TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

Hong, S.; Dobricic, V.; Bos, I.; Vos, S. J. B.; Prokopenko, D.; Tijms, B. M.; Andreasson, U.; Blennow, K.; Vandenberghe, R.; Gabel, S.; Scheltens, P.; Teunissen, C. E.; Engelborghs, S.; Frisoni, G.; Blin, O.; Richardson, J. C.; Bordet, R.; Lleo, A.; Alcolea, D.; Popp, J.; Clark, C.; Peyratout, G.; Martinez-Lage, P.; Tainta, M.; Dobson, R. J. B.; Legido-Quigley, C.; Sleegers, K.; Broeckhoven, C. V.; Tanzi, R. E.; Kate, M. t.; Wittig, M.; Franke, A.; Barkhof, F.; Lovestone, S.; Streffer, J.; Zetterberg, H.; Visser, P. J.; Bertram, L.

doi:10.1101/2020.05.31.125633

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bioRxiv · 10.1101/2020.05.31.125633

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

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Abstract

BackgroundNeurofilament light (NF-L), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are utilized as biomarkers for Alzheimers disease (AD), to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Here we performed genome-wide association study (GWAS) analyses using all three biomarkers as outcome. MethodsDNA and cerebrospinal fluid (CSF) samples originated from the European Medical Information Framework AD Multimodal Biomarker Discovery (EMIF-AD MBD) study. Overlapping genotype/phenotype data were available for n=671 (NF-L), 677 (YKL-40), and 672 (Ng) individuals. GWAS analyses applied linear regression models adjusting for relevant covariates. FindingsWe identify novel genome-wide significant associations with markers in TMEM106B and CSF levels of NF-L. Additional novel signals were observed with DNA variants in CPOX and CSF levels of YKL-40. Lastly, we confirmed previous work suggesting that YKL-40 levels are regulated by cis protein quantitative trait loci (pQTL) in CHI3L1. InterpretationOur study provides important new insights into the genetic architecture underlying inter-individual variation in all three tested AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

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Hong, S., Dobricic, V., Bos, I., Vos, S. J. B., Prokopenko, D., Tijms, B. M., Andreasson, U., Blennow, K., Vandenberghe, R., Gabel, S., Scheltens, P., Teunissen, C. E., Engelborghs, S., Frisoni, G., Blin, O., Richardson, J. C., Bordet, R., Lleo, A., Alcolea, D., Popp, J., Clark, C., Peyratout, G., Martinez-Lage, P., Tainta, M., Dobson, R. J. B., Legido-Quigley, C., Sleegers, K., Broeckhoven, C. V., Tanzi, R. E., Kate, M. t., Wittig, M., Franke, A., Barkhof, F., Lovestone, S., Streffer, J., Zetterberg, H., Visser, P. J., Bertram, L.. 2020-06-01. TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels. https://doi.org/10.1101/2020.05.31.125633

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