GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy

Carlos Cruchaga; Jigyasha Timsina; Chenyang Jiang; Daniel McCartney; Feifei Tao; Maria Carolina Dalmasso; Jenna Najar; Federica Anastasi; Olena Ohlei; Raquel Puerta; Joseph Bradley; Daniel Western; Muhammad Ali; Ciyang Wang; Chengran Yang; Ying Wu; Menghan Liu; John Budde; Julie Williams; Rebecca Mahoney; Atahualpa Castillo; Timothy Hohman; Logan Dumitrescu; Ting-Chen Wang; Niccoló Tesi; Silke Kern; Margda Waern; Ingmer Skoog; Argonde van Harten; Wiesje van der Flier; Pascual Sánchez-Juan; Eloy Rodriguez-Rodriguez; Luca Kleineidam; Oliver Peters; Anja Schneider; Fahri Küçükali; Céline Bellenguez; Benjamin Grenier-Boley; Sami Heikkinen; Itziar de Rojas; Dan Rujescu; Norbert Scherbaum; Lucrezia Hausner; Emrah Duzel; Timo Grimmer; Jens Wiltfang; Rik Vandenberghe; Sebastiaan Engelborghs; Stefanie Heilmann-Heimbach; Matthias Schmid; Thomas Tegos; Nikolaos Scarmeas; Oriol Dols-Icardo; Fermin Moreno; Jordi Pérez-Tur; María J Bullido; Raquel Sanchez-Valle; Victoria Álvarez; Pablo Garcia-Gonzalez; Pablo Mir; Luis Real; Gerard Piñol-Ripoll; Jose María García-Alberca; Harro Seelaar; Inez Ramakers; Janne Papma; Marc Hulsman; Christoph Laske; Stefan Teipel; Josef Priller; Robert Perneczky; Katharina Buerger; Markus Nöthen; Piotr Lewczuk; Johannes Kornhuber; Wolfgang Maier; Harald Hampel; Ina Giegling; Oliver Goldhardt; Janine Diehl-Schmid; Victor Andrade; Michael Heneka; Lutz Froelich; Jonathan Vogelgsang; Caroline Graff; Håkan Thonberg; Abbe Ullgren; Goran Papenberg; Anne Boland; Jean-François Deleuze; Michael Wagner; Frank Jessen; Henne Holstege; Cornelia van Duijn; Thibaud Lebouvier; Olivier Hanon; Ville Leinonen; Hilkka Soininen; Sanna-Kaisa Herukka; Vilmantas Giedraitis; Malin Löwenmark; Lena Kilander; Patricia Genius; Blanca Rodríguez; Emma Luckett; Arcadi Navarro; Amanda Cano; Marta Marquié; Kaj Blennow; Henrik Zetterberg; Alberto Lleo; Mercè Boada; Agustin Ruiz Laza; Virginia Lee; Vivianna Van Deerlin; Yuetiva Deming; Sterling Johnson; Corinne Engelman; Pau Pastor; Ignacio Alvarez; Elaine Peskind; Amanda Heslegrave; Andrew Saykin; Kwangsik Nho; Suzanne Schindler; John Morris; David Holtzman; Eric McDade; Alan Renton; Alison Goate; Laura Ibanez; Matthias Riemenschneider; Marilyn Albert; Simon Laws; Tenielle Porter; Eleanor O'Brien; Leslie Shaw; Betty Tijms; Martin Ingelsson; Pieter Jelle Visser; Mikko Hiltunen; Kristel Sleegers; Craig Ritchie; Rebecca Sims; Jean-Charles Lambert; Natàlia Vilor-Tejedor; Maria Fernández; Qingqin Li; Michael Nagle; Riccardo Marioni; Alfredo Ramirez; Lars Bertram; Sven van der Lee

doi:10.21203/rs.3.rs-6597595/v1

GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy

Carlos Cruchaga
, Jigyasha Timsina
, Chenyang Jiang
, Daniel McCartney
, Feifei Tao
, Maria Carolina Dalmasso
, Jenna Najar
, Federica Anastasi
, Olena Ohlei
, Raquel Puerta
, Joseph Bradley
, Daniel Western
, Muhammad Ali
, Ciyang Wang
, Chengran Yang
, Ying Wu
, Menghan Liu
, John Budde
, Julie Williams
, Rebecca Mahoney

