The Epistasis Project: A Multi-Cohort Study of the Effects of BDNF, DBH, and SORT1 Epistasis on Alzheimer’s Disease Risk

Article type: Research Article

Authors: Belbin, Olivia^{a; b; *} | Morgan, Kevin^c | Medway, Chris^d | Warden, Donald^e | Cortina-Borja, Mario^f | van Duijn, Cornelia M.^g | Adams, Hieab H.H.^g | Frank-Garcia, Ana^{b; h} | Brookes, Keeley^c | Sánchez-Juan, Pascual^{b; i} | Alvarez, Victoria^j | Heun, Reinhard^k | Kölsch, Heike^k | Coto, Eliecer^j | Kehoe, Patrick G.^l | Rodriguez-Rodriguez, Eloy^{b; i} | Bullido, Maria J^{b; h} | Ikram, M. Arfan^g | Smith, A. David^e | Lehmann, Donald J.^e

Affiliations: [a] Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain | [b] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain | [c] Human Genetics School of Life Sciences, University of Nottingham, UK | [d] Institute of Medical Genetics, University Hospital Wales, Cardiff, UK | [e] Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Oxford, UK | [f] Clinical Epidemiology, Nutrition and Biostatistics, UCL Great Ormond Street Institute of Child Health, London, UK | [g] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands | [h] Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain | [i] Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander, Spain | [j] Laboratorio de Genética, AGC Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, Spain | [k] Department of Psychiatry, University of Bonn, Bonn, Germany | [l] Dementia Research Group, Bristol Medical School Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol, UK

Correspondence: [*] Correspondence to: Olivia Belbin, PhD, IIB-Sant Pau, Pabellón 19, c/Sant Antoni Maria Claret 167 08025 Barcelona, Spain. Tel.: +34 93 291 90 00 /Ext 8233; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, dopamine beta-hydroxylase, epistasis, genetics, neurotrophins, Sortilin

DOI: 10.3233/JAD-181116

Journal: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1535-1547, 2019