GWAS meta-analysis of cerebrospinal fluid Alzheimer’s biomarkers reveals loci regulating lipids, brain volume and autophagy
Jigyasha Timsina (Washington University School of Medicine)
Chenyang Jiang (Vrije Universiteit Amsterdam, Amsterdam UMC)
Daniel L. McCartney (The University of Edinburgh)
Feifei Tao (Eisai Inc.)
Maria Carolina Dalmasso (Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), University Hospital Cologne)
Jenna Najar (Vrije Universiteit Amsterdam, University of Gothenburg, Amsterdam UMC)
Federica Anastasi (Barcelona Institute of Science and Technology, Pasqual Maragall Foundation, IMIM Medical Research Institute)
Olena Ohlei (University of Lübeck)
Niccolo’ Tesi (Vrije Universiteit Amsterdam, TU Delft - Electrical Engineering, Mathematics and Computer Science, Amsterdam Neuroscience)
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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.
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