A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder

Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN 37614, USA.
Schizophrenia Research (Impact Factor: 3.92). 10/2010; 124(1-3):192-9. DOI: 10.1016/j.schres.2010.09.002
Source: PubMed

ABSTRACT Schizophrenia and bipolar disorder both have strong inherited components. Recent studies have indicated that schizophrenia and bipolar disorder may share more than half of their genetic determinants. In this study, we performed a meta-analysis (combined analysis) for genome-wide association data of the Affymetrix Genome-Wide Human SNP array 6.0 to detect genetic variants influencing both schizophrenia and bipolar disorder using European-American samples (653 bipolar cases and 1034 controls, 1172 schizophrenia cases and 1379 controls). The best associated SNP rs11789399 was located at 9q33.1 (p=2.38 × 10(-6), 5.74 × 10(-4), and 5.56 × 10(-9), for schizophrenia, bipolar disorder and meta-analysis of schizophrenia and bipolar disorder, respectively), where one flanking gene, ASTN2 (220kb away) has been associated with attention deficit/hyperactivity disorder and schizophrenia. The next best SNP was rs12201676 located at 6q15 (p=2.67 × 10(-4), 2.12 × 10(-5), 3.88 × 10(-8) for schizophrenia, bipolar disorder and meta-analysis, respectively), near two flanking genes, GABRR1 and GABRR2 (15 and 17kb away, respectively). The third interesting SNP rs802568 was at 7q35 within CNTNAP2 (p=8.92 × 10(-4), 1.38 × 10(-5), and 1.62 × 10(-7) for schizophrenia, bipolar disorder and meta-analysis, respectively). Through meta-analysis, we found two additional associated genes NALCN (the top SNP is rs2044117, p=4.57 × 10(-7)) and NAP5 (the top SNP is rs10496702, p=7.15 × 10(-7)). Haplotype analyses of above five loci further supported the associations with schizophrenia and bipolar disorder. These results provide evidence of common genetic variants influencing schizophrenia and bipolar disorder. These findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in schizophrenia and bipolar disorder.

