Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset

Shengjun Hong, Dmitry Prokopenko, Valerija Dobricic, Fabian Kilpert, Isabelle Bos, Stephanie J. B. Vos, Betty M. Tijms, Ulf Andreasson, Kaj Blennow, Rik Vandenberghe, Isabelle Cleynen, Silvy Gabel, Jolien Schaeverbeke, Philip Scheltens, Charlotte E. Teunissen, Ellis Niemantsverdriet, Sebastiaan Engelborghs, Giovanni Frisoni, Olivier Blin, Jill C. RichardsonRegis Bordet, José Luis Molinuevo, Lorena Rami, Petronella Kettunen, Anders Wallin, Alberto Lleó, Isabel Sala, Julius Popp, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J. B. Dobson, Cristina Legido-Quigley, Kristel Sleegers, Christine van Broeckhoven, Mara ten Kate, Frederik Barkhof, Henrik Zetterberg, Simon Lovestone, Johannes Streffer, Michael Wittig, Andre Franke, Rudolph E. Tanzi, Pieter Jelle Visser, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Lars Bertram*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 derived from quantifications of five separate 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.
Original languageEnglish
Article number403
JournalTranslational psychiatry
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2020

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