Common variants on 8p12 and 1q24.2 confer risk of schizophrenia

Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, China.
Nature Genetics (Impact Factor: 29.35). 12/2011; 43(12):1224-7. DOI: 10.1038/ng.980
Source: PubMed


Schizophrenia is a severe mental disorder affecting ∼1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10(-10)) and 1q24.2 (rs10489202, P = 9.50 × 10(-9)). Our findings provide new insights into the pathogenesis of schizophrenia.

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    • "Family, twin and adoption studies have revealed a strong genetic component in schizophrenia with estimations of heritability about 80% [1]. So far, a great number of genetic studies on schizophrenia have been performed, and several susceptibility genes have been identified through linkage analyses [2], candidate gene association studies [3]–[5], and genome-wide association studies (GWASs) [6]–[8] etc. However, many of them cannot be successfully replicated across different populations, likely due to the already known genetic heterogeneity between different ethnic populations. "
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    ABSTRACT: Recent genetic analyses have implicated several candidate susceptibility variants for schizophrenia. The single nucleotide polymorphism (SNP) rs7294919 is likely a schizophrenia-susceptibility variant according to its significant association with hippocampal volume, hippocampus function, and cognitive performance as well as the nominal association with schizophrenia. However, all previous analyses were conducted only in Europeans, and whether rs7294919 is associated with schizophrenia in other populations are yet to be tested. Here, we conducted a case-control analysis of rs7294919 with schizophrenia in six independent Chinese (N = 3) and Japanese (N = 3) samples, including a total of 7,352 cases and 10,824 controls. The results of our association analysis were not able to confirm the association of rs7294919 with schizophrenia (p = 0.51 in total samples, odds ratio = 1.02 for allele[C]). The absence of rs7294919's association in Chinese and Japanese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating associations of schizophrenia across different ethnic populations.
    PLoS ONE 11/2013; 8(11):e80696. DOI:10.1371/journal.pone.0080696 · 3.23 Impact Factor
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    • "By using the case-control approach, previous GWAS of schizophrenia have detected several noteworthy candidate genes [4,5]. However there has been little consistency in those findings. "
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    ABSTRACT: Reduced Gray matter (GM) volume is a core feature of schizophrenia. Mapping genes that is associated with the heritable disease-related phenotypes may be conducive to elucidate the pathogenesis of schizophrenia. This study aims to identify the common genetic variants that underlie the deficits of GM volume in schizophrenia. High-resolution T1 images and whole genome genotyping data were obtained from 74 first-episode treatment-naïve patients with schizophrenia and 51 healthy controls in the Mental Health Centre of the West China Hospital, Sichuan University. All participants were scanned using a 3T MR imaging system and were genotyped using the HumanHap660 Bead Array. Reduced GM volumes in three brain areas including left hOC3v in the collateral sulcus of visual cortex (hOC3vL), left cerebellar vermis lobule 10 (vermisL10) and right cerebellar vermis lobule 10 (vermisR10) were found in patients with schizophrenia. There was a group by genotype interaction when genotypes from genome-wide scan were subsequently considered in the case-control analyses. SNPs from three genes or chromosomal regions (TBXAS1, PIK3C2G and HS3ST5) were identified to predict the changes of GM volume in hOC3vL, vermisL10 and vermisR10. These results also highlighted the usefulness of endophenotype in exploring the pathogenesis of neuropsychiatric diseases such as schizophrenia although further independent replication studies are needed in the future.
    PLoS ONE 09/2013; 8(9):e75083. DOI:10.1371/journal.pone.0075083 · 3.23 Impact Factor
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    • "The precise manner in which these genes are altered is likely to be complex and remains to be determined. A number of SNPs in the MHC region associated with schizophrenia (Purcell et al, 2009; Shi et al, 2009, 2011; Stefansson et al, 2009; Yue et al, 2011). Supplementary Table 10 lists the SNPs located in, or close to, NF-κB-binding sites that may be associated with susceptibility to schizophrenia. "
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    ABSTRACT: Schnurri-2 (Shn-2), an NF-kappa B site-binding protein, tightly binds to the enhancers of major histocompatibility complex (MHC) class I genes and inflammatory cytokines, which have been shown to harbor common variant single nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout results in schizophrenia. Here, we show that Shn-2 knockout mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 knockout mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest building behaviors in Shn-2 KO mice. These results suggest that genetically-induced changes in immune system can be a predisposing factor in schizophrenia.Neuropsychopharmacology accepted article preview online, 6 February 2013; doi:10.1038/npp.2013.38.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2013; 38(8). DOI:10.1038/npp.2013.38 · 7.05 Impact Factor
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