Pocklington, A. J. | Search bioRxiv

bioRxiv2018

Dynamic expression of risk genes for schizophrenia and bipolar disorder across development

AO_SCPCAPBSTRACTC_SCPCAPCommon genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between schizophrenia and bipolar disorder. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genes associated with schizophrenia have a strong bias towards increased expression in the prefrontal cortex during early midfetal development and early infancy, and decreased expression during late childhood which normalises in adolescence. Risk-associated genes for bipolar disorder shared this postnatal expression profile but did not exhibit a bias towards expression at any prenatal stage. These results emphasise the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the view that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.

neuroscience↗

bioRxiv2018

Association between schizophrenia and both loss of function and missense mutations in paralog conserved sites of voltage-gated sodium channels

Sequencing studies have highlighted candidate sets of genes involved in schizophrenia, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Two genes, SETD1A and RBM12, have also been associated with robust statistical evidence. Larger samples and novel methods for identifying disease-associated missense variants are needed to reveal novel genes and biological mechanisms associated with schizophrenia. We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5,207 cases and 4,991 controls. Included were members of ARC and NMDAR post-synaptic protein complexes, as well as voltage-gated sodium and calcium channels. We observed a significant case excess of rare (<0.1% in frequency) loss-of-function (LoF) mutations across all 187 genes (OR = 1.36; Pcorrected = 0.0072) but no individual gene was associated with schizophrenia after correcting for multiple testing. We found novel evidence that LoF and missense variants at paralog conserved sites were enriched in sodium channels (OR = 1.26; P = 0.0035). Meta-analysis of our new data with published sequencing data (11,319 cases, 15,854 controls and 1,136 trios) supported and refined this association to sodium channel alpha subunits (P = 0.0029). Meta-analysis also confirmed association between schizophrenia and rare variants in ARC (P = 4.0 x 10-4) and NMDAR (P = 1.7 x 10-5) synaptic genes. No association was found between rare variants in calcium channels and schizophrenia.\n\nIn one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis, and increase the evidence for association between rare variants in ARC and NMDAR post-synaptic complexes and schizophrenia. Larger samples are required to identify specific genes and variants driving these associations.\n\nAuthor SummaryCommon and rare genetic variations are known to play a substantial role in the development of schizophrenia. Recently, sequencing studies have started to highlight specific sets of genes that are enriched for rare variation in schizophrenia, such as the synaptic gene sets ARC and NMDAR, as well as voltage-gated sodium and calcium channels. To confirm the role of these gene sets in schizophrenia, and identify specific risk genes, we sequenced 187 genes in a new sample of 5,207 schizophrenia cases and 4,991 controls. We find an excess of protein truncating mutations with a frequency <0.1% in all 187 targeted genes, and provide novel evidence that mutations altering amino acids conserved across sodium channel proteins are risk factors for schizophrenia. Through meta-analysing our new data with previously published sequencing data sets, for a total of 11,319 cases, 15,854 controls and 1,136 trios, we increase the evidence for association between rare coding variants and schizophrenia in voltage-gated sodium channels, as well as in synaptic gene sets ARC and NMDAR. Although no individual gene was associated with schizophrenia, these findings suggest larger studies will identify the specific genes driving these associations.

genetics↗