Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Abstract

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

A conditional gene-based association framework integrating isoform-level eQTL data reveals new susceptibility genes for schizophrenia

“…The overlapped potential susceptibility genes (accounting for 51.2% in eDESE:dist and 17.0% in MAGMA) were enriched with plenty of neuronal- or synaptic signaling-related GO terms. Similar results of a recent large-scale GWAS were obtained by gene-set analyses ( Trubetskoy et al, 2022 ; Legge et al, 2021 ). The comparison of MAGMA and eDESE:dist revealed the advantage of conditional association analysis, that is, removing the redundantly associated genes.…”

“…We had demonstrated that the conditional gene-based analysis based on the improved ECS was more powerful than the likelihood ratio test in each simulation scenario. To evaluate the performance of the ECS and eDESE in the real-world data, we used a recent large-scale GWAS summary statistics dataset ( Trubetskoy et al, 2022 ) and gene expression profiles (GTEx v8) of multiple human tissues ( Consortium, 2020 ) to identify the susceptibility genes of schizophrenia. We found that the improved ECS identified 739 significant genes without conditioning on gene-expression profiles.…”

“…Interestingly, four of the five optimized brain regions (i.e. Brain-Anterior cingulate cortex (BA24), Brain-Cerebellum, Brain-Frontal Cortex (BA9), and Brain-Hippocampus) were also reported by the Schizophrenia Working Group of the Psychiatric Genomics Consortium, in which the genes with high relative specificity for bulk expression were strongly enriched with schizophrenia associations ( Trubetskoy et al, 2022 ).…”

“…The variants in the major histocompatibility complex (MHC) region, i.e., chr6:27,477,797–34,448,354, were excluded in the present study because of the high polymorphism. Detailed descriptions of population cohorts, quality control methods and association analysis methods can be found in reference ( Trubetskoy et al, 2022 ).…”

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

“…Expression patterns of genes in SCZ neurons may further elucidate the molecular mechanisms of the disease and drug discovery 23 . The Psychiatry Genome Consortium wave 3 (PGC3) meta-analysis has reported 287 genomic loci containing common alleles associated with schizophrenia, highlighting the complex genetic architecture enriched by neurodevelopmental genes as well as synapse-related pathways as being of central importance 24 .…”