or control subjects.
Key findings
– First-degree relatives of bipolar disorder patients (FDRs-BD) showed significantly larger intracranial volume (ICV), a measure that includes total brain tissue and cerebrospinal fluid. Larger ICV is commonly interpreted as a marker of early brain development.
– First-degree relatives of schizophrenia patients (FDRs-SZ) displayed smaller thalamic volumes relative to control subjects. After correcting for ICV, FDRs-SZ also showed reductions in total brain volume, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and the thalamus. Cortical thickness was reduced and the third ventricle was larger in FDRs-SZ. These differences were statistically significant and were not explained by the presence of psychiatric symptoms in the relatives or controls.
Interpretation
The divergent ICV effects—enlarged ICV in relatives of bipolar disorder patients versus smaller brain measures in relatives of schizophrenia patients—suggest distinct early neurodevelopmental pathways linked to familial risk. Larger ICV in FDRs-BD implies that familial risk for bipolar disorder may influence brain growth in early life, while the pattern seen in FDRs-SZ aligns with neurodevelopmental processes that reduce brain tissue and cortical thickness.
Implications for research
These results highlight the importance of considering categorical diagnostic distinctions alongside dimensional, cross-diagnostic approaches. Although schizophrenia and bipolar disorder share some genetic factors and clinical features, familial risk produces different structural brain signatures. Future imaging and genetic studies should account for these disorder-specific patterns when investigating the biology of psychosis and mood disorders.
Family relationship and environment
The study also reported variation in brain anomalies when relatives were grouped by relationship to the patient (for example, parent, sibling, or offspring). No single pattern emerged tied strictly to relative type, suggesting that environmental risk factors shared within families—alongside genetics—play a role in shaping brain structure in at-risk individuals.
Significance of the ENIGMA approach
By pooling well-characterized cohorts and applying standardized image analysis, the ENIGMA-Relatives study provides robust, large-scale evidence about how familial risk for major psychiatric disorders relates to brain anatomy. Studying unaffected relatives reduces confounds related to medication and chronic illness, making it easier to identify risk-related neurodevelopmental features.
Source:
Elsevier
Media contacts:
Rhiannon Bugno – Elsevier
Image source:
Image in the public domain.
Original research: Closed access
Title: “The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder” — Sonja M.C. de Zwarte et al.
Journal: Biological Psychiatry. DOI: 10.1016/j.biopsych.2019.03.985
Abstract summary
Background: Schizophrenia and bipolar disorder share genetic liability and some overlapping structural brain abnormalities. First-degree relatives of schizophrenia patients have been shown to exhibit brain differences similar to patients but with smaller effect sizes. Findings in first-degree relatives of bipolar disorder patients have been inconsistent, with some recent reports of regional volume increases.
Methods: A meta-analysis of global and subcortical brain measures from 6,008 individuals across 34 family cohorts used standardized methods to compare first-degree relatives of schizophrenia and bipolar disorder patients against control subjects and patients. Analyses included correction for intracranial volume and for the presence of psychopathology in relatives and controls.
Results: Relatives of bipolar disorder patients had larger ICV (effect size d = +0.16), while relatives of schizophrenia patients showed smaller thalamic volume (d = −0.12). After adjusting for ICV, relatives of schizophrenia patients showed widespread reductions in brain volumes and cortical thickness and enlargements in the third ventricle. These findings remained after accounting for psychopathology in relatives or control groups.
Conclusions: Despite shared genetic risk, first-degree relatives of schizophrenia and bipolar disorder patients display distinct structural brain patterns, particularly a divergent effect in intracranial volume. This suggests that different neurodevelopmental processes underlie familial risk for these disorders.