Gene expression in the prefrontal cortex during adolescence: implications for the onset of schizophrenia

<p>Abstract</p> <p>Background</p> <p>Many critical maturational processes take place in the human brain during postnatal development. In particular, the prefrontal cortex does not reach maturation until late adolescence and this stage is associated with substantial white matter volume increases. Patients with schizophrenia and other major psychiatric disorders tend to first present with overt symptoms during late adolescence/early adulthood and it has been proposed that this developmental stage represents a "window of vulnerability".</p> <p>Methods</p> <p>In this study we used whole genome microarrays to measure gene expression in post mortem prefrontal cortex tissue from human individuals ranging in age from 0 to 49 years. To identify genes specifically altered in the late adolescent period, we applied a template matching procedure. Genes were identified which showed a significant correlation to a template showing a peak of expression between ages 15 and 25.</p> <p>Results</p> <p>Approximately 2000 genes displayed an expression pattern that was significantly correlated (positively or negatively) with the template. In the majority of cases, these genes in fact reached a plateau during adolescence with only subtle changes thereafter. These include a number of genes previously associated with schizophrenia including the susceptibility gene neuregulin 1 (NRG1). Functional profiling revealed peak expression in late adolescence for genes associated with energy metabolism and protein and lipid synthesis, together with decreases for genes involved in glutamate and neuropeptide signalling and neuronal development/plasticity. Strikingly, eight myelin-related genes previously found decreased in schizophrenia brain tissue showed a peak in their expression levels in late adolescence, while the single myelin gene reported increased in patients with schizophrenia was decreased in late adolescence.</p> <p>Conclusion</p> <p>The observed changes imply that molecular mechanisms critical for adolescent brain development are disturbed in schizophrenia patients.</p

Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis.

BackgroundPolycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS.Methods and findingsUsing biochemical and genotype data from a previously published PCOS genome-wide association study (GWAS), we investigated whether there were reproducible phenotypic subtypes of PCOS with subtype-specific genetic associations. Unsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped cohort of 893 PCOS cases (median and interquartile range [IQR]: age = 28 [25-32], body mass index [BMI] = 35.4 [28.2-41.5]). The clusters were replicated in an independent, ungenotyped cohort of 263 PCOS cases (median and IQR: age = 28 [24-33], BMI = 35.7 [28.4-42.3]). The clustering revealed 2 distinct PCOS subtypes: a "reproductive" group (21%-23%), characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low BMI and insulin levels, and a "metabolic" group (37%-39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in 4 loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN, P = 2.2 × 10-10; IQCA1, P = 2.8 × 10-9; BMPR1B/UNC5C, P = 9.7 × 10-9; CDH10, P = 1.2 × 10-8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P = 1.0 × 10-8). We developed a predictive model to classify a separate, family-based cohort of 73 women with PCOS (median and IQR: age = 28 [25-33], BMI = 34.3 [27.8-42.3]) and found that the subtypes tended to cluster in families and that carriers of previously reported rare variants in DENND1A, a gene that regulates androgen biosynthesis, were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by National Institutes of Health (NIH) criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated.ConclusionsIn conclusion, we have found reproducible reproductive and metabolic subtypes of PCOS. Furthermore, these subtypes were associated with novel, to our knowledge, susceptibility loci. Our results suggest that these subtypes are biologically relevant because they appear to have distinct genetic architecture. This study demonstrates how phenotypic subtyping can be used to gain additional insights from GWAS data

When do governments resort to election violence?

When are governments most likely to use election violence, and what factors can mitigate government incentives to resort to violence? How do the dynamics of election violence differ in the pre- and post-election periods? The central argument of this article is that an incumbent's fear of losing power as the result of an election, as well as institutionalized constraints on the incumbent's decision-making powers, are pivotal in her decision to use election violence. While it may seem obvious to suggest that incumbents use election violence in an effort to fend off threats to their power, it is not obvious how to gauge these threats. Thus, a central objective of this article is to identify sources of information about the incumbent's popularity that can help predict the likelihood of election violence. The observable implications of this argument are tested using newly available cross-national evidence on elections, government use of pre- and post-election violence, and post-election protests from 1981 to 2004

Top 10 small RNA reads of <i>M. tuberculosis in vivo</i>.

a<p>Exact identity to a small RNA obtained <i>in vitro</i> is indicated.</p>b<p>The predicted stem-loop structures and origin of these small RNAs is depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106434#pone.0106434.s005" target="_blank">Fig. S5</a>.</p><p>Top 10 small RNA reads of <i>M. tuberculosis in vivo</i>.</p

Deep-sequencing of small RNAs in <i>L. pneumophila</i>-infected cells.

<p>Results of deep-sequencing for <i>L. pneumophila</i>. The figures were generated as described in Fig. 1.</p

Top 10 small RNA reads of <i>M. smegmatis</i>.

a<p>The predicted stem-loop structures and origin of these small RNAs is depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106434#pone.0106434.s004" target="_blank">Fig. S4</a>.</p><p>Top 10 small RNA reads of <i>M. smegmatis</i>.</p

Top 10 small RNA reads of <i>M. marinum</i>.

a<p>The predicted stem-loop structure and origin of several small RNAs is depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106434#pone.0106434.s003" target="_blank">Fig. S3</a>.</p>b<p>Predicted stem-loop structure and origin of this small RNA is depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106434#pone-0106434-g003" target="_blank">Fig. 3C</a>.</p><p>Top 10 small RNA reads of <i>M. marinum</i>.</p

Top 10 most prevalent small RNA reads of <i>L. pneumophila</i> origin.

a<p>Predicted stem-loop structure and origin of small RNA are depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106434#pone.0106434.s002" target="_blank">Fig. S2</a>. as, anti-sense.</p><p>Top 10 most prevalent small RNA reads of <i>L. pneumophila</i> origin.</p