GWAS meta-analysis of cerebrospinal fluid Alzheimer’s biomarkers reveals loci regulating lipids, brain volume and autophagy
Abstract
Abstract Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer’s disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrate that these variants have significant association with Alzheimer’s disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE , coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation.
Article Details
Authors (155)
Jigyasha Timsina
Chenyang Jiang
Daniel L. McCartney
Feifei Tao
Maria Carolina Dalmasso
Jenna Najar
Federica Anastasi
Olena Ohlei
Raquel Puerta Fuentes
Chenyu Yang
National Synchrotron Radiation Laboratory
Joseph Bradley
Daniel Western
Muhammad Ali
Ciyang Wang
Chengran Yang
Ying Wu
Menghan Liu
John Budde
Julie Williams
Rebecca Mahoney
Atahualpa Castillo Morales
Timothy J. Hohman
Logan Dumitrescu
Ting-Chen Wang
Niccolo’ Tesi
Silke Kern
Margda Waern
Ingmar Skoog
Argonde van Harten
Yolande A. L. Pijnenburg
Wiesje M. 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 Düzel
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 Sánchez-Valle
Victoria Álvarez
Pablo García-González
Pablo Mir
Luis M. 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 M. Nöthen
Piotr Lewczuk
Johannes Kornhuber
Harald Hampel
Ina Giegling
Oliver Goldhardt
Janine Diehl-Schmid
Victor Andrade
Michael MT. Heneka
Lutz Frölich
Jonathan Vogelgsang
Caroline Graff
Håkan Thonberg
Abbe Ullgren
Goran Papenberg
Jean-François Deleuze
Carole Dufouil
Michael Wagner
Frank Jessen
Henne Holstege
Cornelia van Duijn
Thibaud Lebouvier
Olivier Hannon
Ville Leinonen
Hilkka Soininen
Sanna-Kaisa Herukka
Vilmantas Giedraitis
Malin Löwenmark
Lena Kilander
Patricia Genius
Blanca Rodríguez
Emma S. Luckett
Arcadi Navarro
Amanda Cano
Marta Marquié
Kaj Blennow
Henrik Zetterberg
Alberto Lleo
Mercè Boada
Agustin Ruiz
Virginia Man-Yee Lee
Vivianna M. Van Deerlin
Yuetiva Deming
Sterling C. Johnson
Corinne D. Engelman
Pau Pastor
Ignacio Alvarez
Elaine R. Peskind
Amanda J. Heslegrave
Andrew J. Saykin
Kwangsik Nho
Suzanne E. Schindler
John C. Morris
David M. Holtzman
Eric McDade
Alan E. Renton
Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
Alison Goate
Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
Laura Ibanez
Matthias Riemenschneider
Marilyn S. Albert
Simon M. Laws
Tenielle Porter
Eleanor K. O’Brien
Leslie M. Shaw
Betty M. Tijms
Martin Ingelsson
Pieter Jelle Visser
Mikko Hiltunen
Kristel Sleegers
Craig W. Ritchie
Rebecca Sims
Michael Belloy
Jean-Charles Lambert
Natalia Vilor-Tejedor
Maria Victoria Fernández
Qingqin S. Li
Michael W. Nagle
Riccardo E. Marioni
Alfredo Ramirez
Lars Bertram
Sven J. van der Lee
Carlos Cruchaga