Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3

Daniel J. Panyard; Lianne M. Reus; Muhammad Ali; Jihua Liu; Yuetiva K. Deming; Qiongshi Lu; Gwendlyn Kollmorgen; Margherita Carboni; Norbert Wild; Pieter J. Visser; Lars Bertram; Henrik Zetterberg; Kaj Blennow; Johan Gobom; Dan Western; Yun Ju Sung; Cynthia M. Carlsson; Sterling C. Johnson; Sanjay Asthana; Carlos Cruchaga; Betty M. Tijms; Corinne D. Engelman; Michael P. Snyder

doi:10.1002/alz.13848

Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3

Daniel J. Panyard^*, Lianne M. Reus, Muhammad Ali, Jihua Liu, Yuetiva K. Deming, Qiongshi Lu, Gwendlyn Kollmorgen, Margherita Carboni, Norbert Wild, Pieter J. Visser, Lars Bertram, Henrik Zetterberg, Kaj Blennow, Johan Gobom, Dan Western, Yun Ju Sung, Cynthia M. Carlsson, Sterling C. Johnson, Sanjay Asthana, Carlos CruchagaBetty M. Tijms, Corinne D. Engelman, Michael P. Snyder^*

^*Korrespondierende/r Autor/-in für diese Arbeit

6 Zitate (Scopus)

Abstract

INTRODUCTION: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269). RESULTS: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10⁻⁵) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10⁻⁷). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10⁻⁶) and CSF p-tau levels (P = 4.38 × 10⁻⁹). DISCUSSION: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. Highlights: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.

Originalsprache	Englisch
Zeitschrift	Alzheimer's and Dementia
Jahrgang	20
Ausgabenummer	7
Seiten (von - bis)	5044-5053
Seitenumfang	10
ISSN	1552-5260
DOIs	https://doi.org/10.1002/alz.13848
Publikationsstatus	Veröffentlicht - 07.2024

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We would like to thank the participants and staff of the WRAP, WI ADRC, EMIF‐AD MBD, and Knight ADRC. Without their efforts this research would not be possible. 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. L.M.R. was funded by the Memorabel fellowship (ZonMW project number: 10510022110012). Y.K.D. was supported by a training grant from the National Institute on Aging (T32AG000213). P.J.V. 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). H.Z. 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 program 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. J.G. is supported by Alzheimerfonden (AF‐930934) and the Foundation of Gamla Tjänarinnor. C.C. receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, RF1AG058501, U01AG058922, R01AG064614, 1RF1AG074007), and the Chan 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. L.M.R., P.J.V., and B.M.T. are supported by the ZonMW Memorabel grant programma (#733050824), and P.J.V. 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. C.C. 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. C.C. is a member of the advisory board of Vivid Genomics, Halia Therapeutics, and ADx Healthcare. H.Z. 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. K.B. 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. G.K. is a full‐time employee of Roche Diagnostics GmbH. M.C. is a full‐time employee and shareholder of Roche Diagnostics International Ltd. N.W. is a full‐time employee of Roche Diagnostics GmbH. S.C.J. serves as a consultant to Roche Diagnostics and receives research funding from Cerveau Technologies. M.P.S. is a cofounder and scientific advisor of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, Protos, RTHM, Iollo, Marble Therapeutics, Crosshair Therapeutics, NextThought, and Mirvie. He is a scientific advisor of Jupiter, Neuvivo, Swaza, Mitrix, Yuvan, TranscribeGlass, and Applied Cognition. Other authors have no competing interests to declare. Author disclosures are available in the supporting information .

Träger	Trägernummer
Alzheimer's Association
Departments of Neurology and Psychiatry at Washington University School of Medicine
Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden
Familjen Erling-Perssons Stiftelse
Hope Center for Neurological Disorders, Washington University in St. Louis
Wisconsin Alumni Research Foundation
Cerveau Technologies
European Commission
Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin-Madison
Cosmetic Surgery Foundation
Olav Thon Stiftelsen
Swedish government
AD Strategic Fund
NCDC	73305095005
National Institute on Aging	T32AG000213
Vetenskapsrådet	2018‐02532
Memorabel program of ZonMw	733050824
EMIF	115372
Horizon 2020	860197
ZonMw	10510022110012
Foundation of Gamla Tjänarinnor	U01AG058922, RF1AG058501, 1RF1AG074007, R01AG064877, R01AG044546, R01AG064614, P01AG003991, P30AG066444, RF1AG053303
UK Dementia Research Institute	2017‐00915
NIA Center	P30AG017266
University of Wisconsin-Madison	P2CHD047873
National Institutes of Health	R01AG27161, R01AG037639, R21AG067092, R01AG021155, P41GM108538, R01AG054047
Alzheimerfonden	‐968270, ‐930351, ‐939721, #ALZ2022‐0006
Redefining Alzheimer's disease	P30AG062715, P50AG033514
National Center for Advancing Translational Sciences (NCATS)	UL1TR000427
Alzheimer's Drug Discovery Foundation	201809‐2016862
European Research Council	101053962
Innovative Medicines Initiative	101034344, 806999, 733050824736, 115952
County Councils	965240, AF‐930934, 715986, ZEN‐21‐848495
Swedish State Support for Clinical Research	720931

