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NatureGenetic & Genomic MedicinePeer-reviewed journal article

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Vassily TrubetskoyiD, Antonio F. PardiñasiD, Ting QiiD, Georgia PanagiotaropoulouiD, Swapnil AwasthiiD, Tim B. BigdeliiD, Julien BryoisiD, Chia‐Yen CheniD, Charlotte A. DennisoniD, Lynsey S. HalliD, Max LamiD, Kyoko WatanabeiD, Oleksandr FreiiD, Tian GeiD, Janet C HarwoodiD, Frank KoopmansiD, Sigurður H. MagnússoniD, Alexander L. RichardsiD, Julia SidorenkoiD, Yang WuiD, Jian ZengiD, Jakob GroveiD, Minsoo KimiD, Zhiqiang LiiD, Georgios VoloudakisiD, , Elliot S. GershoniD

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Abstract

Schizophrenia is a psychiatric disorder whose pathophysiology is largely unknown. It has a heritability of 60-80%, much of which is attributable to common risk alleles, suggesting genome-wide association studies can inform our understanding of aetiology1. Here, in 69,369 people with schizophrenia and 236,642 controls, we report common variant associations at 270 distinct loci. Using fine-mapping and functional genomic data, we prioritise 19 genes based on protein-coding or UTR variation, and 130 genes in total as likely to explain these associations. 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 autism and developmental disorder. Associations were concentrated in genes expressed in CNS neurons, both excitatory and inhibitory, but not other tissues or cell types, and implicated fundamental processes related to neuronal function, particularly synaptic organisation, differentiation and transmission. We identify biological processes of pathophysiological relevance to schizophrenia, show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders, and provide a rich resource of priority genes and variants to advance mechanistic studies.

In-depth summary

Claude Opus 5.5 · xhigh effort · 5 Nov 2026 · from the full text of version 1 (13 Sept 2020)

A genome-wide association study of 69,369 schizophrenia cases and 236,642 controls identifies 270 risk loci, prioritizes 130 genes, and links common and rare risk variants to neuronal synaptic biology.

Common genetic variants account for much of schizophrenia's 60-80% heritability, but earlier genome-wide association studies (GWAS) identified up to 176 loci without resolving causal genes. Expanding sample size across European and East Asian cohorts and integrating fine-mapping, brain eQTLs, and Hi-C pinpoints 130 priority genes converging on synaptic biology.

Key results

  1. ShownTrans-ancestry GWAS meta-analysis and replication identify 329 independent genome-wide significant SNPs across 270 distinct genomic loci with identical common-variant genetic liability between sexes.

    Primary meta-analysis of 7,585,078 SNPs (MAF >= 1%) across 90 cohorts (67,390 cases, 94,015 controls) found 294 independent SNPs (r2 < 0.1, p < 5e-8) in 248 loci; combining with deCODE Genetics (1,979 cases, 142,627 controls) yielded 329 independent SNPs in 270 loci and male-female rg = 0.992 (SE 0.024). · Abstract; Association Meta-Analysis; Overview of Samples; Association / Meta-analysis

  2. ShownCommon variants explain 24% of schizophrenia liability, and polygenic risk scores strongly stratify extremes of risk in research cohorts despite insufficient population-level diagnostic accuracy.

    SNP-based heritability (h2SNP) was 0.24 (SE 0.007); leave-one-out polygenic risk scores explained up to 0.077 of liability variance (p < 0.05; 0.026 for genome-wide significant SNPs) with mean AUC 0.71, and top 1% PRS European individuals had OR = 44 (95% CI 31-63) vs the lowest centile and 7.0 (CI 5.8-8.3) vs the rest. · Heritability and Polygenic Prediction; Polygenic Prediction; Figure legends

  3. ShownSchizophrenia common-variant associations are selectively enriched in central nervous system excitatory and inhibitory neurons and synaptic ontology pathways.

    Across 37 GTEx tissues, 16 human brain single-nucleus types, and 265 mouse nervous system single-cell types, associations were enriched in cortical and hippocampal excitatory pyramidal and granule neurons, inhibitory interneurons, and striatal medium spiny neurons (not glia), mapping to 9 conditional GO terms and postsynaptic SynGO terms. · Tissue and cell types; Biological Processes; Tissue and cell types; Ontology Gene sets

  4. ShownBayesian fine-mapping, brain eQTL colocalization, and Hi-C chromatin interactions prioritize 130 candidate genes across associated loci.

