Ultra-rare and common genetic variant analysis converge to implicate negative selection and neuronal processes in the aetiology of schizophrenia

Abstract

Both common and rare genetic variants (minor allele frequency >1% and <0.1% respectively) have been implicated in the aetiology of schizophrenia. In this study, we integrate single-cell gene expression data with publicly available Genome-Wide Association Study (GWAS) and exome sequenced data in order to investigate in parallel, the enrichment of common and (ultra-)rare variants related to schizophrenia in several functionally relevant gene-sets. Four types of gene-sets were constructed 1) protein-truncating variant (PTV)-intolerant (PI) genes 2) genes expressed in brain cell types and neurons ascertained from mouse and human brain tissue 3) genes defined by synaptic function and location and 4) intersection genes, i.e., PI genes that are expressed in the human and mouse brain cell gene-sets. We show that common as well as ultra-rare schizophrenia-associated variants are overrepresented in PI genes, in excitatory neurons from the prefrontal cortex and hippocampus, medium spiny neurons, and genes enriched for synaptic processes. We also observed stronger enrichment in the intersection genes. Our findings suggest that across the allele frequency spectrum, genes and genetic variants likely to be under stringent selection, and those expressed in particular brain cell types, are involved in the same biological pathways influencing the risk for schizophrenia.

Fig. 1. Common variant enrichment in PI and brain cell gene sets.

Black stars denote significant gene-sets after multiple testing correction. ASC astrocytes, exCA1/exCA3 pyramidal neurons from the Hippocampal Cornu Ammonis regions, exDG granule neurons from the Hippocampal dentate gyrus region, exPFC1/exPFC2 pyramidal neurons from the prefrontal cortex, GABA1/GABA2 GABAergic interneurons. Although not included in the figure, the synaptic gene-sets were included in multiple testing correction.

Fig. 2. (Ultra-)rare variant enrichment in PI and brain cell gene sets.

Black stars denote significant gene-sets after multiple testing correction. ASC astrocytes, exCA1/exCA3 pyramidal neurons from the Hippocampal Cornu Ammonis regions, exDG granule neurons from the Hippocampal dentate gyrus region, exPFC1/exPFC2 pyramidal neurons from the prefrontal cortex, GABA1/GABA2 GABAergic interneurons. Although not included in the figure, the synaptic gene-sets were included in multiple testing correction. Regressions are corrected for sex, PCs and exome-wide (ultra)-rare PTV burden.

Fig. 3. Correlation between gene set enrichment in common vs ultra-rare variants.

Point sizes represent the weight assigned to each correlation estimate, obtained by calculating the inverse of the product of both standard errors. Correlation estimate is 0.531, while weighted correlation is 0.700. Labelled gene-sets are significantly enriched across both common and ultra-rare variants.

Fig. 4. Cross-ancestry correlation between gene-set enrichment in common variants from East-Asian ancestry and ultra-rare variants from European ancestry.

Point sizes represent the weight assigned to each correlation estimate, obtained by calculating the inverse of the product of both standard errors. Correlation estimate is 0.668, while weighted correlation is 0.563. Labelled gene-sets are significantly enriched across both common variants from individuals of East Asian ancestry and ultra-rare variants from individuals of European ancestry.