Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer’s disease implicates mediation through GPX3

The recently reported TNIP1 / GPX3 locus from AD GWAS studies was investigated. Using proteomics and other functional omics data, we identified evidence for a functional mechanism linking variants in this locus to decreased CSF GPX3 levels as AD progresses, suggesting a new potential target for intervention. ### Competing Interest Statement Author CC receives research support from Biogen, EISAI, Alector, GSK and Parabon; these funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Author CC is a member of the advisory board of Vivid Genomics, Halia Therapeutics and ADx Healthcare. Author HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Author KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Author GK is a full-time employee of Roche Diagnostics GmbH. Author IS is a full-time employee and shareholder of Roche Diagnostics International Ltd. Author NW is a full-time employee of Roche Diagnostics GmbH. Author SCJ serves as a consultant to Roche Diagnostics and receives research funding from Cerveau Technologies. Author MPS is a cofounder and scientific advisor of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, Protos, RTHM, Iollo, Marble Therapeutics and Mirvie. He is a scientific advisor of Genapsys, Jupiter, Neuvivo, Swaza, and Mitrix. Other authors have no competing interests to declare. ### Funding Statement This research is supported by National Institutes of Health (NIH) grants R01AG27161 (Wisconsin Registry for Alzheimer Prevention: Biomarkers of Preclinical AD), R01AG054047 (Genomic and Metabolomic Data Integration in a Longitudinal Cohort at Risk for Alzheimer's Disease), P41GM108538 (National Center for Quantitative Biology of Complex Systems), R01AG037639 (White Matter Degeneration: Biomarkers in Preclinical Alzheimer's Disease), R01AG021155 (The Longitudinal Course of Imaging Biomarkers in People at Risk of AD), R21AG067092 (Identifying Metabolomic Risk Factors in Plasma and CSF for Alzheimer's Disease), and P50AG033514 and P30AG062715 (Wisconsin Alzheimer's Disease Research Center Grant), the Clinical and Translational Science Award (CTSA) program through the NIH National Center for Advancing Translational Sciences (NCATS) grant UL1TR000427, and the University of Wisconsin-Madison Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation. Computational resources were supported by a core grant to the Center for Demography and Ecology at the University of Wisconsin-Madison (P2CHD047873). We also acknowledge use of the facilities of the Center for Demography of Health and Aging at the University of Wisconsin-Madison, funded by NIA Center grant P30AG017266. Author LMR was funded by the Memorabel fellowship "Identifying biological and clinical relevance of (epi)genetic risk factors in sporadic FTD" (ZonMW project number: 10510022110012). Author YKD was supported by a training grant from the National Institute on Aging (T32AG000213). Author PJV was supported by grants from the European Commission, IMI (AMYPAD: 115952; RADAR-AD: 806999; and EPND: 101034344) and the ZonMW (Redefining Alzheimer's disease, #733050824736, and NCDC, #73305095005). Author HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#101053962), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL (#UKDRI-1003). Author KB is supported by the Swedish Research Council (#2017-00915), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), and the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author JG is supported by Alzheimerfonden (AF-930934) and the Foundation of Gamla Tjänarinnor. Author CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, R01AG064614, 1RF1AG074007), and the Chuck Zuckerberg Initiative (CZI). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the NeuroGenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/) and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Authors LMR, PJV, and BMT are supported by the ZonMW Memorabel grant programma (#733050824), and author PJV is additionally supported by the Innovative Medicines Initiative Joint Undertaking under the EMIF grant agreement (#115372). ELECSYS, COBAS and COBAS E are trademarks of Roche. The Roche NeuroToolKit robust prototype assays are for investigational purposes only and are not approved for clinical use. We thank the University of Wisconsin Madison Biotechnology Center Gene Expression Center for providing Illumina Infinium genotyping services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. ### Author Declarations 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: University of Wisconsin data sets: This study was performed as part of the GeneRations Of WRAP (GROW) study, which was approved by the University of Wisconsin Health Sciences Institutional Review Board. Participants in the ADRC and WRAP studies provided written informed consent. The institutional review boards of all participating institutions approved the procedures for this study. EMIF-AD MBD cohort data sets: Written informed consent was obtained from all participants or surrogates, and the procedures for this study were approved by the institutional review boards of all participating institutions, including the following (see Bos et al 2018 for full listing): Aristotle University of Thessaloniki Medical School Ethics Committee; Ethics Committee of the Medical Faculty Mannheim, University of Heidelberg; Ethic and Clinical Research Committee Donostia; Ethics committee Inserm and Aix Marseille University; The Healthcare Ethics Committee of the Hospital Clínic; Central Clinical Research and Clinical Trials Unit (UICEC Sant Pau); INSERM Ethical Committee; Ethic Committee of the IRCCS San Giovanni di Dio FBF; Comitato Etico IRCCS Pascale - Napoli; Ethics Committee at Karolinska Institutet; Ethische commissie onderzoek UZ/KU Leuven; Research Ethics Committee Lausanne University Hospital; Medical ethical committee Maastricht University Medical Center; Committee on Health Research Ethics, Region of Denmark; Ethics committee of Mediterranean University; University of Lille Ethics committee; Ethical Committee at the Medical Faculty, Leipzig University; Ethical Committee at the Medical Faculty, University Hospital Essen; Ethics committee University of Antwerp; Ethical Committee of University of Genoa; Ethics Committee, University of Gothenburg; Human ethics Committee of the University of Perugia; and the Medical ethics committee VU Medical Center. Washington University in St. Louis cohort data sets: The study was approved by an Institutional Review Board at Washington University School of Medicine in St. Louis. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data sets analyzed from the Wisconsin ADRC and WRAP studies may be requested at https://www.adrc.wisc.edu/apply-resources. Microglia eQTL summary statistics may be requested through the European Genome-Phenome Archive (EGAD00001005736) and the Wellcome Sanger Institute Data Access Committee. The EMIF-AD proteomics data may be requested from the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier 10.6019/PXD019910. The Knight ADRC proteomic data is available at NIAGADS: NG00102 collection and can be interactively explored at http://ngi.pub:3838/ONTIME_Proteomics/.