Dataset Information

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.

ABSTRACT: Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.

SUBMITTER: Forstner AJ

PROVIDER: S-EPMC5293228 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.

Forstner Andreas J AJ Hecker Julian J Hofmann Andrea A Maaser Anna A Reinbold Céline S CS Mühleisen Thomas W TW Leber Markus M Strohmaier Jana J Degenhardt Franziska F Treutlein Jens J Mattheisen Manuel M Schumacher Johannes J Streit Fabian F Meier Sandra S Herms Stefan S Hoffmann Per P Lacour André A Witt Stephanie H SH Reif Andreas A Müller-Myhsok Bertram B Lucae Susanne S Maier Wolfgang W Schwarz Markus M Vedder Helmut H Kammerer-Ciernioch Jutta J Pfennig Andrea A Bauer Michael M Hautzinger Martin M Moebus Susanne S Schenk Lorena M LM Fischer Sascha B SB Sivalingam Sugirthan S Czerski Piotr M PM Hauser Joanna J Lissowska Jolanta J Szeszenia-Dabrowska Neonila N Brennan Paul P McKay James D JD Wright Adam A Mitchell Philip B PB Fullerton Janice M JM Schofield Peter R PR Montgomery Grant W GW Medland Sarah E SE Gordon Scott D SD Martin Nicholas G NG Krasnov Valery V Chuchalin Alexander A Babadjanova Gulja G Pantelejeva Galina G Abramova Lilia I LI Tiganov Alexander S AS Polonikov Alexey A Khusnutdinova Elza E Alda Martin M Cruceanu Cristiana C Rouleau Guy A GA Turecki Gustavo G Laprise Catherine C Rivas Fabio F Mayoral Fermin F Kogevinas Manolis M Grigoroiu-Serbanescu Maria M Becker Tim T Schulze Thomas G TG Rietschel Marcella M Cichon Sven S Fier Heide H Nöthen Markus M MM

PloS one 20170206 2

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). T ...[more]

PMID: 28166306

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Project description:BACKGROUND:A challenge of understanding the mechanisms underlying cognition including neurodevelopmental and neuropsychiatric disorders is mainly given by the potential severity of cognitive disorders for the quality of life and their prevalence. However, the field has been focused predominantly on protein coding variation until recently. Given the importance of tightly controlled gene expression for normal brain function, the goal of the study was to assess the functional variation including non-coding variation in human genome that is likely to play an important role in cognitive functions. To this end, we organized and utilized available genome-wide datasets from genomic, transcriptomic and association studies into a comprehensive data corpus. We focused on genomic regions that are enriched in regulatory activity-overlapping transcriptional factor binding regions and repurpose our data collection especially for identification of the regulatory SNPs (rSNPs) that showed associations both with allele-specific binding and allele-specific expression. We matched these rSNPs to the nearby and distant targeted genes and then selected the variants that could implicate the etiology of cognitive disorders according to Genome-Wide Association Studies (GWAS). Next, we use DeSeq 2.0 package to test the differences in the expression of the certain targeted genes between the controls and the patients that were diagnosed bipolar affective disorder and schizophrenia. Finally, we assess the potential biological role for identified drivers of cognition using DAVID and GeneMANIA. RESULTS:As a result, we selected fourteen regulatory SNPs locating within the loci, implicated from GWAS for cognitive disorders with six of the variants unreported previously. Grouping of the targeted genes according to biological functions revealed the involvement of processes such as 'posttranscriptional regulation of gene expression', 'neuron differentiation', 'neuron projection development', 'regulation of cell cycle process' and 'protein catabolic processes'. We identified four rSNP-targeted genes that showed differential expression between patient and control groups depending on brain region: NRAS-in schizophrenia cohort, CDC25B, DDX21 and NUCKS1-in bipolar disorder cohort. CONCLUSIONS:Overall, our findings are likely to provide the keys for unraveling the mechanisms that underlie cognitive functions including major depressive disorder, bipolar disorder and schizophrenia etiopathogenesis.

Project description:ImportanceGenome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders.ObjectiveTo identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS).Data sourcesFour independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data.Study selectionThe 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample.Data extraction and synthesisWe identified 966 genes that contained 2 or more variants associated with BP at P < .05 in 3 of 4 GWAS data sets (n = 12,127 [5253 cases, 6874 controls]). Simulations using 10,000 replicates of these data sets corrected for gene size and allowed the calculation of an empirical P value for each gene; empirically significant genes were entered into a pathway analysis. Each of these pathways was then tested in the replication sample (n = 8396 [3507 cases, 4889 controls]) using gene set enrichment analysis for single-nucleotide polymorphisms. The 226 genes were also compared with results from a meta-analysis of gene expression in the dorsolateral prefrontal cortex.Main outcomes and measuresEmpirically significant genes and biological pathways. RESULTS Among 966 genes, 226 were empirically significant (P < .05). Seventeen pathways were overrepresented in analyses of the initial data set. Six of the 17 pathways were associated with BP in both the initial and replication samples: corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy signaling. Among the 226 genes, 9 differed in expression in the dorsolateral prefrontal cortex in patients with BP: CACNA1C, DTNA, FOXP1, GNG2, ITPR2, LSAMP, NPAS3, NCOA2, and NTRK3.Conclusions and relevancePathways involved in the genetic predisposition to BP include hormonal regulation, calcium channels, second messenger systems, and glutamate signaling. Gene expression studies implicate neuronal development pathways as well. These results tend to reinforce specific hypotheses regarding BP neurobiology and may provide clues for new approaches to treatment and prevention.

Dataset Information

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.

Publications

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.

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