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    • "Of these studies, 4 focused on MDD (Lee et al., 2012; Lewis et al., 2010; Shyn et al., 2011; Wray et al., 2012), 3 on SZ (Jia et al., 2012; Shi et al., 2009; Wang et al., 2012), 2 on ADHD (Ebejer et al., 2013; Neale et al., 2010), 1 on BD (Goes et al., 2012) and 1 on AD (Otowa et al., 2012). We also identified one other study that conducted a meta-analysis across GWAS data of SZ and BD patients combined (Wang et al., 2010). With the exception of several variants identified for SZ (including known variants HIST1H2BJ rs6913660 and TRNAI20 rs13194053 (Shi et al., 2009) which achieved a p value less than 5 Â 10 À8 ), no other variants from these GWAS studies reached genome-wide significance. "
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    ABSTRACT: Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.
    Journal of Psychiatric Research 09/2014; 60. DOI:10.1016/j.jpsychires.2014.09.014 · 3.96 Impact Factor
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    • "Of these 107 CpG sites, 79 sites (73.8%) demonstrated higher DNA methylation in schizophrenia than in controls (Figure 1). Examples of diagnostic-biased genes include GRIA4 (glutamate receptor, inotropic, AMPA4) and ASTN2 (astrotactin 2) (Figure 2), both of these genes have been previously implicated in schizophrenia (Makino et al., 2003; Vrijenhoek et al., 2008; Wang et al., 2010). When the 79 sites hypermethylated in schizophrenia were classified into four categories (CGI, CGI shore, CGI shelf, and others), most of them (87.3%) were located in the CGIs and in the regions flanking CGIs (CGI: 31 sites; CGI shore: 35 sites; CGI shelf: 3 sites; others: 9 sites). "
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    ABSTRACT: Background: Schizophrenia is a complex psychiatric disorder with a lifetime morbidity rate of 0.5–1.0%. The pathophysiology of schizophrenia still remains obscure. Accumulating evidence indicates that DNA methylation, which is the addition of a methyl group to the cytosine in a CpG dinucleotide, might play an important role in the pathogenesis of schizophrenia. Methods: To gain further insight into the molecular mechanisms underlying schizophrenia, a genome-wide DNA methylation profiling (27,578 CpG dinucleotides spanning 14,495 genes) of the human dorsolateral prefrontal cortex (DLPFC) was conducted in a large cohort (n = 216) of well characterized specimens from individuals with schizophrenia and non-psychiatric controls, combined with an analysis of genetic variance at ~880,000 SNPs. Results: Aberrant DNA methylation in schizophrenia was identified at 107 CpG sites at 5% Bonferroni correction (p < 1.99 × 10−6). Of these significantly altered sites, hyper-DNA methylation was observed at 79 sites (73.8%), mostly in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 31 sites; CGI shore: 35 sites; CGI shelf: 3 sites). Furthermore, a large number of cis-methylation quantitative trait loci (mQTL) were identified, including associations with risk SNPs implicated in schizophrenia. Conclusions: These results suggest that altered DNA methylation might be involved in the pathophysiology and/or treatment of schizophrenia, and that a combination of epigenetic and genetic approaches will be useful to understanding the molecular mechanism of this complex disorder.
    Frontiers in Genetics 08/2014; 5:280. DOI:10.3389/fgene.2014.00280
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    • "Considering the central participation of HSF1 in so many important biological functions, it is surprising that so little is known about genetic variations in elements of the human heat shock response, especially HSF1, and the potential impact on human health and disease. While specific studies of human HSF1 genetic variation have not yet been performed, genomewide association studies (GWAS) have linked 8q24.3, the location of the HSF1 gene, to schizophrenia, bipolar disorder (Wang et al. 2010), and attention deficit hyperactivity disorder (Lasky-Su et al. 2008), suggesting HSF1 genetic variation may contribute to neuropsychiatric disease. Recently, Li et al. (2011) reported two novel single nucleotide polymorphisms (SNPs) in the bovine HSF1 gene that are disproportionately associated with thermal tolerance in Chinese Holstein cattle, including one SNP in the 3′-untranslated region (3′ UTR) that disrupts a potential microRNA (miRNA)-binding sequence in HSF1 (Li et al. 2011) and is disproportionately associated with heat tolerance in Chinese Holstein cows. "
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    ABSTRACT: The stress-activated transcription factor, heat shock factor-1 (HSF1), regulates many genes including cytoprotective heat shock proteins (HSPs). We hypothesized that polymorphisms in HSF1 may alter the level or function of HSF1 protein accounting for interindividual viability in disease susceptibility or prognosis. We searched for exomic variants in HSF1 by querying human genome databases and directly sequencing DNA from 80 anonymous genomic DNA samples. Overall, HSF1 sequence was highly conserved, with no common variations. We found 31 validated deviations from a reference sequence in the dbSNP database and an additional 5 novel variants by sequencing, with allele frequencies that were 0.06 or less. Of these 36, 2 were in 5'-untranslated region (5'UTR), 10 in 3'UTR, and 24 in the coding region. The potential effects of 5'UTR on secondary structure, protein structure/function, and 3'UTR targets of microRNAs were analyzed using RNAFold, PolyPhen-2, SIFT, and MicroSNiper. One of the 5'UTR variants was predicted to strengthen secondary structure. Eight of 3'UTR variants were predicted to modify microRNA target sequences. Eight of the coding region variants were predicted to modify HSF1 structure/function. Reducing HSF1 levels in A549 cells using short hairpin RNA (shRNA) increased sensitivity to heat-induced killing demonstrating the impact that genetic variants that reduce HSF1 levels might have. Using the pmirGLO expression system, we found that the wild-type HSF1 3'UTR suppressed translation of a firefly luciferase reporter plasmid by 65 %. Introducing two of four 3'UTR single nucleotide polymorphisms (SNPs) increased HSF1 3'UTR translational suppression by 27-44 % compared with the wild-type HSF1 3'UTR sequence while a third SNP reduced suppression by 25 %. HSF1 variants may alter HSF1 protein levels or function with potential effects on cell functions, including sensitivity to stress.
    Cell Stress and Chaperones 07/2014; 20(1). DOI:10.1007/s12192-014-0524-5 · 3.16 Impact Factor
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