Psychiatric genetics: Progress amid controversy. Nature Reviews Genetics, 9, 527-540

Molecular and Behavioral Neuroscience Institute, University of Michigan, 5061 BSRB, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200, USA.
Nature Reviews Genetics (Impact Factor: 36.98). 08/2008; 9(7):527-40. DOI: 10.1038/nrg2381
Source: PubMed

ABSTRACT Several psychiatric disorders--such as bipolar disorder, schizophrenia and autism--are highly heritable, yet identifying their genetic basis has been challenging, with most discoveries failing to be replicated. However, inroads have been made by the incorporation of intermediate traits (endophenotypes) and of environmental factors into genetic analyses, and through the identification of rare inherited variants and novel structural mutations. Current efforts aim to increase sample sizes by gathering larger samples for case-control studies or through meta-analyses of such studies. More attention on unique families, rare variants, and on incorporating environment and the emerging knowledge of biological function and pathways into genetic analysis is warranted.

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    • "Recently, the NIMH Research Criteria Project suggested that cognition should be one of five core research domains in the field of psychiatric diseases (Morris and Cuthbert, 2012). SCZ and BD are highly heritable disorders (Lichtenstein et al., 2009) with complex genetic and environmental interactions involved (Burmeister et al., 2008). Several lines of research indicate that the immune system may be involved in these interactions (Kinney et al., 2010) and it has been suggested that mononuclear phagocyte cells including microglial cells may play a key role in their pathogenesis. "
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    ABSTRACT: The mechanisms underlying cognitive impairment in schizophrenia and bipolar disorders are largely unknown. Immune abnormalities have been found in both disorders, and inflammatory mediators may play roles in cognitive function. We investigated if inflammatory markers are associated with general cognitive abilities. Participants with schizophrenia spectrum (N=121) and bipolar spectrum (N=111) disorders and healthy controls (N=241) were included. General intellectual abilities were assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serum concentrations of the following immune markers were measured: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin, von Willebrand factor, C-reactive protein, interleukin-6 and CD40 ligand. After adjusting for age, sex and diagnostic group, significant negative associations with general cognitive function were found for sTNF-R1 (p=2×10(-5)), IL-1Ra (p=0.002) and sCD40 ligand (p=0.003). Among patients, the associations remained significant (p=0.006, p=0.005 and p=0.02) after adjusting for possible confounders including education, smoking, psychotic and affective symptoms, body mass index, cortisol, medication and time of blood sampling. Subgroup analysis, showed that general cognitive abilities were significantly associated with IL-1Ra and sTNF-R1 in schizophrenia patients, with sCD40L and IL-1Ra in bipolar disorder patients and with sTNF-R1 in healthy controls. The study shows significant negative associations between inflammatory markers and general cognitive abilities after adjusting for possible confounders. The findings strongly support a role for inflammation in the neurophysiology of cognitive impairment. Copyright © 2015. Published by Elsevier B.V.
    Schizophrenia Research 05/2015; 165(2-3). DOI:10.1016/j.schres.2015.04.004 · 3.92 Impact Factor
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    • "The results of GWAS (Johnson and O'Donnell, 2009) contain many false positives (Burmeister et al., 2008). Current replicable GWAS results account for only a small percentage of the estimated heritability (Ozomaro et al., 2013) and their systematic biological interpretation is lacking. "
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    ABSTRACT: The number of Genome Wide Association Studies (GWAS) of schizophrenia is rapidly growing. However, the small effect of individual genes limits the number of reliably implicated genes, which are too few and too diverse to perform reliable pathway analysis; hence the biological roles of the genes implicated in schizophrenia are unclear. To overcome these limitations we combine GWAS with genome-wide expression data from human post-mortem brain samples of schizophrenia patients and controls, taking these steps: 1) Identify 36 GWAS-based genes which are expressed in our dataset. 2) Find a cluster of 19 genes with highly correlated expression. We show that this correlation pattern is robust and statistically significant. 3) GO-enrichment analysis of these 19 genes reveals significant enrichment of ion channels and calcium-related processes. This finding (based on analyzing a small number of coherently expressed genes) is validated and enhanced in two ways: First, the emergence of calcium channels and calcium signaling is corroborated by identifying proteins that interact with those encoded by the cluster of 19. Second, extend the 19 cluster genes into 1028 genes, whose expression is highly correlated with the cluster's average profile. When GO-enrichment analysis is performed on this extended set, many schizophrenia related pathways appear, with calcium-related processes enriched with high statistical significance. Our results give further, expression-based validation to GWAS results, support a central role of calcium-signaling in the pathogenesis of schizophrenia, and point to additional pathways potentially related to the disease. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 02/2015; 164(1-3). DOI:10.1016/j.schres.2015.02.001 · 3.92 Impact Factor
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    • "Based on 6 studies of 2509 patients with bipolar I disorder, the weighted mean age of onset falls into 3 groups, having peaks at ages 18.1, 26.9 and 42.7 years, with 55% of patients in the middle or late onset groups (Bellivier et al., 2001, 2003; González Pinto et al., 2009; Hamshere et al., 2009; Lin et al., 2006; Manchia et al., 2008). This broad range of onset and the polygenic basis of bipolar disorder suggest that environmental factors have an influential role (Burmeister et al., 2008; Craddock and Sklar, 2013; Wright et al., 2003). Environmental factors associated with a younger age of onset are cannabis use (González-Pinto et al., 2008; Lagerberg et al., 2011), stressful life events (Horesh et al., 2011) and childhood abuse (Garno et al., 2005; Leverich et al., 2002), while neurological illness is associated with an older onset (Depp and Jeste, 2004). "
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