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Querschnittsbereich: Medizinische Genetik

DFG-Fachsystematik

2.23-06 Molekulare und zelluläre Neurologie und Neuropathologie

Dokumente

10.1002/alz.13848

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Panyard, D. J., Reus, L. M., Ali, M., Liu, J., Deming, Y. K., Lu, Q., Kollmorgen, G., Carboni, M., Wild, N., Visser, P. J., Bertram, L., Zetterberg, H., Blennow, K., Gobom, J., Western, D., Sung, Y. J., Carlsson, C. M., Johnson, S. C., Asthana, S., ... Snyder, M. P. (2024). Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3. Alzheimer's and Dementia, 20(7), 5044-5053. https://doi.org/10.1002/alz.13848

@article{02d618f4bbee4f9e90fa1838ce4c548f,

title = "Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3",

abstract = "INTRODUCTION: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269). RESULTS: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10−5) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10−7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10−6) and CSF p-tau levels (P = 4.38 × 10−9). DISCUSSION: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. Highlights: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.",

author = "Panyard, \{Daniel J.\} and Reus, \{Lianne M.\} and Muhammad Ali and Jihua Liu and Deming, \{Yuetiva K.\} and Qiongshi Lu and Gwendlyn Kollmorgen and Margherita Carboni and Norbert Wild and Visser, \{Pieter J.\} and Lars Bertram and Henrik Zetterberg and Kaj Blennow and Johan Gobom and Dan Western and Sung, \{Yun Ju\} and Carlsson, \{Cynthia M.\} and Johnson, \{Sterling C.\} and Sanjay Asthana and Carlos Cruchaga and Tijms, \{Betty M.\} and Engelman, \{Corinne D.\} and Snyder, \{Michael P.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = jul,

doi = "10.1002/alz.13848",

language = "English",

volume = "20",

pages = "5044--5053",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc",

number = "7",

}

Panyard, DJ, Reus, LM, Ali, M, Liu, J, Deming, YK, Lu, Q, Kollmorgen, G, Carboni, M, Wild, N, Visser, PJ, Bertram, L, Zetterberg, H, Blennow, K, Gobom, J, Western, D, Sung, YJ, Carlsson, CM, Johnson, SC, Asthana, S, Cruchaga, C, Tijms, BM, Engelman, CD & Snyder, MP 2024, 'Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3', Alzheimer's and Dementia, Jg. 20, Nr. 7, S. 5044-5053. https://doi.org/10.1002/alz.13848

TY - JOUR

T1 - Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3

AU - Panyard, Daniel J.

AU - Reus, Lianne M.

AU - Ali, Muhammad

AU - Liu, Jihua

AU - Deming, Yuetiva K.

AU - Lu, Qiongshi

AU - Kollmorgen, Gwendlyn

AU - Carboni, Margherita

AU - Wild, Norbert

AU - Visser, Pieter J.

AU - Bertram, Lars

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - Gobom, Johan

AU - Western, Dan

AU - Sung, Yun Ju

AU - Carlsson, Cynthia M.

AU - Johnson, Sterling C.

AU - Asthana, Sanjay

AU - Cruchaga, Carlos

AU - Tijms, Betty M.

AU - Engelman, Corinne D.

AU - Snyder, Michael P.

PY - 2024/7

Y1 - 2024/7

N2 - INTRODUCTION: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269). RESULTS: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10−5) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10−7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10−6) and CSF p-tau levels (P = 4.38 × 10−9). DISCUSSION: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. Highlights: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.

AB - INTRODUCTION: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269). RESULTS: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10−5) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10−7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10−6) and CSF p-tau levels (P = 4.38 × 10−9). DISCUSSION: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. Highlights: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.

UR - https://www.scopus.com/pages/publications/85194530454

U2 - 10.1002/alz.13848

DO - 10.1002/alz.13848

M3 - Journal articles

AN - SCOPUS:85194530454

SN - 1552-5260

VL - 20

SP - 5044

EP - 5053

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 7

ER -

Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3

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