The epistasis project: a multi-cohort study of the effects of BDNF, DBH, and SORT1 epistasis on Alzheimer's disease risk

Belbin, O., Morgan, K., Medway, C., Warden, D., Cortina-Borja, M., Van Duijn, C.M., Adams, H.H.H., Frank-Garcia, A., Brookes, K. ORCID: 0000-0003-2427-2513, Sánchez-Juan, P., Alvarez, V., Heun, R., Kölsch, H., Coto, E., Kehoe, P.G., Rodriguez-Rodriguez, E., Bullido, M.J., Ikram, M.A., Smith, A.D., Lehmann, D.J. and Vitorica, J., 2019. The epistasis project: a multi-cohort study of the effects of BDNF, DBH, and SORT1 epistasis on Alzheimer's disease risk. Journal of Alzheimer's Disease, 68 (4), pp. 1535-1547. ISSN 1387-2877

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Abstract

Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer’s disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF, DBH, and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1–1.2, p = 0.005–0.3), an effect size that was consistent in the Northern European (OR = 1.1–1.2, p = 0.002–0.8) but not the smaller Spanish (OR = 0.8–1.6, p = 0.4–1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3–1.5 p = 0.002–0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2–1.3, p = 0.007–0.00008) than men (OR = 0.9–1.0, p = 0.3–0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.

Item Type: Journal article
Publication Title: Journal of Alzheimer's Disease
Creators: Belbin, O., Morgan, K., Medway, C., Warden, D., Cortina-Borja, M., Van Duijn, C.M., Adams, H.H.H., Frank-Garcia, A., Brookes, K., Sánchez-Juan, P., Alvarez, V., Heun, R., Kölsch, H., Coto, E., Kehoe, P.G., Rodriguez-Rodriguez, E., Bullido, M.J., Ikram, M.A., Smith, A.D., Lehmann, D.J. and Vitorica, J.
Publisher: IOS Press
Date: 2019
Volume: 68
Number: 4
ISSN: 1387-2877
Identifiers:
NumberType
10.3233/jad-181116DOI
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 13 May 2019 12:52
Last Modified: 20 May 2019 10:16
URI: http://irep.ntu.ac.uk/id/eprint/36475

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