The Genetic and Environmental Determinants of the Association Between Brain Abnormalities and Schizophrenia: The Schizophrenia Twins and Relatives Consortium

University Medical Center Utrecht, Department of Psychiatry, Division of Neuroscience, Rudolf Magnus Institute, Utrecht, The Netherlands.
Biological psychiatry (Impact Factor: 10.26). 02/2012; 71(10):915-21. DOI: 10.1016/j.biopsych.2012.01.010
Source: PubMed


Structural brain abnormalities are consistently found in schizophrenia (Sz) and have been associated with the familial risk for the disorder. We aim to define the relative contributions of genetic and nongenetic factors to the association between structural brain abnormalities and Sz in a uniquely powered cohort (Schizophrenia Twins and Relatives consortium).
An international multicenter magnetic resonance imaging collaboration was set up to pool magnetic resonance imaging scans from twin pairs in Utrecht (The Netherlands), Helsinki (Finland), London (United Kingdom), and Jena (Germany). A sample of 684 subjects took part, consisting of monozygotic twins (n = 410, with 51 patients from concordant and 52 from discordant pairs) and dizygotic twins (n = 274, with 39 patients from discordant pairs). The additive genetic, common, and unique environmental contributions to the association between brain volumes and risk for Sz were estimated by structural equation modeling.
The heritabilities of most brain volumes were significant and ranged between 52% (temporal cortical gray matter) and 76% (cerebrum). Heritability of cerebral gray matter did not reach significance (34%). Significant phenotypic correlations were found between Sz and reduced volumes of the cerebrum (-.22 [-.30/-.14]) and white matter (-.17 [-.25/-.09]) and increased volume of the third ventricle (.18 [.08/.28]). These were predominantly due to overlapping genetic effects (77%, 94%, and 83%, respectively).
Some of the genes that transmit the risk for Sz also influence cerebral (white matter) volume.

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Available from: N.E.M. Van Haren
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    • "Further it is observed that brain volume is highly heritable in both disorders, but more consistently in SZ than in BD. Indeed, the Schizophrenia Twins and Relatives consortium recently observed that the heritability of most brain volumes were ranged between 52% (temporal cortical GM) to 76% (cerebrum) (27). Interestingly, it has been shown that the genetic influences and the disease-related deficits affect GM in partially non-overlapping areas of predominantly heteromodal association cortex, thus suggesting synergistic actions to produce the symptom severity and cognitive dysfunction of the disorder (28). "
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    ABSTRACT: Introduction: Schizophrenia (SZ) and Bipolar disorder (BD) are considered as severe multifactorial diseases, stemming from genetic and environmental influences. Growing evidence supports gene x environment (GxE) interactions in these disorders and neuroimaging studies can help us to understand how those factors mechanistically interact. No reviews synthesized the existing data of neuroimaging studies in these issues. Methods: We conduct a systematic review on the neuroimaging studies exploring GxE interactions relative to SZ or BD in PubMed. Results: First results of the influence of genetic and environmental risks on brain structures came from monozygotic twin pairs concordant and discordant for SZ or BD. Few structural magnetic resonance imaging (sMRI) studies have explored the GxE interactions. No other imaging methods were found. Two main GxE interactions on brain volumes have arisen. First, an interaction between genetic liability to SZ and obstetric complications on gray matter, cerebrospinal fluid, and hippocampal volumes. Second, cannabis use and genetic liability interaction effects on cortical thickness and white matter volumes. Conclusion: Combining GxE interactions and neuroimaging domains is a promising approach. Genetic risk and environmental exposures such as cannabis or obstetrical complications seem to interact leading to specific neuroimaging cerebral alterations in SZ. They are suggestive of GxE interactions that confer phenotypic abnormalities in SZ and possibly BD. We need further, larger neuroimaging studies of GxE interactions for which we may propose a framework focusing on GxE interactions data already known to have a clinical effect such as infections, early stress, urbanicity, and substance abuse.
    Full-text · Article · Oct 2013 · Frontiers in Psychiatry
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    • "These are called endophenotypes when they are (1) associated with the illness, (2) heritable, (3) primarily state independent and (4) co-segregate with illness in families (Gottesman & Gould, 2003). Brain volume is an example of an endophenotype of schizophrenia, as it is robustly associated with disease (Wright et al. 2000), is highly heritable (van Haren et al. 2012) and cosegregates with illness in families (Boos et al. 2007). It is an objectively assessed quantitative measure. "
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    ABSTRACT: Background: Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence. Method: IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a sample collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate individual PSSs in our independent sample of 350 schizophrenia patients and 322 healthy controls. Results: Although significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R 2 = 0.055, p = 2.1 × 10-7) and with IQ in the entire sample (R 2 = 0.018, p = 0.0008) but the effect on IQ disappeared after correction for disease status. Conclusions: Our data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk.
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    Full-text · Article · Apr 2012 · Psychiatry Research
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