EMA study at a false discovery rate of 5%. We also find associations at a false discovery rate of 5% for six genes that did not pass this statistical threshold in the SCHEMA study (SLC6A1, PCLO, ZMYND11, BSCL2, KLC1 and CGREF1). Among these genes, SLC6A1 and KLC1 are associated with damaging missense variants alone. STAG1, SLC6A1, ZMYND11 and CGREF1 are also enriched for rare coding variants in other developmental and psychiatric
interesting!!!
rare (MAF < 0.01) copy number variants (CNVs) and ultra-rare (MAF < 2 × 10−5) coding variant
Good Quote
Rare coding variants (RCVs) contributing to schizophrenia are concentrated among a set of around 3000 genes known to be under selective constraint in humans against stop-gain, essential splice site, and frameshift mutations, collectively termed protein-truncating variants (PTVs
We know this is related to schizophrenia, but is it related to our disorder?
we report exome-wide significant associations for STAG1 and ZNF136, genes that were previously implicated in schizophrenia
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Constrained genes are defined as those with pLi scores ≥ 0.9 in gnomAD (n genes = 3051)10. The measure of centre is the odds ratio value and error bars denote 95% confidence intervals of odds ratio estimates. Odds ratios are plotted on a log scale. Odds ratios in the new case-control sample were derived from Firth’s logistic regression models (Supplementary Methods). Published odds ratios from the SCHEMA sample were taken from Singh et al. (2022). PTV protein-truncating variants, MPC ‘missense badness, Polyphen-2 and constraint’ score, pLi probability of being loss of function intolerant. Source data for Fig. 1 are provided as a Source Data file.
This figure is comparing rate and effect sizes between an older SCHEMA study and the new case control cohort from the current study. Singleton synonymous variants in constrained gene were significantly higher than the new controls. This graph also shows which types of mutations drive risk. Which one is STAG?
We identified two novel risk genes at exome-wide significance (Table 1): STAG1 was associated with rare PTVs and missense
STAG1 achieves strict exome-wide significance in schizophrenia. Menaing they are highly confident that this genetic mutation can impact schizophrenia after looking at a large scale of the genome.
PTVs and missense (MPC > 2) variants (P = 3.7 × 10−8)
STAG gene mutations are caused by PTV and missense mutations (in this case, does this relate to our disorder?). STAG encodes a core subunit of cohesin and stengthens the link between disrupted chromatin organization
STAG1 and KLC1 overlap genomic loci with genome-wide significant common variant associations in the largest schizophrenia GWAS to date4. STAG1 narrowly failed the conservative criteria adopted in that study for prioritising a gene as likely to be causal.
What does it mean for a gene to be "casual"?
Summary statistics for the PGC3 schizophrenia GWAS4 were downloaded from the PGC website (https://pgc.unc.edu/for-researchers/download-results/) and visualised using LocusZoom57. The y axis shows unadjusted two-sided P values of each SNP from the PGC3 schizophrenia GWAS summary statistics4, and the colour of each triangle shows the linkage disequilibrium with the index SNP. Shown below are the unadjusted two-sided P-values and odds ratios (OR) for each gene within 200KB of KLC1. P-values are from the case-control-de novo meta-analysis and ORs are from the Cochran–Mantel–Haenszel case-control analysis. P values and ORs are shown for the class of variant most strongly associated with schizophrenia.
KLC1 is the only gene in that entire GWAS locus with a signifigant rare coding mutation sign. This graph does not directly include the STAG1 mutation and would likely not be a good figure to discuss in our paper.
Genes enriched for RCVs are known to overlap between schizophrenia and other psychiatric and developmental disorders.
Could this overlap with our disorder? I didn't see much talk about STAG being enriched for RCVs.
In STAG1, both PTVs and missense variants are associated with schizophrenia and DD (Table 2)
Table 2 is showing the 8 primary risk genes identified in this study are also enriched for rare coding mutations in other psychiatric and neurodevelopmental conditions. For STAG, there is also evidence that it encodes for developmental disorders.
STAG1 encodes a subunit of cohesin, a protein complex required for correct chromosomal segregation during cell division18. Defects in cohesin subunits and interactors are associated with a heterogeneous class of neurodevelopmental disorders termed cohesinopathies, whose pathology is thought to be mediated by a further role of cohesin in 3D genome organisation19.
Why is STAG so important? What happens when it is mutated?
STAG1, is associated with disrupted patterns of chromatin contact and gene expression, including genes with functions related to neuronal development
Good quote
etiological role for disrupted chromatin organisation in this disorder
Specific for this disorder, however this could be the similar affect that STAG1 has on our disorder.
STAG1 and ZNF136 were provisionally implicated by the SCHEMA study at FDR < 5%12, but our findings with a larger sample indicate that these genes reach exome-wide significance after Bonferroni correction for multiple testing.
STAG has been studied relating to development and psychiatric disorders before.
four genes which show both fine-mapped common variant signals in schizophrenia GWAS and an excess of RCVs in cases at either exome-wide significance (GRIN2A and SP4) or FDR < 5% (STAG1 and FAM120A
^^STAG1 does show an excess of RCVs in this case.
Previous studies have provided evidence for pleiotropic effects from individual RCVs across schizophrenia, autism and developmental disorders
RCVs could also have an impact on the developmental disorder we are studying.