Atahualpa Castillo, Timothy Hohman, Logan Dumitrescu, Ting-Chen Wang, Niccoló Tesi, Silke Kern, Margda Waern, Ingmer Skoog, Argonde van Harten, Wiesje van der Flier, Pascual Sánchez-Juan, Eloy Rodriguez-Rodriguez, Luca Kleineidam, Oliver Peters, Anja Schneider, Fahri Küçükali, Céline Bellenguez, Benjamin Grenier-Boley, Sami Heikkinen, Itziar de Rojas, Dan Rujescu, Norbert Scherbaum, Lucrezia Hausner, Emrah Duzel, Timo Grimmer, Jens Wiltfang, Rik Vandenberghe, Sebastiaan Engelborghs, Stefanie Heilmann-Heimbach, Matthias Schmid, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols-Icardo, Fermin Moreno, Jordi Pérez-Tur, María J Bullido, Raquel Sanchez-Valle, Victoria Álvarez, Pablo Garcia-Gonzalez, Pablo Mir, Luis Real, Gerard Piñol-Ripoll, Jose María García-Alberca, Harro Seelaar, Inez Ramakers, Janne Papma, Marc Hulsman, Christoph Laske, Stefan Teipel, Josef Priller, Robert Perneczky, Katharina Buerger, Markus Nöthen, Piotr Lewczuk, Johannes Kornhuber, Wolfgang Maier, Harald Hampel, Ina Giegling, Oliver Goldhardt, Janine Diehl-Schmid, Victor Andrade, Michael Heneka, Lutz Froelich, Jonathan Vogelgsang, Caroline Graff, Håkan Thonberg, Abbe Ullgren, Goran Papenberg, Anne Boland, Jean-François Deleuze, Michael Wagner, Frank Jessen, Henne Holstege, Cornelia van Duijn, Thibaud Lebouvier, Olivier Hanon, Ville Leinonen, Hilkka Soininen, Sanna-Kaisa Herukka, Vilmantas Giedraitis, Malin Löwenmark, Lena Kilander, Patricia Genius, Blanca Rodríguez, Emma Luckett, Arcadi Navarro, Amanda Cano, Marta Marquié, Kaj Blennow, Henrik Zetterberg, Alberto Lleo, Mercè Boada, Agustin Ruiz Laza, Virginia Lee, Vivianna Van Deerlin, Yuetiva Deming, Sterling Johnson, Corinne Engelman, Pau Pastor, Ignacio Alvarez, Elaine Peskind, Amanda Heslegrave, Andrew Saykin, Kwangsik Nho, Suzanne Schindler, John Morris, David Holtzman, Eric McDade, Alan Renton, Alison Goate, Laura Ibanez, Matthias Riemenschneider, Marilyn Albert, Simon Laws, Tenielle Porter, Eleanor O'Brien, Leslie Shaw, Betty Tijms, Martin Ingelsson, Pieter Jelle Visser, Mikko Hiltunen, Kristel Sleegers, Craig Ritchie, Rebecca Sims, Jean-Charles Lambert, Natàlia Vilor-Tejedor, Maria Fernández, Qingqin Li, Michael Nagle, Riccardo Marioni, Alfredo Ramirez, Lars Bertram, Sven van der Lee

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Abstract

Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation.

Original language	English
Journal	Research square
DOIs	https://doi.org/10.21203/rs.3.rs-6597595/v1
Publication status	Published - 21 May 2025

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10.21203/rs.3.rs-6597595/v1

Gwas-meta-analysis-of-csf-alzheimers-disease-biomarkers-18948-individuals-reveal-novel-loci-and-genes-regulating-lipid.pdfFinal published version, 3.45 MBLicence: Taverne

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Cruchaga, C., Timsina, J., Jiang, C., McCartney, D., Tao, F., Dalmasso, M. C., Najar, J., Anastasi, F., Ohlei, O., Puerta, R., Bradley, J., Western, D., Ali, M., Wang, C., Yang, C., Wu, Y., Liu, M., Budde, J., Williams, J., ... van der Lee, S. (2025). GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy. Research square. https://doi.org/10.21203/rs.3.rs-6597595/v1

