Disrupted-in-Schizophrenia 1 (DISC1) is a well researched candidate gene for schizophrenia and affective disorders with a range of functions relating to neurodevelopment. Several human brain imaging studies investigating correlations between common and rare variants in DISC1 and brain structure and function have shown conflicting results. A meta-analysis of case/control data showed no association between schizophrenia and any common SNP in DISC1. Therefore it is timely to review the literature to plan the direction of future studies.
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"Consequently, there is a large and ever growing number of publications, particularly for genetic polymorphisms known to be relevant to psychiatric illness and behavioural problems, as reviewed (e.g. Iofrida et al. 2014; Erhardt and Spoormaker 2013; Duff et al. 2013; Flint and Munafo 2013; Tost et al. 2012; Hasler and Northoff 2011; Meyer-Lindenberg 2010; Durston 2010). This work builds on the broader literature of gene characterisation, including studies of gene structure and the identification of critical polymorphisms, protein expression in the brain, as well as physiological function and implication in brainrelated illnesses (e.g. "
[Show abstract][Hide abstract]ABSTRACT: A wealth of empirical evidence is accumulating on the genetic mediation of brain structure phenotypes. This comes from twin studies that assess heritability and genetic covariance between traits, candidate gene associations, and genome-wide association studies (GWAS) that can identify specific genetic variants. Here we review the major findings from each of these approaches and consider how they inform on the genetic architecture of brain structure. The findings from twin studies show there is a strong genetic influence (heritability) on brain structure, and overlap of genetic effects (pleiotropy) between structures, and between structure and cognition. However, there is also evidence for genetic specificity, with distinct genetic effects across some brain regions. Candidate gene associations show little convergence; most have been under powered to detect effect sizes of the magnitude now expected. GWAS have identified 19 genetic variants for brain structure, though no replicated associations account for more than 1 % of the variance. Together these studies are revealing new insights into the genetic architecture of brain morphology. As the scope of inquiry broadens, including measures that capture the complexity of the brain, along with larger samples and new analyses, such as genome-wide common trait analysis (GCTA) and polygenic scores, which combine variant effects for a phenotype, as well as whole-genome sequencing, more genetic variants for brain structure will be identified. Increasingly, large-scale multi-site studies will facilitate this next wave of studies, and promise to enhance our understanding of the etiology of variation in brain morphology, as well as brain disorders.
Full-text · Article · Mar 2015 · Neuropsychology Review
"Given that a number of previous studies both in psychiatric patients and transgenic mouse models have emphasised links between DISC1 and structural and functional changes in the frontal cortex and hippocampus (Callicott et al., 2005, Duff et al., 2013, Thomson et al., 2013), it is perhaps surprising that our brain-wide association study failed to support this, other than in terms of the functional link between the precuneus and the triangular inferior frontal gyrus. This may reflect the fact that we only found links with novel DISC1 polymorphisms, whereas previous studies showing DISC1 associations with the frontal cortex and hippocampus have focussed mainly on L607F (rs6675281) and S704C (rs821616). "
"The effect of rs821616 is among the most studied, with the A (Ser704) allele, associated with impact on neurodevelopment and brain structure in health and disease (Duff et al. 2013), in our sample both under-transmitted and over-transmitted haplotypes, containing this allele was detected. A limitation of our study is the small sample size affecting the power to detect the presumed weak effect of the investigated SNP. "