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 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

Low Genetic Diversity in Wide-Spread Eurasian Liver Fluke <i>Opisthorchis felineus</i> Suggests Special Demographic History of This Trematode Species

<div><p></p><p><i>Opisthorchis felineus</i> or Siberian liver fluke is a trematode parasite (Opisthorchiidae) that infects the hepato-biliary system of humans and other mammals. Despite its public health significance, this wide-spread Eurasian species is one of the most poorly studied human liver flukes and nothing is known about its population genetic structure and demographic history. In this paper, we attempt to fill this gap for the first time and to explore the genetic diversity in <i>O. felineus</i> populations from Eastern Europe (Ukraine, European part of Russia), Northern Asia (Siberia) and Central Asia (Northern Kazakhstan). Analysis of marker DNA fragments from <i>O. felineus</i> mitochondrial <i>cytochrome c oxidase subunit 1</i> and <i>3</i> (<i>cox1, cox3</i>) and nuclear rDNA <i>internal transcribed spacer 1</i> (<i>ITS1</i>) sequences revealed that genetic diversity is very low across the large geographic range of this species. Microevolutionary processes in populations of trematodes may well be influenced by their peculiar biology. Nevertheless, we suggest that lack of population genetics structure observed in <i>O. felineus</i> can be primarily explained by the Pleistocene glacial events and subsequent sudden population growth from a very limited group of founders. Rapid range expansion of <i>O. felineus</i> through Asian and European territories after severe bottleneck points to a high dispersal potential of this trematode species.</p></div

The statistical parsimony networks of <i>cox1, ITS1</i> and <i>cox3</i> haplotypes.

<p>The sizes of haplotypes are proportional to the number of samples. Small black circles indicate un-sampled or extinct haplotypes.</p

Geographical localities where the specimens were collected.

<p>Lettered names of collection sites correspond to those in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062453#pone-0062453-t001" target="_blank">Table 1</a>.</p

Pairwise fixation indices (Fst values) between <i>O. felineus</i> populations calculated from the nucleotide datasets for c<i>ox1</i>/<i>cox3</i>/<i>ITS1</i>.

*<p>- p<0.05,</p>**<p>- 0.1>p>0.05.</p

Diversity indices calculated from the nucleotide data sets for <i>cox1</i>, <i>cox3</i> and <i>ITS1</i>.

<p>Abbreviations are number of isolates examined (N), segregating sites (S), number of haplotypes (H), haplotype diversity (Hd) and nucleotide diversity (π).</p>*<p>- p<0.05.</p

Mismatch distribution curve for <i>O. felineus</i> haplotypes.

<p>Expected values under expanding population model and observed values are shown as solid green and dashed red lines, respectively (r – ruggedness index).</p

Neutrality indices calculated from the nucleotide datasets for <i>cox1</i>, <i>cox3</i> and <i>ITS1</i>.

*<p>- p<0.05.</p