@article{8692e0d62ce647afb0dd1d3ec26ebb33,

title = "GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy",

abstract = "Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation. ",

author = "Carlos Cruchaga and Jigyasha Timsina and Chenyang Jiang and Daniel McCartney and Feifei Tao and Dalmasso, \{Maria Carolina\} and Jenna Najar and Federica Anastasi and Olena Ohlei and Raquel Puerta and Joseph Bradley and Daniel Western and Muhammad Ali and Ciyang Wang and Chengran Yang and Ying Wu and Menghan Liu and John Budde and Julie Williams and Rebecca Mahoney and Atahualpa Castillo and Timothy Hohman and Logan Dumitrescu and Ting-Chen Wang and Niccol{\'o} Tesi and Silke Kern and Margda Waern and Ingmer Skoog and \{van Harten\}, Argonde and \{van der Flier\}, Wiesje and Pascual S{\'a}nchez-Juan and Eloy Rodriguez-Rodriguez and Luca Kleineidam and Oliver Peters and Anja Schneider and Fahri K{\"u}{\c c}{\"u}kali and C{\'e}line Bellenguez and Benjamin Grenier-Boley and Sami Heikkinen and \{de Rojas\}, Itziar and Dan Rujescu and Norbert Scherbaum and Lucrezia Hausner and Emrah Duzel and Timo Grimmer and Jens Wiltfang and Rik Vandenberghe and Sebastiaan Engelborghs and Stefanie Heilmann-Heimbach and Matthias Schmid and Thomas Tegos and Nikolaos Scarmeas and Oriol Dols-Icardo and Fermin Moreno and Jordi P{\'e}rez-Tur and Bullido, \{Mar{\'i}a J\} and Raquel Sanchez-Valle and Victoria {\'A}lvarez and Pablo Garcia-Gonzalez and Pablo Mir and Luis Real and Gerard Pi{\~n}ol-Ripoll and Garc{\'i}a-Alberca, \{Jose Mar{\'i}a\} and Harro Seelaar and Inez Ramakers and Janne Papma and Marc Hulsman and Christoph Laske and Stefan Teipel and Josef Priller and Robert Perneczky and Katharina Buerger and Markus N{\"o}then and Piotr Lewczuk and Johannes Kornhuber and Wolfgang Maier and Harald Hampel and Ina Giegling and Oliver Goldhardt and Janine Diehl-Schmid and Victor Andrade and Michael Heneka and Lutz Froelich and Jonathan Vogelgsang and Caroline Graff and H{\aa}kan Thonberg and Abbe Ullgren and Goran Papenberg and Anne Boland and Jean-Fran{\c c}ois Deleuze and Michael Wagner and Frank Jessen and Henne Holstege and \{van Duijn\}, Cornelia and Thibaud Lebouvier and Olivier Hanon and Ville Leinonen and Hilkka Soininen and Sanna-Kaisa Herukka and Vilmantas Giedraitis and Malin L{\"o}wenmark and Lena Kilander and Patricia Genius and Blanca Rodr{\'i}guez and Emma Luckett and Arcadi Navarro and Amanda Cano and Marta Marqui{\'e} and Kaj Blennow and Henrik Zetterberg and Alberto Lleo and Merc{\`e} Boada and Laza, \{Agustin Ruiz\} and Virginia Lee and Deerlin, \{Vivianna Van\} and Yuetiva Deming and Sterling Johnson and Corinne Engelman and Pau Pastor and Ignacio Alvarez and Elaine Peskind and Amanda Heslegrave and Andrew Saykin and Kwangsik Nho and Suzanne Schindler and John Morris and David Holtzman and Eric McDade and Alan Renton and Alison Goate and Laura Ibanez and Matthias Riemenschneider and Marilyn Albert and Simon Laws and Tenielle Porter and Eleanor O'Brien and Leslie Shaw and Betty Tijms and Martin Ingelsson and Visser, \{Pieter Jelle\} and Mikko Hiltunen and Kristel Sleegers and Craig Ritchie and Rebecca Sims and Jean-Charles Lambert and Nat{\`a}lia Vilor-Tejedor and Maria Fern{\'a}ndez and Qingqin Li and Michael Nagle and Riccardo Marioni and Alfredo Ramirez and Lars Bertram and \{van der Lee\}, Sven",

