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.

New insights from the last decade of research in psychiatric genetics: discoveries, challenges and clinical implications

“…In schizophrenia, well-powered datasets on both common and rare variants have allowed for a more comprehensive mechanistic interrogation, with emerging biological convergence across both ends of the allelic frequency spectrum 64,106,111,138 . Both rare and common variant associations with schizophrenia have strongly implicated genes influencing synaptic organization, differentiation and signaling, at both presynaptic and postsynaptic locations 64,106,139 .…”

“…The evolutionary constrained genes have a high probability of being intolerant to loss‐of‐function mutations, and are relatively depleted of equivalent protein‐disrupting variants in the general population 110 . Recently, such genes have also been implicated by common variant findings for schizophrenia 111 .…”

Common and rare variant associations with latent traits underlying depression, bipolar disorder, and schizophrenia

“…Unlike other literature, this study did not use sequence or exome array data due to a lack of availability for large symptomlevel data, but the UK Biobank Axiom array also covers variation in exonic regions and areas of rare coding variation including protein-truncating variants [78]. The lower coverage of these genomic regions means the results of this study are not informative about the contribution of ultra-rare, de novo and private mutations, which have been implicated in previous studies of psychiatric illness [11,15,79].…”

“…In psychiatry, few studies have focused on rare genetic variants associated with major depression [9,10], while several have investigated schizophrenia and bipolar disorder [11][12][13]. Studies of some psychiatric disorders including schizophrenia have found an enrichment of ultra-rare disruptive variants [11,14,15] and studies of common variants for complex diseases have found enrichment of genes associated with matched Mendelian disorders [16].…”