{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T20:03:26Z","timestamp":1757621006104,"version":"3.44.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":250,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Key Science and Technology Research Project of Henan Province","award":["Nos. 242102310103,252102520024,252102240125"],"award-info":[{"award-number":["Nos. 242102310103,252102520024,252102240125"]}]},{"DOI":"10.13039\/501100006407","name":"Natural Science Foundation of Henan Province","doi-asserted-by":"publisher","award":["No. 242300420242"],"award-info":[{"award-number":["No. 242300420242"]}],"id":[{"id":"10.13039\/501100006407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key R & D and Promotion Special Program of Henan Province","award":["No. 212102310988"],"award-info":[{"award-number":["No. 212102310988"]}]},{"name":"the Young Backbone Teacher Funding Scheme of Henan","award":["No. 2019GGJS079"],"award-info":[{"award-number":["No. 2019GGJS079"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["Nos. 61673008"],"award-info":[{"award-number":["Nos. 61673008"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Comorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely reported, but the underlying intrinsic link between Alzheimer\u2019s disease (AD) and inflammatory bowel disease (IBD) is not adequately understood.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>To identify pathogenic cell types of AD and IBD and explore their shared genetic architecture, we developed Pathogenic Cell types and shared Genetic Loci (PCGL) framework, which studied AD and IBD and its two subtypes of ulcerative colitis (UC) and Crohn\u2019s disease (CD).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We found that monocytes and CD8 T cells were the enriched pathogenic cell types of AD and IBDs, respectively. By PCGL framework, there was a significant global genetic correlation between AD and each of IBD, UC, and CD. Especially, local genetic correlations between AD and IBD showed strong signals in chr6. Bidirectional two-sample MR Analyses also validated these. Cross-trait meta-analysis identified two key genetic loci rs660895 (on chr6) and rs917117 (on chr7), which have not been previously reported. Two loci are located on the genes HLA-DRB1 and JAZF1, respectively. MAGMA genome-wide gene-based analysis identified six overlapping genes including HLA-DRB1. Subsequently, for one thing, SMR analyses further validated six shared genes in specific tissues and monocytes. For another, pathway enrichment analysis revealed shared genes were enriched in several natural killer cell mediated cytotoxicity and chemokine signaling pathways.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>PCGL not only revealed the significant genetic correlations underlying AD and IBDs but also identified enriched pathogenic cell types and new shared loci and genes. We highlighted the mediation of HLA-DRB1 effects in the comorbidity mechanisms.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bfgp\/elaf013","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T11:41:58Z","timestamp":1757331718000},"source":"Crossref","is-referenced-by-count":0,"title":["Identification of pathogenic cell types and shared genetic loci and genes for Alzheimer\u2019s disease and inflammatory bowel disease"],"prefix":"10.1093","volume":"24","author":[{"given":"Jingjing","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Mathematics and Statistics, Henan University of Science and Technology , No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471000 ,","place":["China"]},{"name":"Longmen Laboratory , Henan University of Science and Technology, No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471003 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqing","family":"Yan","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University , No. 1, Shizishan Street, Hongshan District, Wuhan, Hubei 430074 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liqin","family":"Han","sequence":"additional","affiliation":[{"name":"School of Mathematics and Statistics, Henan University of Science and Technology , No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471000 ,","place":["China"]},{"name":"Longmen Laboratory , Henan University of Science and Technology, No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471003 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Qiao1","sequence":"additional","affiliation":[{"name":"School of Mathematics and Statistics, Henan University of Science and Technology , No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471000 ,","place":["China"]},{"name":"Longmen Laboratory , Henan University of Science and Technology, No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471003 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6801-2030","authenticated-orcid":false,"given":"Xiaohui","family":"Niu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University , No. 1, Shizishan Street, Hongshan District, Wuhan, Hubei 430074 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5545-6185","authenticated-orcid":false,"given":"Peiluan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Mathematics and Statistics, Henan University of Science and Technology , No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471000 ,","place":["China"]},{"name":"Longmen Laboratory , Henan University of Science and Technology, No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471003 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"2025090807415125800_ref1","doi-asserted-by":"crossref","first-page":"937486","DOI":"10.3389\/fnagi.2022.937486","article-title":"Global, regional, and national burden of Alzheimer's disease and other dementias, 1990\u20132019","volume":"14","author":"Li","year":"2022","journal-title":"Front Aging Neurosci"},{"key":"2025090807415125800_ref2","doi-asserted-by":"publisher","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the global burden of disease study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"2025090807415125800_ref3","doi-asserted-by":"publisher","first-page":"708","DOI":"10.4103\/1673-5374.353484","article-title":"Targeting