{"doi":"10.1038/s41588-024-01685-y","title":"Cell subtype-specific effects of genetic variation in the Alzheimer’s disease brain","abstract":"The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.","journal":"Nature Genetics","year":2024,"id":9026,"datarank":2.028393042635732,"base_score":4.976733742420574,"endowment":4.976733742420574,"self_citation_contribution":0.7465100613630863,"citation_network_contribution":1.281882981272646,"self_endowment_contribution":0.7465100613630863,"citer_contribution":1.281882981272646,"corpus_percentile":64.60537021969081,"corpus_rank":436,"citation_count":173,"citer_count":115,"citers_with_citation_signal":67,"citers_with_endowment":67,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.6814,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-03-21","fair_score":31.3333,"fair_percentile":13.390501319261213,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":63299,"name":"Zongmei Gao","orcid":null,"position":1,"is_corresponding":false},{"id":32027,"name":"Lu Zeng","orcid":"0000-0001-9381-7690","position":2,"is_corresponding":false},{"id":15891,"name":"Cristin McCabe","orcid":"0000-0002-7209-7847","position":3,"is_corresponding":false},{"id":32025,"name":"Charles C. White","orcid":"0009-0009-2377-8556","position":4,"is_corresponding":false},{"id":5263,"name":"Bernard Ng","orcid":"0000-0002-8688-3873","position":5,"is_corresponding":false},{"id":32022,"name":"Gilad Sahar Green","orcid":"0009-0002-3507-7684","position":6,"is_corresponding":false},{"id":16979,"name":"Devan R. Phillips","orcid":"0000-0002-9240-4912","position":8,"is_corresponding":false},{"id":55475,"name":"Liat Amir-Zilberstein","orcid":null,"position":9,"is_corresponding":false},{"id":63300,"name":"Hyo Lee","orcid":"0000-0002-4741-0707","position":10,"is_corresponding":false},{"id":63301,"name":"Richard V. Pearse","orcid":"0000-0003-3972-1457","position":11,"is_corresponding":false},{"id":63302,"name":"Atlas Khan","orcid":"0000-0002-6651-2725","position":12,"is_corresponding":false},{"id":63303,"name":"Badri N. Vardarajan","orcid":"0000-0002-5560-4085","position":13,"is_corresponding":false},{"id":58245,"name":"Krzysztof Kiryluk","orcid":"0000-0002-5047-6715","position":14,"is_corresponding":false},{"id":2802,"name":"Chun Jimmie Ye","orcid":"0000-0001-6560-3783","position":15,"is_corresponding":false},{"id":32745,"name":"Hans‐Ulrich Klein","orcid":"0000-0002-6382-9428","position":16,"is_corresponding":false},{"id":29324,"name":"Gao Wang","orcid":"0000-0001-9336-402X","position":17,"is_corresponding":false},{"id":29633,"name":"Prisca Liberali","orcid":"0000-0003-0695-6081","position":18,"is_corresponding":false},{"id":7418,"name":"Naomi Habib","orcid":"0000-0002-6049-2487","position":19,"is_corresponding":false},{"id":7426,"name":"Julie A. Schneider","orcid":"0000-0002-9482-1752","position":20,"is_corresponding":false},{"id":63304,"name":"Yanling Wang","orcid":"0009-0003-0061-9946","position":21,"is_corresponding":false},{"id":63306,"name":"Tracy L. 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Frankel","orcid":"0000-0003-2241-5314","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":"38514782","pmcid":"PMC12288883","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":64.0,"fair_a":48.0,"fair_i":0.0,"fair_r":13.3333,"fair_zscore":-1.2553,"fair_rationale":{"fair_score":31.33,"has_llm":true,"dimensions":{"F":{"name":"Findable","score":64.0,"criteria":[{"key":"f_has_doi","label":"Has a persistent DOI","kind":"deterministic","weight":1.0,"fraction":1.0,"signal":"DOI present","rationale":null},{"key":"f_repository_presence","label":"Indexed in repositories / literature DBs","kind":"deterministic","weight":1.0,"fraction":1.0,"signal":"datacite=0, pmcid=True, pmid=True","rationale":null},{"key":"f_persistent_ids","label":"Resolvable scholarly identifiers (OpenAlex)","kind":"deterministic","weight":0.5,"fraction":0.0,"signal":"no OpenAlex id","rationale":null},{"key":"f_metadata_richness","label":"Rich, machine-readable metadata","kind":"llm","weight":1.0,"fraction":0.0,"signal":null,"rationale":"The text does not mention any machine-readable metadata or metadata standards."}]},"A":{"name":"Accessible","score":48.0,"criteria":[{"key":"a_open_access","label":"Open Access / files deposited","kind":"deterministic","weight":1.5,"fraction":1.0,"signal":"Open Access","rationale":null},{"key":"a_retrievable","label":"Free full text retrievable","kind":"deterministic","weight":1.0,"fraction":0.0,"signal":"0 OA location(s)","rationale":null},{"key":"a_access_protocol","label":"Clear data/code access protocol","kind":"llm","weight":1.0,"fraction":0.0,"signal":null,"rationale":"No protocol for accessing the data or code is described."}]},"I":{"name":"Interoperable","score":0.0,"criteria":[{"key":"i_linked_data","label":"Linked datasets / DataCite relations","kind":"deterministic","weight":1.0,"fraction":0.0,"signal":"linked_datasets=0, datacite=0","rationale":null},{"key":"i_standard_ids","label":"References data via standard accessions","kind":"deterministic","weight":1.0,"fraction":0.0,"signal":"accessions=0, trials=0","rationale":null},{"key":"i_standards","label":"Standard formats, vocabularies & identifiers","kind":"llm","weight":1.0,"fraction":0.0,"signal":null,"rationale":"No reference to standard formats, vocabularies, or persistent identifiers."}]},"R":{"name":"Reusable","score":13.33,"criteria":[{"key":"r_license","label":"Clear, open reuse license","kind":"deterministic","weight":1.5,"fraction":0.0,"signal":"no license","rationale":null},{"key":"r_downloads","label":"Demonstrated reuse (downloads)","kind":"deterministic","weight":0.5,"fraction":0.0,"signal":"downloads=0","rationale":null},{"key":"r_version","label":"Versioned / maintained","kind":"deterministic","weight":0.5,"fraction":0.0,"signal":"no version chain","rationale":null},{"key":"r_dataset","label":"Classified as a data resource","kind":"deterministic","weight":0.5,"fraction":1.0,"signal":"is_dataset","rationale":null},{"key":"r_reusability","label":"Data-availability statement, license & reproducibility","kind":"llm","weight":2.0,"fraction":0.0,"signal":null,"rationale":"No data-availability statement, license, or reproducibility information is provided."}]}},"suggestions":["Include a data-availability statement specifying a public repository (e.g., GEO, Synapse) and a license.","Deposit the single-nucleus RNA-seq data and processed results in a FAIR-aligned repository with persistent identifiers.","Provide machine-readable metadata (e.g., ISA-Tab, JSON-LD) describing samples, cell types, and variants.","Use standard file formats (e.g., BAM, HDF5, VCF) and reference genome assemblies with versioned identifiers.","Document the analysis code and software versions in a reproducible workflow (e.g., Docker, Snakemake)."],"model":"deepseek/deepseek-v4-flash","agent_version":"fair_agent_v2","fulltext_source":"abstract_only"},"fair_model":"deepseek/deepseek-v4-flash","fair_agent_version":"fair_agent_v2","fair_fulltext_source":"abstract_only","fair_has_llm":true,"fair_computed_at":"2026-06-18T00:37:33.688504Z","clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}