Genetic Study of Neurexin and Neuroligin Genes in Alzheimer's Disease

Article type: Research Article

Authors: Martinez-Mir, Amalia^a | González-Pérez, Antonio^{b; c} | Gayán, Javier^{b; d} | Antúnez, Carmen^e | Marín, Juan^e | Boada, Mercé^{f; g} | Lopez-Arrieta, Jesús María^h | Alzheimer's Disease Neuroimaging Initiative¹ | Fernández, Evaristo^b | Ramírez-Lorca, Reposo^b | Sáez, María Eugenia^{b; c} | Ruiz, Agustín^{b; f} | Scholl, Francisco G.^{a; i} | Real, Luis Miguel^{b; *}

Affiliations: [a] Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain | [b] Departamento de Genómica Estructural, Neocodex, Sevilla, Spain | [c] Centro Andaluz de Estudios Bioinformáticos (CAEBi), Sevilla, Spain | [d] Bioinfosol, Sevilla, Spain | [e] Unidad de Demencia, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain | [f] Fundació ACE. Barcelona Alzheimer Treatment & Reserch Center, Barcelona, Spain | [g] Hospital Universitari Vall d'Hebron - Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain | [h] Unidad de Memoria, Hospital Universitario La Paz-Cantoblanco, Madrid, Spain | [i] Facultad de Medicina, Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Spain

Correspondence: [*] Correspondence to: Luis Miguel Real, Departamento de Genómica Estructural, Neocodex SL C/Chaparro 8, esc. 3, Bloq.1, 1°A, 41020-Sevilla, Spain. Tel: +34 954078382; Fax: +34 955923101; E-mail: [email protected].

Note: [1] Some data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.ucla.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer's disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD. To explore this hypothesis, we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1, 256 SNPs in the NRXN1, NRXN2, NRXN3, and NLGN1 genes (3,009 cases and 3,006 control individuals). We identified a marker in the NRXN3 gene (rs17757879) that showed a consistent protective effect in all GWAS, however, the statistical significance obtained did not resist multiple testing corrections (OR = 0.851, p = 0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A combined meta-analysis of the former five GWAS together with a replication Spanish sample consisting of 1,785 cases and 1,634 controls confirmed this observation (rs17757879, OR = 0.742, 95% CI = 0.632–0.872, p = 0.00028, final meta-analysis). We conclude that NRXN3 might have a role in susceptibility to AD in males.

Keywords: Alzheimer's disease, genetics, genome-wide association study, meta-analysis, neurexins, neuroligins, NRXN3

DOI: 10.3233/JAD-122257

Journal: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 403-412, 2013