De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia

Abstract

Data availability De novo variants discovered from the new trios are published in Supplementary Table S12. The data that support the findings of this study are available from the corresponding author upon request. Code availability A description of the R functions used for statistical analysis can be found in the Life Sciences Reporting Summary. Author contributions MCOD, MJO, JTRW, PH and ER conceived and designed the research. ER analysed the data. JH, JM and NC performed and managed the sequencing experiments. JH and MD performed the Sanger sequencing validation experiment. VEP, AJP, LH, SEL, AFP and ALR contributed to the interpretation of the results.

Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

“…Indeed, there is evidence that the outcome for pathogenic CNVs is in uenced by common genetic variation [25][26][27] . The situation for rare coding variants in schizophrenia is less clear 8 , but it is likely that similar considerations will apply. Our ndings also indicate that the same changes in gene function can underlie both NDDs and schizophrenia, pointing to a shared molecular aetiology and therefore likely overlapping pathophysiology.…”

“…Common risk alleles collectively contribute to around a third of the genetic liability 2,3 , and at least 8 rare copy number variants have been identi ed as risk factors 4,5 . Exome-sequencing studies have also shown a contribution to risk from ultra-rare proteincoding variants; the de novo mutation rate is modestly elevated above the expected population rate, and there is an excess of ultra-rare damaging coding variants (frequency < 0.0001 in population) in genes with evidence for strong selective constraint against protein-truncating variants (PTVs) [6][7][8][9] . SETD1A is currently the only gene in which rare coding variants are associated with schizophrenia at genome-wide signi cance 10 .…”

“…Consistent with genic pleiotropy, exonic deletions of NRXN1 increase liability to schizophrenia and NDDs, but there is marked heterogeneity in the exons affected and the deletion sizes 12 , leaving uncertainty as to whether precisely the same mutation can cause schizophrenia and NDD. In contrast, sequencing studies provide strong support for the hypothesis of genic pleiotropy, with genes that are enriched for ultra-rare coding variants in people with NDDs being enriched for de novo variants in people with schizophrenia 7,8 . Moreover, SETD1A is not only genome-wide signi cantly associated with schizophrenia, is also is associated with DD 13 While SETD1A is enriched for PTVs in both schizophrenia and DD 10,13 , the degree to which pleiotropic effects across these disorders are con ned to the same functional class of variant within genes is unknown.…”

DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition

“…The de novo LoF mutations for SZ analysed here are described in (Rees et al, 2019b). De novo LoF mutations for NDD, ASD and unaffected siblings of individuals with ASD were taken from (Satterstrom et al, 2019): these were re-annotated using VEP (McLaren et al, 2016) and mutations mapping to > 2 genes (once readthrough annotations had been discarded) were removed from the analysis.…”

If there is not one cure for schizophrenia, there may be many

“…The diverse presentation of symptoms experienced by patients with schizophrenia is matched only by the complexity of the genetic architecture that underlies disease risk. To date, hundreds of rare 1,2,3 and common 4,5 genetic variants have been associated with schizophrenia. Growing evidence supports the link between genotype and patient outcome, portending a future of precision medicine in psychiatry.…”