A Validation Study of Vascular Cognitive Impairment Genetics Meta-Analysis Findings in an Independent Collaborative Cohort

Article type: Research Article

Authors: Skrobot, Olivia Anna^a | McKnight, Amy Jayne^b | Passmore, Peter Anthony^c | Seripa, Davide^d | Mecocci, Patrizia^e | Panza, Francesco^{d; f} | Kalaria, Rajesh^g | Wilcock, Gordon^h | Munafò, Marcusⁱ | Erkinjuntti, Timo^j | Karhunen, Pekka^{k; l} | Pessi, Tanja^{k; l} | Martiskainen, Mika^{k; l} | Love, Seth^a | the Genetic and Environmental Risk for Alzheimer’s disease Consortium (GERAD1)¹ | Kehoe, Patrick Gavin^{a; *}

Affiliations: [a] Dementia Research Group, University of Bristol, Level 1, Learning & Research, Southmead Hospital, Bristol, UK | [b] Centre for Public Health, Queen’s University of Belfast, c/o Regional Genetics Centre, Level A, Tower Block, Belfast City Hospital, Belfast, UK | [c] Institute of Clinical Sciences, Block B, Queens University Belfast, Royal Victoria Hospital, Belfast, UK | [d] Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, I.R.C.C.S. “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy | [e] Institute of Gerontology and Geriatrics, University of Perugia, Ospedale S.M. della Misericordia, Perugia, Italy | [f] Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Policlinico, Bari, Italy | [g] Institute of Neuroscience, NIHR Biomedical Research Building, Campus for Ageing & Vitality Newcastle upon Tyne, UK | [h] Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Headington, Oxford, UK | [i] MRC Integrative Epidemiology Unit, UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK | [j] Department of Neurology and Memory Research Unit, Helsinki University Central Hospital, HUS, Finland | [k] School of Medicine, University of Tampere, Finland | [l] Fimlab Laboratories Ltd, Tampere University Hospital region, Finland

Correspondence: [*] Correspondence to: Patrick Kehoe, Dementia Research Group, University of Bristol, Level 1, Learning & Research, Southmead Hospital, Bristol, BS10 5NB, UK. Tel.: +44 0117 4147821; Fax: +44 0 117 4147822; E-mail: [email protected].

Note: [1] Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report.

Abstract: Vascular cognitive impairment (VCI), including its severe form, vascular dementia (VaD), is the second most common form of dementia. The genetic etiology of sporadic VCI remains largely unknown. We previously conducted a systematic review and meta-analysis of all published genetic association studies of sporadic VCI prior to 6 July 2012, which demonstrated that APOE (ɛ4, ɛ2) and MTHFR (rs1801133) variants were associated with susceptibility for VCI. De novo genotyping was conducted in a new independent relatively large collaborative European cohort of VaD (nmax = 549) and elderly non-demented samples (nmax = 552). Where available, genotype data derived from Illumina’s 610-quad array for 1210 GERAD1 control samples were also included in analyses of genes examined. Associations were tested using the Cochran-Armitage trend test: MTHFR rs1801133 (OR = 1.36, 95% CI 1.16–1.58, p = <0.0001), APOE rs7412 (OR = 0.62, 95% CI 0.42–0.90, p = 0.01), and APOE rs429358 (OR = 1.59, 95% CI 1.17–2.16, p = 0.003). Association was also observed with APOE epsilon alleles; ɛ4 (OR = 1.85, 95% CI 1.35–2.52, p = <0.0001) and ɛ2 (OR = 0.67, 95% CI 0.46–0.98, p = 0.03). Logistic regression and Bonferroni correction in a subgroup of the cohort adjusted for gender, age, and population maintained the association of APOE rs429358 and ɛ4 allele.

Keywords: Association, cognitive impairment, dementia, gene, meta-analysis, vascular

DOI: 10.3233/JAD-150862

Journal: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 981-989, 2016