TY - JOUR
T1 - Identification of circulating proteins associated with general cognitive function among middle-aged and older adults final
AU - Tin, Adrienne
AU - Fohner, Alison E.
AU - Yang, Qiong
AU - Brody, Jennifer A.
AU - Davies, Gail
AU - Yao, Jie
AU - Liu, Dan
AU - Caro, Ilana
AU - Lindbohm, Joni V.
AU - Duggan, Michael R.
AU - Meirelles, Osorio
AU - Harris, Sarah E.
AU - Gudmundsdottir, Valborg
AU - Taylor, Adele M.
AU - Henry, Albert
AU - Beiser, Alexa S.
AU - Shojaie, Ali
AU - Coors, Annabell
AU - Fitzpatrick, Annette L.
AU - Langenberg, Claudia
AU - Satizabal, Claudia L.
AU - Sitlani, Colleen M.
AU - Wheeler, Eleanor
AU - Tucker-Drob, Elliot M.
AU - Bressler, Jan
AU - Coresh, Josef
AU - Bis, Joshua C.
AU - Candia, Julián
AU - Jennings, Lori L.
AU - Pietzner, Maik
AU - Lathrop, Mark
AU - Lopez, Oscar L.
AU - Redmond, Paul
AU - Gerszten, Robert E.
AU - Rich, Stephen S.
AU - Heckbert, Susan R.
AU - Austin, Thomas R.
AU - Hughes, Timothy M.
AU - Tanaka, Toshiko
AU - Emilsson, Valur
AU - Vasan, Ramachandran S.
AU - Guo, Xiuqing
AU - Zhu, Yineng
AU - Tzourio, Christophe
AU - Rotter, Jerome I.
AU - Walker, Keenan A.
AU - Ferrucci, Luigi
AU - Kivimäki, Mika
AU - Breteler, Monique M. B.
AU - Cox, Simon R.
AU - Debette, Stephanie
AU - Mosley, Thomas H.
AU - Gudnason, Vilmundur G.
AU - Launer, Lenore J.
AU - Psaty, Bruce M.
AU - Seshadri, Sudha
AU - Fornage, Myriam
N1 - Funding: The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Funding was also supported by 5RC2HL102419, R01NS087541 and R01HL131136. Neurocognitive data were collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD). Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Cardiovascular Heath Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL085251, R01HL144483, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, and R01AG20098 from the National Institute on Aging (NIA). AEF is supported by K01AG071689. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195, HHSN268201500001I and 75N92019D00031). This work was also supported by grant R01AG063507, R01AG054076, R01AG049607, R01AG059421, R01AG033040, R01AG066524, P30AG066546, U01 AG052409, U01 AG058589 from from the National Institute on Aging and R01 AG017950, UH2/3 NS100605, UF1 NS125513 from National Institute of Neurological Disorders and Stroke and R01HL132320. AGES has been funded by NIA contracts N01-AG012100 and HSSN271201200022C, NIH Grant No. 1R01AG065596-01A1, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). M. R. Duggan, T. Tanaka, J. Candia, K. A. Walker, L. Ferrucci, L.J. Launer, O. Meirelles are funded by the National Institute on Aging Intramural Research Program. This study was funded, in part, by the National Institute on Aging Intramural Research Program. We thank the BLSA participants and staff for their participation and continued dedication. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201800003I, HHSN268201800004I, HHSN268201800005I, HHSN268201800006I, and HHSN268201800007I from the National Heart, Lung, and Blood Institute (NHLBI). The LBC1921 was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society, and The Chief Scientist Office of the Scottish Government. Genotyping was funded by the BBSRC (BB/F019394/1). LBC1936 is supported by the Biotechnology and Biological Sciences Research Council, and the Economic and Social Research Council [BB/W008793/1], Age UK (Disconnected Mind project), and the University of Edinburgh. Genotyping was funded by the BBSRC (BB/F019394/1). The Olink® Neurology Proteomics assay was supported by a National Institutes of Health (NIH) research grant R01AG054628. Phenotype harmonization, data management, sample-identity QC, and general study coordination of the MESA were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1), and TOPMed MESA Multi-Omics (HHSN2682015000031/HSN26800004). The MESA projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for the Multi-Ethnic Study of Atherosclerosis (MESA) projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, and R01HL105756. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. The Rhineland Study is funded by the German Center for Neurodegenerative Disease (DZNE). This work was further partly supported by the German Research Foundation (DFG) under Germany’s Excellence Strategy (EXC2151-390873048) and SFB1454 - project number 432325352; the Federal Ministry of Education and Research under the Diet-Body-Brain Competence Cluster in Nutrition Research (grant numbers 01EA1410C and 01EA1809C) and in the framework “PreBeDem - Mit Prävention und Behandlung gegen Demenz” (grant numbers 01KX2230); and the Helmholtz Association under the Initiative and Networking Fund (grant number RA-285/19) and the 2023 Innovation Pool. The 3 C Study is supported by a grant overseen by the French National Research Agency (ANR) as part of the “Investment for the Future Programme” ANR-18-RHUS-0002. It has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667375. The project also received funding from the French National Research Agency (ANR) through the VASCOGENE and SHIVA projects and from the Leducq TNE 2012 on small vessel disease (PI A Joutel, M Nelson). Computations were performed on the Bordeaux Bioinformatics Center (CBiB) computer resources, University of Bordeaux. Funding support for additional computer resources has been provided to S.D. by the Fondation Claude Pompidou. The Three City Study: The Three City (3 C) Study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Bordeaux, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3 C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Programme “Cohortes et collections de données biologiques.” Ilana Caro received a grant from the EUR digital public health. This PhD program is supported within the framework of the PIA3 (Investment for the future). Project reference 17-EURE-0019.
PY - 2023/11
Y1 - 2023/11
N2 - Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer’s disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.
AB - Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer’s disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.
UR - https://doi.org/10.6084/m9.figshare.24069354
UR - https://www.decode.com/summarydata/
UR - https://gwas.mrcieu.ac.uk/
UR - https://www.ebi.ac.uk/gwas/
UR - https://ctg.cncr.nl/software/summary_statistics
UR - https://gtexportal.org/home/datasets
U2 - 10.1038/s42003-023-05454-1
DO - 10.1038/s42003-023-05454-1
M3 - Article
SN - 2399-3642
VL - 6
JO - Communications Biology
JF - Communications Biology
M1 - 1117
ER -