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

Belbin, Olivia; Morgan, Kevin; Medway, Chris; Warden, Donald; Cortina-Borja, Mario; van Duijn, Cornelia M.; Adams, Hieab H.H.; Frank-Garcia, Ana; Brookes, Keeley; Sáchez-Juan, Pascual; Alvarez, Victoria; Heun, Reinhard; Kölsch, Heike; Coto, Eliecer; Kehoe, Patrick G.; Rodriguez-Rodriguez, Eloy; Bullido, Maria J.; Arfan Ikram, M.; David Smith, A.; Lehmann, Donald J.

Authors

Olivia Belbin

Pascual Sáchez-Juan

Victoria Alvarez

Reinhard Heun

Heike Kölsch

Eliecer Coto

Patrick G. Kehoe

Eloy Rodriguez-Rodriguez

Maria J. Bullido

M. Arfan Ikram

A. David Smith

Kevin Morgan

Donald J. Lehmann

Chris Medway

Donald Warden

Mario Cortina-Borja

Cornelia M. van Duijn

Hieab H.H. Adams

Ana Frank-Garcia

Keeley Brookes

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.

Journal Article Type Article
Publication Date Mar 18, 2019
Journal Journal of Alzheimer's Disease
Print ISSN 1387-2877
Electronic ISSN 1875-8908
Publisher IOS Press
Peer Reviewed Peer Reviewed
Volume 68
Issue 4
Pages 1535-1547
DOI https://doi.org/10.3233/JAD-181116
Keywords Alzheimer’s disease, brain-derived neurotrophic factor, dopamine beta-hydroxylase, epistasis, genetics, neurotrophins, Sortilin
Publisher URL https://content.iospress.com/articles/journal-of-alzheimers-disease/jad181116

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