Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460: 748-752

Uppsala University, Uppsala, Uppsala, Sweden
Nature (Impact Factor: 41.46). 06/2009; 460(7256):748-752. DOI: 10.1038/nature08185
Source: PubMed


Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

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    • "Intriguingly, through this approach, we identified an IRF3 eQTL SNP rs11880923 showed a significant association with schizophrenia, although it did not achieve the genome-wide level of statistical significance. Previous aggregated analyses have indicated that there may be true findings among those markers passing nominal significance (International Schizophrenia Consortium et al., 2009), and the herein observed OR for rs11880923 is 1.075, which is comparable with those observed ORs in other large-scale association studies (Chen et al., 2011; Li et al., 2014; Luo et al., 2014b). More importantly, the risk SNP rs11880923 is associated with schizophrenia not only in PGC1 caseecontrol sample, but also showed strong and marginal significant associations in two familybased samples (Caucasians and Jewish 02), respectively. "
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    ABSTRACT: Schizophrenia is a brain disorder with high heritability. Recent studies have implicated genes involved in the immune response pathway in the pathogenesis of schizophrenia. Interferon regulatory factor 3 (IRF3), a virus-immune-related gene, activates the transcription of several interferon-induced genes, and functionally interacts with several schizophrenia susceptibility genes. To test whether IRF3 is a schizophrenia susceptibility gene, we analyzed the associations of its SNPs with schizophrenia in independent population samples as well as reported data from expression quantitative trait loci (eQTL) in healthy individuals. We observed multiple independent SNPs in IRF3 showing nominally significant associations with schizophrenia (P < 0.05); more intriguingly, a SNP (rs11880923), which is significantly correlated with IRF3 expression in independent samples (P < 0.05), is also consistently associated with schizophrenia across different cohorts and in combined samples (odds ratio = 1.075, Pmeta = 2.08 × 10(-5)), especially in Caucasians (odds ratio = 1.078, Pmeta = 2.46 × 10(-5)). These results suggested that IRF3 is likely a risk gene for schizophrenia, at least in Caucasians. Although the clinical associations of IRF3 with diagnosis did not achieve genome-wide level of statistical significance, the observed odds ratio is comparable with other susceptibility loci identified through large-scale genetic association studies on schizophrenia, which could be regarded simply as small but detectable effects. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Psychiatric Research 03/2015; 64. DOI:10.1016/j.jpsychires.2015.03.008 · 3.96 Impact Factor
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    • "Studies conducted by the International Schizophrenia Consortium attribute one-third of genetic susceptibility for schizophrenia (estimated to be 80% (Sullivan et al., 2003)) to the collective effect of hundreds of common polygenic variants, each contributing a small effect (Purcell et al., 2009; Gejman et al., 2011). "
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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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    • "In fact, evidence from neuroimaging studies indicates that there are similar structural and functional brain abnormalities in BD and SZ, i.e., decreased size or hypoactivation of the prefrontal cortex [6]. Both syndromes also have genetic susceptibility and a similar polygenic base [7]. Thus, the main goal of the modern psychiatrist should be to make the most accurate diagnosis and provide effective treatment, thus leading to better prognoses. "
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    ABSTRACT: Although diagnosis is a central issue in medical care, in psychiatry its value is still controversial. The function of diagnosis is to indicate treatments and to help clinicians take better care of patients. The fundamental role of diagnosis is to predict outcome and prognosis. To date serious concern persists regarding the clinical utility and predictive validity of the diagnosis system in psychiatry, which is at the most syndromal. Schizophrenia and bipolar disorder, which nosologists consider two distinct disorders, are the most discussed psychiatric illnesses. Recent findings in different fields of psychiatric research, such as neuroimaging, neuropathology, neuroimmunology, neuropsychology and genetics, have led to other conceptualizations. Individuals with schizophrenia or bipolar disorder vary greatly with regard to symptoms, illness course, treatment response, cognitive and functional impairment and biological correlates. In fact, it is possible to find heterogeneous correlates even within the same syndrome, i.e., from one stage of the disorder to another. Thus, it is possible to identify different subsyndromes, which share some clinical and neurobiological characteristics. The main goal of modern psychiatry is to ovethrow these barriers and to obtain a better understanding of the biological profiles underlying heterogeneous clinical features and thus reduce the variance and lead to a homogeneous definition. The translational research model, which connects the basic neuroscience research field with clinical experience in psychiatry, aims to investigate different neurobiological features of syndromes and of the shared neurobiological features between two syndromes. In fact, this approach should help us to better understand the neurobiological pathways underlying clinical entities, and even to distinguish different, more homogeneous, diagnostic subtypes. Copyright © 2015. Published by Elsevier B.V.
    Clinica Chimica Acta 02/2015; 449. DOI:10.1016/j.cca.2015.02.029 · 2.82 Impact Factor
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