Depicting spatial distributions of disease-relevant cells is crucial for understanding disease pathology. Here, we present a method, gsMap, that integrates spatial transcriptomics (ST) data with genome-wide association study (GWAS) summary statistics to map cells to human complex traits, including diseases, in a spatially resolved manner. Using embryonic ST datasets covering 25 organs, we benchmarked gsMap through simulation and by corroborating known trait-associated cells or regions in various organs. Applying gsMap to brain ST data, we revealed that the spatial distribution of glutamatergic neurons (glu-neurons) associated with schizophrenia more closely resembles that for cognitive traits than that for mood traits, such as depression. The schizophrenia-associated glu-neurons were distributed near the dorsal hippocampus, with upregulated calcium signaling and regulation genes, while the depression-associated glu-neurons were distributed near the deep medial prefrontal cortex, with upregulated neuroplasticity genes. Our study provides a method for spatially resolved mapping trait-associated cells and demonstrates the gain of biological insights (e.g., spatial distribution of trait-relevant cells and related signature genes) through these maps.

The authors have declared no competing interest.

This research was supported by the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (2021R01013), "Pioneer" and "Leading Goose" R&D Program of Zhejiang (2022SDXHDX0001 and 2024SSYS0032), the National Natural Science Foundation of China (U23A20165), and the Westlake University Research Center for industries of the Future (WU2022C002 and WU2023C010).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Ethics Committee of Westlake University (approval no. 20200722YJ001). This study used GWAS summary statistics for 110 traits, as summarized in Supplementary Table 1. The mouse embryonic and brain ST data are available at https://db.cngb.org/search/project/CNP0001543/. The macaque cortex ST data are available at https://db.cngb.org/search/project/CNP0002035/. The ST data for human DLPFC are available at https://research.libd.org/globus/. The reference LD data, generated from 1KGP3, are available at ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/2013050. The baseline annotations of LDSC are available at https://data.broadinstitute.org/alkesgroup/LDSCORE. The DrugBank database is available at https://go.drugbank.com/. The Drug Repurposing Hub database is available at https://www.broadinstitute.org/drug-repurposing-hub. The human, mouse, and macaque reference genome data are available at https://nov2020.archive.ensembl.org/index.html.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

This study used GWAS summary statistics for 110 traits, as summarized in Supplementary Table 1. The mouse embryonic and brain ST data are available at https://db.cngb.org/search/project/CNP0001543/. The macaque cortex ST data are available at https://db.cngb.org/search/project/CNP0002035/. The ST data for human DLPFC are available at https://research.libd.org/globus/. The reference LD data, generated from 1KGP3, are available at ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/2013050. The baseline annotations of LDSC are available at https://data.broadinstitute.org/alkesgroup/LDSCORE. The DrugBank database is available at https://go.drugbank.com/. The Drug Repurposing Hub database is available at https://www.broadinstitute.org/drug-repurposing-hub. The human, mouse, and macaque reference genome data are available at https://nov2020.archive.ensembl.org/index.html. The gsMap results for different traits and ST datasets can be visualized and downloaded at https://yanglab.westlake.edu.cn/gsmap/home.