Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia

Abstract

BackgroundA 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.ResultsAs 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.ConclusionsOverall, 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.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0414-3) contains supplementary material, which is available to authorized users.

Cognitive Deficits in Psychotic Disorders: A Lifespan Perspective

“…Several studies have observed static cognitive deficit trajectories in the bipolar disorder (Samame et al 2014; Bora and Ozerdem 2017; Martino et al 2018), and several studies demonstrate cognitive improvements after the first manic episode (Torres et al 2014; Torrent et al 2018). It is also plausible that premorbid cognitive functioning impairments in bipolar disorder are associated with specific genetic variants (Arts et al 2013; Bryzgalov et al 2018; Flowers et al 2016) that may be associated with neural development (Tabares-Seisdedos et al 2008) and thus may not be present in all individuals premorbidly. Overall, the heterogeneity of findings regarding the presence of premorbid cognitive deficits in bipolar disorder during childhood and adolescence points to the necessity that future studies incorporate consistent methodology using large samples to better understand whether premorbid deficits exist in bipolar disorder.…”

Manifold Learning Analysis for Allele-Skewed DNA Modification SNPs for Psychiatric Disorders

“…The underlying etiology of the neuropsychiatric disorders is not well understood or even unknown, but various research efforts have been made to decipher their genetic mechanisms from different standing points. Recent large-scale genomewide association studies (GWAS) have revealed that psychiatric disorders share some common genetic risk loci [3]- [5]. For example, the Psychiatric Genomics Consortium GWAS identified 108 independently associated loci for schizophrenia, about 75% of which contain protein-coding genes that play essential roles in neurodevelopment and brain function [6].…”

Nucks1 gene polymorphism rs823114 is associated with the positive symptoms and neurocognitive function of patients with schizophrenia in parts of southern China

“…To date, the association between the nucks1 gene and schizophrenia has not been reported. In addition, genome-wide association study (GWAS) data has identified 14 unique SNPs associated with the risk of cognitive impairment, including the rs4951261 and rs823114 polymorphisms of the nucks1 gene ( Bryzgalov et al ., 2018 ). Based on the above, we reasonably speculate that the nucks1 gene may be a logical candidate gene for the potential causes of schizophrenia.…”

“…Rs823114 is located in an intergenic region proximal to nucks1, which has been found to be related to the transcript level of the nucks1 ( Liu et al ., 2011 ; Zhu et al ., 2018 ; Lv et al ., 2017 ). Bryzgalov proposed that the two polymorphisms rs4951261 and rs823114 are considered to be related to the risk of cognitive impairment ( Bryzgalov et al ., 2018 ). Rs951366 is located in the 3’-untranslated region of nucks1 and may be involved in regulating its transcriptional activity ( Xu et al ., 2017 ).…”