year = "2025",

month = may,

day = "21",

doi = "10.21203/rs.3.rs-6597595/v1",

language = "English",

journal = "Research square",

issn = "2693-5015",

}

Cruchaga, C, Timsina, J, Jiang, C, McCartney, D, Tao, F, Dalmasso, MC, Najar, J , Anastasi, F, Ohlei, O, Puerta, R, Bradley, J, Western, D, Ali, M, Wang, C, Yang, C, Wu, Y, Liu, M, Budde, J, Williams, J, Mahoney, R, Castillo, A, Hohman, T, Dumitrescu, L, Wang, T-C, Tesi, N, Kern, S, Waern, M, Skoog, I, van Harten, A , van der Flier, W, Sánchez-Juan, P, Rodriguez-Rodriguez, E, Kleineidam, L, Peters, O, Schneider, A, Küçükali, F, Bellenguez, C, Grenier-Boley, B, Heikkinen, S, de Rojas, I, Rujescu, D, Scherbaum, N, Hausner, L, Duzel, E, Grimmer, T, Wiltfang, J, Vandenberghe, R, Engelborghs, S, Heilmann-Heimbach, S, Schmid, M, Tegos, T, Scarmeas, N, Dols-Icardo, O, Moreno, F, Pérez-Tur, J, Bullido, MJ, Sanchez-Valle, R, Álvarez, V, Garcia-Gonzalez, P, Mir, P, Real, L, Piñol-Ripoll, G, García-Alberca, JM, Seelaar, H, Ramakers, I, Papma, J, Hulsman, M, Laske, C, Teipel, S, Priller, J, Perneczky, R, Buerger, K, Nöthen, M, Lewczuk, P, Kornhuber, J, Maier, W, Hampel, H, Giegling, I, Goldhardt, O, Diehl-Schmid, J, Andrade, V, Heneka, M, Froelich, L, Vogelgsang, J, Graff, C, Thonberg, H, Ullgren, A, Papenberg, G, Boland, A, Deleuze, J-F, Wagner, M, Jessen, F, Holstege, H, van Duijn, C, Lebouvier, T, Hanon, O, Leinonen, V, Soininen, H, Herukka, S-K, Giedraitis, V, Löwenmark, M, Kilander, L, Genius, P, Rodríguez, B, Luckett, E, Navarro, A, Cano, A, Marquié, M, Blennow, K, Zetterberg, H, Lleo, A, Boada, M, Laza, AR, Lee, V, Deerlin, VV, Deming, Y, Johnson, S, Engelman, C, Pastor, P, Alvarez, I, Peskind, E, Heslegrave, A, Saykin, A, Nho, K, Schindler, S, Morris, J, Holtzman, D, McDade, E, Renton, A, Goate, A, Ibanez, L, Riemenschneider, M, Albert, M, Laws, S, Porter, T, O'Brien, E, Shaw, L, Tijms, B, Ingelsson, M, Visser, PJ, Hiltunen, M, Sleegers, K, Ritchie, C, Sims, R, Lambert, J-C, Vilor-Tejedor, N, Fernández, M, Li, Q, Nagle, M, Marioni, R, Ramirez, A, Bertram, L & van der Lee, S 2025, 'GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy', Research square. https://doi.org/10.21203/rs.3.rs-6597595/v1

