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Wang, K. S., Liu, X. F. & Aragam, N. A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder. Schizophr. Res. 124, 192-199

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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    • "Over the past few years many studies have shown association between Caspr2 and several mental disorders including: autism spectrum disorder (ASD) (Alarcon et al., 2008), schizophrenia, bipolar disorder (Wang et al., 2010), epilepsy (Mefford et al., 2010), Alzheimer's disease (van Abel et al., 2012) and language disorders (Newbury et al., 2011). "
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    ABSTRACT: Genome-wide association studies and copy number variation analyses have linked contactin associated protein 2 (Caspr2, gene name Cntnap2) with autism spectrum disorder (ASD). In line with these findings, mice lacking Caspr2 (Cntnap2(-/-)) were shown to have core autism-like deficits including abnormal social behavior and communication, and behavior inflexibility. However the role of Caspr2 in ASD pathogenicity remains unclear. Here we have generated a new Caspr2:tau-LacZ knock-in reporter line (Cntnap2(tlacz/tlacz)), which enabled us to monitor the neuronal circuits in the brain expressing Caspr2. We show that Caspr2 is expressed in many brain regions and produced a comprehensive report of Caspr2 expression. Moreover, we found that Caspr2 marks all sensory modalities: it is expressed in distinct brain regions involved in different sensory processings and is present in all primary sensory organs. Olfaction-based behavioral tests revealed that mice lacking Caspr2 exhibit abnormal response to sensory stimuli and lack preference for novel odors. These results suggest that loss of Caspr2 throughout the sensory system may contribute to the sensory manifestations frequently observed in ASD.
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    • "Importantly, 8 of the top 57 associated CpG sites (p < 1 × 10 −4 ) mapped to genes that have been previously associated with psychiatric or neurological disorders, some of them sharing neurodevelopmental aspects with tics (OCD, autism, bipolar disorder, schizophrenia, some forms of mental retardation), some disorders involving corticostriatal pathways similar to tics (as in the case of Parkinson's disease), and some in which the link with tics seems less clear (Alzheimer's disease) (Supplementary Table T4 summarizes the genes from our top list that have been previously associated with neurological disorders). CpG site cg06026425, located near CLINT1, has been linked to schizophrenia (Leon et al., 2011; Wang et al., 2010). Moreover , cg01321816, located near BLM, and cg00785856, located near ADAM10, involve genes that have been associated with Alzheimer's disease (Schrötter et al., 2013; Vassar, 2013). "
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    ABSTRACT: Tic disorders are moderately heritable common psychiatric disorders that can be highly troubling, both in childhood and in adulthood. In this study, we report results obtained in the first epigenome-wide association study (EWAS) of tic disorders. The subjects are participants in surveys at the Netherlands Twin Register (NTR) and the NTR biobank project. Tic disorders were measured with a self-report version of the Yale Global Tic Severity Scale Abbreviated version (YGTSS-ABBR), included in the 8th wave NTR data collection (2008). DNA methylation data consisted of 411,169 autosomal methylation sites assessed by the Illumina Infinium HumanMethylation450 BeadChip Kit (HM450k array). Phenotype and DNA methylation data were available in 1,678 subjects (mean age = 41.5). No probes reached genome-wide significance (p < 1.2 × 10-7). The strongest associated probe was cg15583738, located in an intergenic region on chromosome 8 (p = 1.98 × 10-6). Several of the top ranking probes (p < 1 × 10-4) were in or nearby genes previously associated with neurological disorders (e.g., GABBRI, BLM, and ADAM10), warranting their further investigation in relation to tic disorders. The top significantly enriched gene ontology (GO) terms among higher ranking methylation sites included anatomical structure morphogenesis (GO:0009653, p = 4.6 × 10-15) developmental process (GO:0032502, p = 2.96 × 10-12), and cellular developmental process (GO:0048869, p = 1.96 × 10-12). Overall, these results provide a first insight into the epigenetic mechanisms of tic disorders. This first study assesses the role of DNA methylation in tic disorders, and it lays the foundations for future work aiming to unravel the biological mechanisms underlying the architecture of this disorder.
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    • "NALCN encodes a nonselective sodium leak channel that plays an important role in the regulation of neuronal excitability (Cahoy et al., 2008; Lu et al., 2007). Suggestive evidence for linkage to bipolar disorder has been observed for chromosome 13q31–34 (Kelsoe et al., 2001; Potash et al., 2003; Shaw et al., 2003), and GWA further implicates NALCN in bipolar disorder (Ollila et al., 2009; Wang et al., 2010). Several of the identified genes are involved in the regulation of neurodevelopment and neuroplasticity. "
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    No preview · Article · Sep 2015 · Journal of Affective Disorders
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