GROUP Investigators, | Search bioRxiv

bioRxiv2019

Analyses of rare and common alleles in parent-proband trios implicate rare missense variants in SLC6A1 in schizophrenia and confirm the involvement of loss of function intolerant and neurodevelopmental disorder genes.

Schizophrenia is a highly polygenic disorder with important contributions coming from both common and rare risk alleles, the latter including CNVs and rare coding variants (RCVs), sometimes occurring as de novo variants (DNVs). We performed DNV analysis in whole exome-sequencing data obtained from a new sample of 613 schizophrenia trios, and combined this with published data for a total of 3,444 trios. Loss-of-function (LoF) DNVs were significantly enriched among 3,488 LoF intolerant genes in our new trio data (rate ratio (RR) (95% CI) = 2.23 (1.31, 3.79); p = 2.2 x 10-3), supporting previous findings. In the full dataset, genes associated with neurodevelopmental disorders (NDD; n=160) were significantly enriched for LoF DNVs (RR (95% CI) = 3.32 (2.0, 5.21); p = 7.4 x 10-6). Within this set of NDD genes, SLC6A1, encoding a gamma-aminobutyric acid transporter, was associated with missense-damaging DNVs (p = 5.2 x 10-5). Using data from a subset of 1,122 trios for which we had genome-wide common variant data, schizophrenia polygenic risk was significantly over-transmitted to probands (p = 2.6 x 10-60), as was bipolar disorder common variant polygenic risk (p = 5.7 x 10-17). We defined carriers of candidate schizophrenia-related DNVs as those with LoF or deletion DNVs in LoF intolerant or NDD genes. These individuals had significantly less over-transmission of common risk alleles than non-carriers (p = 3.5 x 10-4), providing robust support for the hypothesis that this set of DNVs is enriched for those related to schizophrenia.

genetics↗

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↗