TY - JOUR

T1 - GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy

AU - Cruchaga, Carlos

AU - Timsina, Jigyasha

AU - Jiang, Chenyang

AU - McCartney, Daniel

AU - Tao, Feifei

AU - Dalmasso, Maria Carolina

AU - Najar, Jenna

AU - Anastasi, Federica

AU - Ohlei, Olena

AU - Puerta, Raquel

AU - Bradley, Joseph

AU - Western, Daniel

AU - Ali, Muhammad

AU - Wang, Ciyang

AU - Yang, Chengran

AU - Wu, Ying

AU - Liu, Menghan

AU - Budde, John

AU - Williams, Julie

AU - Mahoney, Rebecca

AU - Castillo, Atahualpa

AU - Hohman, Timothy

AU - Dumitrescu, Logan

AU - Wang, Ting-Chen

AU - Tesi, Niccoló

AU - Kern, Silke

AU - Waern, Margda

AU - Skoog, Ingmer

AU - van Harten, Argonde

AU - van der Flier, Wiesje

AU - Sánchez-Juan, Pascual

AU - Rodriguez-Rodriguez, Eloy

AU - Kleineidam, Luca

AU - Peters, Oliver

AU - Schneider, Anja

AU - Küçükali, Fahri

AU - Bellenguez, Céline

AU - Grenier-Boley, Benjamin

AU - Heikkinen, Sami

AU - de Rojas, Itziar

AU - Rujescu, Dan

AU - Scherbaum, Norbert

AU - Hausner, Lucrezia

AU - Duzel, Emrah

AU - Grimmer, Timo

AU - Wiltfang, Jens

AU - Vandenberghe, Rik

AU - Engelborghs, Sebastiaan

AU - Heilmann-Heimbach, Stefanie

AU - Schmid, Matthias

AU - Tegos, Thomas

AU - Scarmeas, Nikolaos

AU - Dols-Icardo, Oriol

AU - Moreno, Fermin

AU - Pérez-Tur, Jordi

AU - Bullido, María J

AU - Sanchez-Valle, Raquel

AU - Álvarez, Victoria

AU - Garcia-Gonzalez, Pablo

AU - Mir, Pablo

AU - Real, Luis

AU - Piñol-Ripoll, Gerard

AU - García-Alberca, Jose María

AU - Seelaar, Harro

AU - Ramakers, Inez

AU - Papma, Janne

AU - Hulsman, Marc

AU - Laske, Christoph

AU - Teipel, Stefan

AU - Priller, Josef

AU - Perneczky, Robert

AU - Buerger, Katharina

AU - Nöthen, Markus

AU - Lewczuk, Piotr

AU - Kornhuber, Johannes

AU - Maier, Wolfgang

AU - Hampel, Harald

AU - Giegling, Ina

AU - Goldhardt, Oliver

AU - Diehl-Schmid, Janine

AU - Andrade, Victor

AU - Heneka, Michael

AU - Froelich, Lutz

AU - Vogelgsang, Jonathan

AU - Graff, Caroline

AU - Thonberg, Håkan

AU - Ullgren, Abbe

AU - Papenberg, Goran

AU - Boland, Anne

AU - Deleuze, Jean-François

AU - Wagner, Michael

AU - Jessen, Frank

AU - Holstege, Henne

AU - van Duijn, Cornelia

AU - Lebouvier, Thibaud

AU - Hanon, Olivier

AU - Leinonen, Ville

AU - Soininen, Hilkka

AU - Herukka, Sanna-Kaisa

AU - Giedraitis, Vilmantas

AU - Löwenmark, Malin

AU - Kilander, Lena

AU - Genius, Patricia

AU - Rodríguez, Blanca

AU - Luckett, Emma

AU - Navarro, Arcadi

AU - Cano, Amanda

AU - Marquié, Marta

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Lleo, Alberto

AU - Boada, Mercè

AU - Laza, Agustin Ruiz

AU - Lee, Virginia

AU - Deerlin, Vivianna Van

AU - Deming, Yuetiva

AU - Johnson, Sterling

AU - Engelman, Corinne

AU - Pastor, Pau

AU - Alvarez, Ignacio

AU - Peskind, Elaine

AU - Heslegrave, Amanda

AU - Saykin, Andrew

AU - Nho, Kwangsik

AU - Schindler, Suzanne

AU - Morris, John

AU - Holtzman, David

AU - McDade, Eric

AU - Renton, Alan

AU - Goate, Alison

AU - Ibanez, Laura

AU - Riemenschneider, Matthias

AU - Albert, Marilyn

AU - Laws, Simon

AU - Porter, Tenielle

AU - O'Brien, Eleanor

AU - Shaw, Leslie

AU - Tijms, Betty

AU - Ingelsson, Martin

AU - Visser, Pieter Jelle

AU - Hiltunen, Mikko

AU - Sleegers, Kristel

AU - Ritchie, Craig

AU - Sims, Rebecca

AU - Lambert, Jean-Charles

AU - Vilor-Tejedor, Natàlia

AU - Fernández, Maria

AU - Li, Qingqin

AU - Nagle, Michael

AU - Marioni, Riccardo

AU - Ramirez, Alfredo

AU - Bertram, Lars

AU - van der Lee, Sven

PY - 2025/5/21

Y1 - 2025/5/21

N2 - Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation.

AB - Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation.

U2 - 10.21203/rs.3.rs-6597595/v1

DO - 10.21203/rs.3.rs-6597595/v1

M3 - Article

C2 - 40470240

SN - 2693-5015

JO - Research square

JF - Research square

ER -

GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy

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