neuroinflammation in Alzheimer\u2019s disease: from mechanisms to clinical applications","volume":"18","author":"Si","year":"2023","journal-title":"Neural Regen Res"},{"key":"2025090807415125800_ref4","first-page":"863","article-title":"Correlation analysis between psychological symptoms and quality of life in patients with inflammatory bowel disease","volume":"44","author":"Zhang","year":"2019","journal-title":"Journal of Bengbu Medical College"},{"key":"2025090807415125800_ref5","first-page":"734","article-title":"Research progress on the association between Parkinson\u2019s disease and inflammatory bowel disease in genetics and gut microbiota","volume":"54","author":"Yanghong","year":"2021","journal-title":"Chinese Journal of Neurology"},{"key":"2025090807415125800_ref6","doi-asserted-by":"publisher","first-page":"110610","DOI":"10.1016\/j.pnpbp.2022.110610","article-title":"Inflammatory bowel disease: a potential pathogenic factor of Alzheimer's disease","volume":"119","author":"Wang","year":"2022","journal-title":"Progress in Neuro-Psychopharmacology and Biological Psychiatry"},{"key":"2025090807415125800_ref7","doi-asserted-by":"crossref","first-page":"1082575","DOI":"10.3389\/fnagi.2022.1082575","article-title":"Association of inflammatory bowel disease and related medication exposure with risk of Alzheimer's disease: an updated meta-analysis","volume":"14","author":"Xing","year":"2023","journal-title":"Front Aging Neurosci"},{"key":"2025090807415125800_ref8","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1038\/ng.3404","article-title":"Partitioning heritability by functional annotation using genome-wide association summary statistics","volume":"47","author":"Finucane","year":"2015","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref9","doi-asserted-by":"crossref","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"elife"},{"key":"2025090807415125800_ref10","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref11","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk","volume":"51","author":"Jansen","year":"2019","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref12","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2023.100263","article-title":"Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer\u2019s disease-specific cis-regulatory elements","volume":"3","author":"Anderson","year":"2023","journal-title":"Cell Genomics"},{"key":"2025090807415125800_ref13","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/ng.3359","article-title":"Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations","volume":"47","author":"Liu","year":"2015","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref14","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1038\/ng.3646","article-title":"Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution","volume":"48","author":"Corces","year":"2016","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref15","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1016\/j.cell.2018.03.074","article-title":"Integrated single-cell analysis maps the continuous regulatory landscape of human hematopoietic differentiation","volume":"173","author":"Buenrostro","year":"2018","journal-title":"Cell"},{"key":"2025090807415125800_ref16","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/s41588-019-0362-6","article-title":"Interrogation of human hematopoiesis at single-cell and single-variant resolution","volume":"51","author":"Ulirsch","year":"2019","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref17","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"The GTEx consortium atlas of genetic regulatory effects across human tissues","volume":"369","author":"GTEx Consortium","year":"2020","journal-title":"Science"},{"key":"2025090807415125800_ref18","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1038\/s41467-022-30893-5","article-title":"Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure","volume":"13","author":"Oelen","year":"2022","journal-title":"Nat Commun"},{"key":"2025090807415125800_ref19","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref20","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes","volume":"491","author":"1000 Genomes Project Consortium","year":"2012","journal-title":"Nature"},{"key":"2025090807415125800_ref21","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/nature09298","article-title":"Integrating common and rare genetic variation in diverse human populations","volume":"467","author":"Altshuler","year":"2010","journal-title":"Nature"},{"key":"2025090807415125800_ref22","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1038\/ng.3406","article-title":"An atlas of genetic correlations across human diseases and traits","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref23","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.ajhg.2017.09.022","article-title":"Local genetic correlation gives insights into the shared genetic architecture of complex traits","volume":"101","author":"Shi","year":"2017","journal-title":"The American Journal of Human Genetics"},{"key":"2025090807415125800_ref24","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet Epidemiol"},{"key":"2025090807415125800_ref25","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1093\/aje\/kwr026","article-title":"Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses","volume":"173","author":"Palmer","year":"2011","journal-title":"Am J Epidemiol"},{"key":"2025090807415125800_ref26","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int J Epidemiol"},{"key":"2025090807415125800_ref27","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref28","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/s41588-017-0009-4","article-title":"Multi-trait analysis of genome-wide association summary statistics using MTAG","volume":"50","author":"Turley","year":"2018","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref29","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.ajhg.2014.11.011","article-title":"Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension","volume":"96","author":"Zhu","year":"2015","journal-title":"The American