    FINEMAP across 233 regions resolved 8 loci to 1 credible SNP (ATP2A2 rs4766428, PP > 0.97), 32 loci to <= 5 SNPs, 19 genes with nonsynonymous/UTR variants at PP >= 0.1 (SLC39A8 rs13107325 PP > 0.99, KLF6 PP > 0.99, IRF3 PP = 0.49), and 65 single-gene credible sets; adding 60 SMR/Hi-C genes yielded 130 priority genes (114 protein-coding). · Abstract; Fine-mapping; Prioritisation by Gene Expression; Figure legends

  5. ShownFine-mapped common-variant candidate genes converge with genes carrying rare disruptive coding variants in schizophrenia, autism spectrum disorder, and developmental disorders.

    Prioritized fine-mapped genes were enriched for SCHEMA rare-variant schizophrenia genes, overlapping exome-wide significant GRIN2A and SP4 and FDR < 0.05 genes STAG1 (85% FINEMAP PP) and FAM120A (70% PP), plus 8 rare-variant autism and developmental disorder genes (FOXP1, MYT1L, RERE, BCL11B, KANSL1, CACNA1C, GRIN2A, SLC39A8). · Abstract; Common and Rare Variant Associations with…; Figure legends

Methods, data and reproducibility

Genotypes from 90 PGC cohorts (161,405 individuals) were imputed against the HRC r1.1 panel (EAGLE2/MINIMAC3 or SHAPEIT3/IMPUTE4), tested via PLINK logistic regression, and meta-analyzed with deCODE Genetics (1,979 cases, 142,627 controls). Downstream analyses used leave-one-out PRS, MR-PRESSO Mendelian randomization, MAGMA/LDSC cell-type and SynGO enrichment, FINEMAP, and SMR/HEIDI brain eQTL and Hi-C integration.

  • Psychiatric Genomics Consortium (PGC) Wave 3 primary GWAS across 90 cohorts (~80% European, ~20% East Asian ancestry) · human · n = 67,390 cases and 94,015 controls (161,405 individuals) · https://www.med.unc.edu/pgc/download-results/
  • deCODE Genetics European-ancestry replication GWAS summary statistics for 1,187 index SNPs (P < 1e-5) · human · n = 1,979 cases and 142,627 controls (total: 69,369 cases, 236,642 controls)
  • Haplotype Reference Consortium (HRC) release 1.1 imputation reference panel · human · n = 54,330 phased haplotypes with 36,678,882 variants · https://ega-archive.org/datasets/EGAD00001002729
  • Bulk and single-cell/single-nucleus RNA-seq datasets (GTEx v8, adult human brain nuclei, mouse brain single-cell atlases) · human, mouse · n = 37 GTEx tissues; 19,550 human nuclei; ~10,000 and ~500,000 mouse cells
  • cis-eQTL summary data for SMR (fetal brain, adult prefrontal cortex, whole blood) and Health and Retirement Study LD reference · human · n = N = 120 (fetal brain), n = ~1,500 (adult brain), n = ~32,000 (blood)
Methods & tools
PLINK, EAGLE 2, MINIMAC3, SHAPEIT 3, IMPUTE4, FINEMAP, MAGMA, LDSC, SMR, GCTA-COJO, MR-PRESSO, SynGO
Software & environment
PLINK v1.9, EAGLE 2, MINIMAC3, SHAPEIT 3, IMPUTE4, MAGMA v1.06, Ensembl release 92 (GRCh37), R packages logistf, metafor, nsROC, biomaRt
Reproducibility gaps
Individual-level genotypes from mainland China cohorts were processed on local Chinese servers under regulatory restrictions and only summary statistics are included.
Limitations (3)
  • Polygenic risk scores explain up to 0.077 of variance in liability with an average AUROC of 0.71, which is insufficient for diagnostic prediction in the general population. · stated by the authors
  • Because ~80% of the discovery sample is of European ancestry and ~20% is of East Asian ancestry, polygenic risk score performance is lower in non-European cohorts. · stated by the authors
  • The extended major histocompatibility complex (MHC) region (chr6:25-35 Mb) had to be excluded from FINEMAP, SMR, and Mendelian randomization analyses due to complex long-range linkage disequilibrium. · stated by the authors

Read this if you study psychiatric genetics, fine-mapping, or synaptic neurobiology and want the PGC3 schizophrenia GWAS summary statistics and 130 prioritized risk genes.

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