Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia
Abstract 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 predomin...
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| Format: | Article |
| Language: | English |
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BMC
2018-04-01
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| Series: | BMC Neuroscience |
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| Online Access: | http://link.springer.com/article/10.1186/s12868-018-0414-3 |
| _version_ | 1818965282724511744 |
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| author | Leonid O. Bryzgalov Elena E. Korbolina Ilja I. Brusentsov Elena Y. Leberfarb Natalia P. Bondar Tatiana I. Merkulova |
| author_facet | Leonid O. Bryzgalov Elena E. Korbolina Ilja I. Brusentsov Elena Y. Leberfarb Natalia P. Bondar Tatiana I. Merkulova |
| author_sort | Leonid O. Bryzgalov |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-20T13:14:32Z |
| format | Article |
| id | doaj.art-12cbdc1364a0445baf9ef0731b24a273 |
| institution | Directory Open Access Journal |
| issn | 1471-2202 |
| language | English |
| last_indexed | 2024-12-20T13:14:32Z |
| publishDate | 2018-04-01 |
| publisher | BMC |
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| series | BMC Neuroscience |
| spelling | doaj.art-12cbdc1364a0445baf9ef0731b24a2732022-12-21T19:39:34ZengBMCBMC Neuroscience1471-22022018-04-0119S1415610.1186/s12868-018-0414-3Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophreniaLeonid O. Bryzgalov0Elena E. Korbolina1Ilja I. Brusentsov2Elena Y. Leberfarb3Natalia P. Bondar4Tatiana I. Merkulova5The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of ScienceThe Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of ScienceThe Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of ScienceThe Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of ScienceThe Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of ScienceThe Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of ScienceAbstract 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.http://link.springer.com/article/10.1186/s12868-018-0414-3Genetic of cognitionMajor depressive disorderBipolar affective disorderSchizophreniaAutism spectrum disordersSNPs |
| spellingShingle | Leonid O. Bryzgalov Elena E. Korbolina Ilja I. Brusentsov Elena Y. Leberfarb Natalia P. Bondar Tatiana I. Merkulova Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia BMC Neuroscience Genetic of cognition Major depressive disorder Bipolar affective disorder Schizophrenia Autism spectrum disorders SNPs |
| title | Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia |
| title_full | Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia |
| title_fullStr | Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia |
| title_full_unstemmed | Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia |
| title_short | Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia |
| title_sort | novel functional variants at the gwas implicated loci might confer risk to major depressive disorder bipolar affective disorder and schizophrenia |
| topic | Genetic of cognition Major depressive disorder Bipolar affective disorder Schizophrenia Autism spectrum disorders SNPs |
| url | http://link.springer.com/article/10.1186/s12868-018-0414-3 |
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