{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T12:28:59Z","timestamp":1771331339808,"version":"3.50.1"},"posted":{"date-parts":[[2023,4,17]]},"group-title":"Genetic and Genomic Medicine","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Myeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immune system, playing a major role in orchestrating innate and adaptive immune responses. Both Alzheimer\u2019s disease (AD) and inflammatory bowel disease (IBD) susceptibility loci are enriched for genes expressed in myeloid cells, but it is not clear whether these myeloid risk factors are shared between the two diseases. Leveraging results of genome-wide association studies, we investigated the causal effect of IBD (including ulcerative colitis (UC) and Crohn\u2019s disease (CD)) variants on AD and its endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD variants. Our results revealed distinct sets of genes and pathways of AD and IBD susceptibility loci. Specifically, AD loci are enriched for microglial eQTLs, while IBD loci are enriched for monocyte eQTLs. However, we also found that genetically determined IBD is associated with a protective effect against AD (p&lt;0.03). Yet, a genetic propensity for the CD subtype is associated with increased amyloid accumulation (beta=7.14, p-value=0.02) and susceptibility to AD. Susceptibility to UC was associated with increased deposition of TDP-43 (beta=7.58, p-value=6.11\u00d710\n                  <jats:sup>-4<\/jats:sup>\n                  ). The relation of these gastrointestinal inflammatory disease to AD is therefore complex; while the different subsets of susceptibility variants preferentially affect different myeloid cell subtypes, there do appear to be certain shared pathways and the possible protective effect of IBD susceptibility on the risk of AD which may provide therapeutic insights.\n                <\/jats:p>","DOI":"10.1101\/2023.04.17.23286845","type":"posted-content","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T01:50:36Z","timestamp":1681782636000},"source":"Crossref","is-referenced-by-count":4,"title":["Genetic insights into the association between inflammatory bowel disease and Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Lu","family":"Zeng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles C.","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans-Ulrich","family":"Klein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024102813200697000_2023.04.17.23286845v2.1","doi-asserted-by":"crossref","unstructured":"Weiskopf K , Schnorr PJ , Pang WW , Chao MP , Chhabra A , Seita J , et al. Myeloid Cell Origins, Differentiation, and Clinical Implications. Microbiol Spectr. 2016;4(5).","DOI":"10.1128\/microbiolspec.MCHD-0031-2016"},{"key":"2024102813200697000_2023.04.17.23286845v2.2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3777"},{"key":"2024102813200697000_2023.04.17.23286845v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2018.09.013"},{"issue":"1","key":"2024102813200697000_2023.04.17.23286845v2.4","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1093\/ibd\/izab031","article-title":"Monocytosis Is a Biomarker of Severity in Inflammatory Bowel Disease: Analysis of a 6-Year Prospective Natural History Registry","volume":"28","year":"2022","journal-title":"Inflamm Bowel Dis"},{"key":"2024102813200697000_2023.04.17.23286845v2.5","doi-asserted-by":"publisher","DOI":"10.1097\/MIB.0000000000000824"},{"key":"2024102813200697000_2023.04.17.23286845v2.6","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.coi.2019.11.011","article-title":"Gut macrophages: key players in intestinal immunity and tissue physiology","volume":"62","year":"2020","journal-title":"Curr Opin Immunol"},{"key":"2024102813200697000_2023.04.17.23286845v2.7","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.120.265058"},{"key":"2024102813200697000_2023.04.17.23286845v2.8","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201709069"},{"issue":"11","key":"2024102813200697000_2023.04.17.23286845v2.9","first-page":"377","article-title":"[Epidemiology of Alzheimer\u2019s disease and other dementias]","volume":"66","year":"2018","journal-title":"Rev Neurol"},{"key":"2024102813200697000_2023.04.17.23286845v2.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.1249547"},{"key":"2024102813200697000_2023.04.17.23286845v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01685-y"},{"issue":"4","key":"2024102813200697000_2023.04.17.23286845v2.12","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.3233\/JAD-210103","article-title":"Association Between Inflammatory Bowel Disease and Dementia: A Retrospective Cohort Study","volume":"80","year":"2021","journal-title":"J Alzheimers Dis"},{"key":"2024102813200697000_2023.04.17.23286845v2.13","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-320789"},{"key":"2024102813200697000_2023.04.17.23286845v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00924-w"},{"key":"2024102813200697000_2023.04.17.23286845v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.10.026"},{"key":"2024102813200697000_2023.04.17.23286845v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3760."},{"key":"2024102813200697000_2023.04.17.23286845v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00921-z"},{"key":"2024102813200697000_2023.04.17.23286845v2.18","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-179939"},{"key":"2024102813200697000_2023.04.17.23286845v2.19","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts163"},{"key":"2024102813200697000_2023.04.17.23286845v2.20","doi-asserted-by":"crossref","unstructured":"Fujita M , Gao Z , Zeng L , McCabe C , White CC , Ng B , et al. Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex. Nature Genetics (in press). 2023.","DOI":"10.1101\/2022.11.07.515446"},{"key":"2024102813200697000_2023.04.17.23286845v2.21","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"2024102813200697000_2023.04.17.23286845v2.22","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu197"},{"key":"2024102813200697000_2023.04.17.23286845v2.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02317-230"},{"key":"2024102813200697000_2023.04.17.23286845v2.24","doi-asserted-by":"crossref","unstructured":"Hemani G , Zheng J , Elsworth B , Wade KH , Haberland V , Baird D , et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018;7.","DOI":"10.7554\/eLife.34408"},{"key":"2024102813200697000_2023.04.17.23286845v2.25","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3406"},{"key":"2024102813200697000_2023.04.17.23286845v2.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00973-1"},{"key":"2024102813200697000_2023.04.17.23286845v2.27","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"2024102813200697000_2023.04.17.23286845v2.28","unstructured":"International Multiple Sclerosis Genetics C. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365(6460)."},{"key":"2024102813200697000_2023.04.17.23286845v2.29","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/s41586-020-2263-3","article-title":"Identification of type 2 diabetes loci in 433,540 East Asian individuals","volume":"582","year":"2020","journal-title":"Nature"},{"key":"2024102813200697000_2023.04.17.23286845v2.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00857-4"},{"key":"2024102813200697000_2023.04.17.23286845v2.31","doi-asserted-by":"publisher","DOI":"10.1038\/S41593-018-0326-7"},{"key":"2024102813200697000_2023.04.17.23286845v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-022-04434-5"},{"key":"2024102813200697000_2023.04.17.23286845v2.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21823-y"},{"key":"2024102813200697000_2023.04.17.23286845v2.34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006641"},{"key":"2024102813200697000_2023.04.17.23286845v2.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00976-y"},{"key":"2024102813200697000_2023.04.17.23286845v2.36","doi-asserted-by":"publisher","DOI":"10.1002\/ibd.20747"},{"key":"2024102813200697000_2023.04.17.23286845v2.37","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-021-00919-z"},{"key":"2024102813200697000_2023.04.17.23286845v2.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2007.06.025"},{"key":"2024102813200697000_2023.04.17.23286845v2.39","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-015-1292-z4351699"},{"key":"2024102813200697000_2023.04.17.23286845v2.40","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2020.1854008"},{"key":"2024102813200697000_2023.04.17.23286845v2.41","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3603"},{"issue":"6","key":"2024102813200697000_2023.04.17.23286845v2.42","doi-asserted-by":"crossref","first-page":"e1018","DOI":"10.1002\/cti2.1018","article-title":"Genome-wide association studies of multiple sclerosis","volume":"7","year":"2018","journal-title":"Clin Transl Immunology"},{"key":"2024102813200697000_2023.04.17.23286845v2.43","doi-asserted-by":"crossref","unstructured":"Hemonnot AL , Hua J , Ulmann L , Hirbec H . Microglia in Alzheimer Disease: Well- Known Targets and New Opportunities. Front Aging Neurosci. 2019;11:233.","DOI":"10.3389\/fnagi.2019.00233"},{"key":"2024102813200697000_2023.04.17.23286845v2.44","doi-asserted-by":"publisher","DOI":"10.1126\/science.1219179"},{"key":"2024102813200697000_2023.04.17.23286845v2.45","doi-asserted-by":"crossref","unstructured":"Li H , Wen Z . Effects of ulcerative colitis and Crohn\u2019s disease on neurodegenerative diseases: A Mendelian randomization study. Front Genet. 2022;13:846005.","DOI":"10.3389\/fgene.2022.846005"},{"issue":"1","key":"2024102813200697000_2023.04.17.23286845v2.46","doi-asserted-by":"crossref","first-page":"5641","DOI":"10.1038\/s41467-021-25768-0","article-title":"Investigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases","volume":"12","year":"2021","journal-title":"Nat Commun"},{"key":"2024102813200697000_2023.04.17.23286845v2.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychores.2017.07.015"},{"key":"2024102813200697000_2023.04.17.23286845v2.48","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izy235"},{"key":"2024102813200697000_2023.04.17.23286845v2.49","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e3283168d1d"},{"key":"2024102813200697000_2023.04.17.23286845v2.50","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-008-0164-y"},{"key":"2024102813200697000_2023.04.17.23286845v2.51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002487"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.04.17.23286845","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:31:53Z","timestamp":1768505513000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2023.04.17.23286845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,17]]},"references-count":51,"URL":"https:\/\/doi.org\/10.1101\/2023.04.17.23286845","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41435-025-00344-4","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,4,17]]},"subtype":"preprint"}}