Journal of Human Genetics"},{"key":"2025090807415125800_ref30","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"The American journal of human genetics"},{"key":"2025090807415125800_ref31","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref32","doi-asserted-by":"publisher","first-page":"e1004219","DOI":"10.1371\/journal.pcbi.1004219","article-title":"MAGMA: generalized gene-set analysis of GWAS data","volume":"11","author":"Leeuw","year":"2015","journal-title":"PLoS Comput Biol"},{"key":"2025090807415125800_ref33","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/wics.147","article-title":"Ggplot2","volume":"3","author":"Wickham","year":"2011","journal-title":"Wiley Interdisciplinary Reviews: Computational Statistics"},{"key":"2025090807415125800_ref34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13195-015-0125-2","article-title":"The dynamics of monocytes and microglia in Alzheimer\u2019s disease","volume":"7","author":"Th\u00e9riault","year":"2015","journal-title":"Alzheimer's Res Ther"},{"key":"2025090807415125800_ref35","doi-asserted-by":"crossref","first-page":"738762","DOI":"10.3389\/fimmu.2021.738762","article-title":"New insights on CD8+ T cells in inflammatory bowel disease and therapeutic approaches","volume":"12","author":"Casalegno Gardu\u00f1o","year":"2021","journal-title":"Front Immunol"},{"key":"2025090807415125800_ref36","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1038\/ng.3954","article-title":"Linkage disequilibrium\u2013dependent architecture of human complex traits shows action of negative selection","volume":"49","author":"Gazal","year":"2017","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref37","doi-asserted-by":"crossref","first-page":"15333175221085066","DOI":"10.1177\/15333175221085066","article-title":"Regulation of the late onset Alzheimer\u2019s disease associated HLA-DQA1\/DRB1 expression","volume":"37","author":"Zhang","year":"2022","journal-title":"Am J Alzheimers Dis Other Demen"},{"key":"2025090807415125800_ref38","doi-asserted-by":"publisher","first-page":"1934","DOI":"10.3390\/genes12121934","article-title":"HLA-DQA1* 05 associates with extensive ulcerative colitis at diagnosis: an observational study in children","volume":"12","author":"Nowak","year":"2021","journal-title":"Genes"},{"key":"2025090807415125800_ref39","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1038\/ng.3176","article-title":"High-density mapping of the MHC identifies a shared role for HLA-DRB1* 01: 03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis","volume":"47","author":"Goyette","year":"2015","journal-title":"Nat Genet"},{"key":"2025090807415125800_ref40","doi-asserted-by":"publisher","DOI":"10.1101\/2023.12.20.23300300","article-title":"Key variants via Alzheimer\u2019s disease sequencing project whole genome sequence data","author":"Wang","year":"2023","journal-title":"medRxiv"},{"key":"2025090807415125800_ref41","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1007\/s12017-020-08612-4","article-title":"HLA in Alzheimer\u2019s disease: genetic association and possible pathogenic roles","volume":"22","author":"Wang","year":"2020","journal-title":"Neuromolecular Med"},{"key":"2025090807415125800_ref42","doi-asserted-by":"publisher","first-page":"3628","DOI":"10.3748\/wjg.v12.i23.3628","article-title":"Genetics of inflammatory bowel disease: the role of the HLA complex","volume":"12","author":"Ahmad","year":"2006","journal-title":"World J Gastroenterol: WJG"},{"key":"2025090807415125800_ref43","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13059-024-03183-0","article-title":"A comparison of marker gene selection methods for single-cell RNA sequencing data","volume":"25","author":"Pullin","year":"2024","journal-title":"Genome Biol"},{"key":"2025090807415125800_ref45","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/j.jad.2024.09.030","article-title":"Association between psychiatric disorders and irritable bowel syndrome: a bidirectional Mendelian randomization study","volume":"368","author":"Wang","year":"2025","journal-title":"J Affect Disord"},{"key":"2025090807415125800_ref46","first-page":"17.23286845","article-title":"Genetic insights into the association between inflammatory bowel disease and Alzheimer\u2019s disease","volume":"2023","author":"Zeng","year":"2024","journal-title":"medRxiv"},{"key":"2025090807415125800_ref47","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1016\/j.immuni.2023.01.002","article-title":"The landscape of immune dysregulation in Crohn\u2019s disease revealed through single-cell transcriptomic profiling in the ileum and colon","volume":"56","author":"Kong","year":"2023","journal-title":"Immunity"},{"key":"2025090807415125800_ref48","doi-asserted-by":"crossref","first-page":"e1250","DOI":"10.1002\/cti2.1250","article-title":"Natural killer cells in inflammatory autoimmune diseases","volume":"10","author":"Yang","year":"2021","journal-title":"Clinical & translational immunology"},{"key":"2025090807415125800_ref49","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/S0197-4580(98)00050-5","article-title":"Increased natural killer cell cytotoxicity in Alzheimer\u2019s disease may involve protein kinase C dysregulation","volume":"19","author":"Solerte","year":"1998","journal-title":"Neurobiol Aging"}],"container-title":["Briefings in Functional Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bfg\/article-pdf\/doi\/10.1093\/bfgp\/elaf013\/64220267\/elaf013.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bfg\/article-pdf\/doi\/10.1093\/bfgp\/elaf013\/64220267\/elaf013.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T11:42:00Z","timestamp":1757331720000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bfg\/article\/doi\/10.1093\/bfgp\/elaf013\/8249064"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025]]},"references-count":48,"URL":"https:\/\/doi.org\/10.1093\/bfgp\/elaf013","relation":{},"ISSN":["2041-2649","2041-2657"],"issn-type":[{"type":"print","value":"2041-2649"},{"type":"electronic","value":"2041-2657"}],"subject":[],"published-other":{"date-parts":[[2025]]},"published":{"date-parts":[[2025]]},"article-number":"elaf013"}}