Linkage to the 8p21.1 Region Including the CLU Gene in Age at Onset Stratified Alzheimer's Disease Families

Article type: Research Article

Authors: Sillén, Anna^a | Lilius, Lena^a | Forsell, Charlotte^a | Kimura, Toru^b | Winblad, Bengt^a | Graff, Caroline^{a; c; *}

Affiliations: [a] Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, KASPAC, Novum, Huddinge, Sweden | [b] Research Division, Dainippon Sumitomo Pharma Co., Ltd, Kasugade-naka, Konohana-ku, Osaka, Japan | [c] Department of Geriatrics, Genetics Unit, Karolinska University Hospital, Huddinge, Stockholm, Sweden

Correspondence: [*] Correspondence to: Caroline Graff, MD, PhD. Tel.: +46 8 585 836 19; Fax: +46 8 585 836 10; E-mail: Caroline.Graff@ki.se.

Abstract: Two powerful genome-wide association studies have recently reported significant association between sporadic late-onset Alzheimer's disease (AD) and markers at the CLU locus in chromosome 8p. In this study, we have stratified our previously analyzed 109 Swedish AD families according to range in age at onset and performed whole-genome linkage analysis and subsequent fine-mapping in 8p21. The subgroup analyzed in the fine-mapping consisted of 28 families with AD, having a within-family onset-range not exceeding 8 years and an age at onset between 49 ≤ 70 years. A maximum non-parametric linkage peak (LOD = 3.5) was found between markers D8S1809 and 236c6-1. Intriguingly this linked 9.5cM region contains clusterin (CLU), which is one of the two top susceptibility genes for AD. Our finding may be a reflection of linkage to the CLU susceptibility gene, in the same way as familial AD has previously been linked to the APOE locus.

Keywords: 8p, age at onset, Alzheimer's disease, clusterin, dementia, linkage analysis

DOI: 10.3233/JAD-2010-101359

Journal: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 13-20, 2011