TY - JOUR T1 - Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset JF - bioRxiv DO - 10.1101/774554 SP - 774554 AU - Shengjun Hong AU - Dmitry Prokopenko AU - Valerija Dobricic AU - Fabian Kilpert AU - Isabelle Bos AU - Stephanie J. B. Vos AU - Betty M. Tijms AU - Ulf Andreasson AU - Kaj Blennow AU - Rik Vandenberghe AU - Isabelle Cleynen AU - Silvy Gabel AU - Jolien Schaeverbeke AU - Philip Scheltens AU - Charlotte E. Teunissen AU - Ellis Niemantsverdriet AU - Sebastiaan Engelborghs AU - Giovanni Frisoni AU - Olivier Blin AU - Jill C. Richardson AU - Regis Bordet AU - José Luis Molinuevo AU - Lorena Rami AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI) AU - Petronella Kettunen AU - Anders Wallin AU - Alberto Lleó AU - Isabel Sala AU - Julius Popp AU - Gwendoline Peyratout AU - Pablo Martinez-Lage AU - Mikel Tainta AU - Richard J. B. Dobson AU - Cristina Legido-Quigley AU - Kristel Sleegers AU - Christine Van Broeckhoven AU - Mara ten Kate AU - Frederik Barkhof AU - Henrik Zetterberg AU - Simon Lovestone AU - Johannes Streffer AU - Michael Wittig AU - Andre Franke AU - Rudolph E Tanzi AU - Pieter Jelle Visser AU - Lars Bertram Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/09/23/774554.abstract N2 - Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures of amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset. ER -