Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Abstract

Schizophrenia has a heritability of 60-80%¹, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Extended Data Figure 1:. Primary GWAS Manhattan plot

The x-axis indicates chromosomal position and the y-axis is the significance of association (−log10(P)). The red line represents genome-wide significance level (5×10−8). SNPs in green are in linkage disequilibrium (LD; R2 >0.1) with index SNPs (diamonds) which represent LD independent genome-wide significant associations.

Extended Data Figure 2:. Polygenic risk prediction

A) Distributions of liability scale R² across 98 left-out-cohorts for polygenic risk scores built from SNPs with different p-value thresholds. Distributions of liability R² (assuming schizophrenia life-time risk of 1%) are shown for each p-value threshold, with point size representing size of the left-out cohort and colour representing ancestry. The median liability R² is represented as a horizontal black line. B) Liability R² of predicted and observed phenotypes in left-out cohorts using variants with p-value threshold p=0.05, from the fixed effect meta-analysis of variant effects, unadjusted for multiple comparisons. The polygenic risk scores are derived from two separate sets of leave-one-out GWAS meta-analyses: y-axis R² based on the results of primary GWAS including all ancestries; x axis R² based on cohorts of the same ancestry as the test samples. Circles denote core PGC samples. Triangles denote African American and Latino samples processed external to PGC by the providing author.

Extended Data Figure 3:. Association between 37 human tissues and schizophrenia.

The mean of the evidence (-log₁₀P) obtained from two methods (MAGMA, LDSC) for testing GWAS data for enrichment of association in genes with high expression in each tissue as determined from bulk RNA-seq. The bar colour indicates whether gene expression in the tissue is significantly associated with both methods, one method or none. The black vertical line represents the significance threshold corrected for the total number of tissues tested in this experiment. We also analysed previous waves of PGC schizophrenia GWAS^, for comparison.

Figure 1:. Overview of GWAS and gene prioritisation.

Flow diagram summarising GWAS, fine-mapping and SMR analyses and how these informed gene prioritisation.

Figure 2:. Gene set enrichment tests at genome-wide level and for protein coding genes containing FINEMAP credible SNPs.

Gene sets tested were retrieved from sequencing studies of schizophrenia (SCHEMA; companion paper), autism-spectrum disorder and developmental disorders. Sets representing genes that are intolerant to loss-of function mutations (LoF-intolerant) and brain-expressed genesare also shown. A) MAGMA gene set enrichment analysis, dotted line indicates nominal significance (p=0.05). B) Logistic regression (with Firth’s bias reduction method) showing the odds-ratio (and 95% CI) for association between protein-coding genes containing at least 1 credible FINEMAP SNP (N=418 after excluding genes with no LoF-intolerance data) and genes from the sets indicated. Odds-ratios are relative to protein-coding genes within GWAS K≤3.5 loci (1,283 genes, squares) or across the genome excluding the xMHC (19,547 genes; circles). Dotted line indicates no enrichment.

Figure 3:. Mapping of all FINEMAP/SMR genes (A) and prioritised genes (B) to synaptic locations using SYNGO.

Sunburst plots depict synaptic locations with child terms in concentric rings, starting with the synapse (center), pre- and postsynaptic locations in the first ring and child terms in subsequent ring. The number of genes in each term is indicated by the colour scheme in the legend. A) FINEMAP/SMR genes are protein coding genes tagged by at least one credible SNP identified by FINEMAP and/or associated using SMR (N=470) of which N=58 are SynGO annotated, 51 to cellular components. B) Prioritised (Extended Data Table 1; N=106) of which 15 are SynGO annotated, 14 to cellular components.

Figure 4:. Associations between schizophrenia and cell types from multiple brain regions in human and mouse.

a, b, The mean of the evidence (−log₁₀ P value) obtained from two methods (MAGMA and LDSC) for testing GWAS data for enrichment of associations in genes with high expression in cell types. 15 human cell types (derived from single nuclei) from the cortex and hippocampus (a) and 24 cell types (derived from single-cell RNA-seq) from 5 different brain regions in mouse (cortex, hippocampus, striatum, midbrain and hypothalamus) and from specific enrichments of oligodendrocytes, serotonergic neurons, dopaminergic neurons and cortical parvalbuminergic interneurons (b). Bar colour indicates whether the cell type is significantly associated with both methods, one method or none. The black vertical line represents the significance threshold corrected for the total number of cell types tested in each analysis. Results obtained for previous iterations of schizophrenia GWAS12,18 are shown for comparison. Pyramidal SS, pyramidal neurons from the somatosensory cortex; pyramidal CA1/CA3, pyramidal neurons from the CA1/CA3 region of the hippocampus. Where types of cell (such as interneurons) formed sub-clusters in the source data, these are designated by the suffix 1 or 2.