RNA-seq analysis of amygdala tissue reveals characteristic expression profiles in schizophrenia.

The amygdala brain region has been implicated in the pathophysiology of schizophrenia through emotion processing. However, transcriptome messages in the amygdala of schizophrenia patients have not been well studied. We used RNA sequencing to investigate gene-expression profiling in the amygdala tissues, and identified 569 upregulated and 192 downregulated genes from 22 schizophrenia patients and 24 non-psychiatric controls. Gene functional enrichment analysis demonstrated that the downregulated genes were enriched in pathways such as 'synaptic transmission' and 'behavior', whereas the upregulated genes were significantly over-represented in gene ontology pathways such as 'immune response' and 'blood vessel development'. Co-expression-based gene network analysis identified seven modules including four modules significantly associated with 'synaptic transmission', 'blood vessel development' or 'immune responses'. Taken together, our study provides novel insights into the molecular mechanism of schizophrenia, suggesting that precision-tailored therapeutic approaches aimed at normalizing the expression/function of specific gene networks could be a promising option in schizophrenia.

The genetic architecture of pediatric cognitive abilities in the Philadelphia Neurodevelopmental Cohort.

The objective of this analysis was to examine the genetic architecture of diverse cognitive abilities in children and adolescents, including the magnitude of common genetic effects and patterns of shared and unique genetic influences. Subjects included 3689 members of the Philadelphia Neurodevelopmental Cohort, a general population sample comprising those aged 8-21 years who completed an extensive battery of cognitive tests. We used genome-wide complex trait analysis to estimate the SNP-based heritability of each domain, as well as the genetic correlation between all domains that showed significant genetic influence. Several of the individual domains suggested strong influence of common genetic variants (for example, reading ability, h(2)g=0.43, P=4e-06; emotion identification, h(2)g=0.36, P=1e-05; verbal memory, h(2)g=0.24, P=0.005). The genetic correlations highlighted trait domains that are candidates for joint interrogation in future genetic studies (for example, language reasoning and spatial reasoning, r(g)=0.72, P=0.007). These results can be used to structure future genetic and neuropsychiatric investigations of diverse cognitive abilities.

Characterisation of a novel NR4A2 mutation in Parkinson's disease brain.

OBJECTIVE: We performed a mutation screen of NR4A2 (also known as NURR1) in 409 Parkinson's disease (PD) patients. We identified a novel single base substitution in the 5'UTR of the NR4A2 (also known as NURR1) gene (c.-309C>T). RESULTS: We have performed expression studies in neuronal cell lines showing that the c.-309C>T mutation reduces NR4A2 mRNA expression in vitro. We have confirmed this finding in vivo by performing allele specific real-time PCR from brain tissue harbouring the 309C>T mutation and show a 3.48+/-1.62 fold reduction in mRNA expression of the mutant allele compared to wild-type. In addition we have undertaken genome wide expression analysis of the mutant NR4A2 brain and shown underexpressed genes were significantly enriched for gene ontology categories in nervous system development and synaptic transmission and overexpressed genes were enriched for unfolded protein response and morphogenesis. Lastly we have shown that the c.-309C>T mutation abrogates the protective effect of wild-type NR4A2 against apoptopic stress. CONCLUSIONS: Our findings indicate the c.-309C>T mutation reduces NR4A2 expression resulting in the downregulation of genes involved in the development and maintenance of the nervous system and synaptic transmission. These downregulated pathways contained genes known to be transactivated by NR4A2 and were not disrupted in idiopathic PD brain suggesting causality of the mutation.