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Candidate Single-Nucleotide Polymorphisms From a Genomewide Association Study of Alzheimer Disease
Hao Li, PhD;
Sally Wetten, MSc;
Li Li, PhD;
Pamela L. St. Jean, PhD;
Ruchi Upmanyu, MSc;
Linda Surh, MD, PhD;
David Hosford, MD, PhD;
Michael R. Barnes, PhD;
James David Briley, BSc;
Michael Borrie, MB, ChB, FRCPC;
Natalie Coletta, MBiotech;
Richard Delisle, MD;
Daniella Dhalla, MBiotech;
Margaret G. Ehm, PhD;
Howard H. Feldman, MD;
Luis Fornazzari, MD;
Serge Gauthier, MD;
Neil Goodgame, BSc;
Danilo Guzman, MD;
Sandra Hammond, HNC;
Paul Hollingworth, PhD;
Ging-Yuek Hsiung, MD;
Joan Johnson, BSc, MEA;
Devon D. Kelly, MSc;
Ron Keren, MD;
Andrew Kertesz, MD;
Karen S. King, BSc;
Simon Lovestone, PhD, MRCPsych;
Inge Loy-English, MD;
Paul M. Matthews, MD, PhD;
Michael J. Owen, PhD, FRCPsych, FMedSci;
Mary Plumpton, PhD;
William Pryse-Phillips, MD, FRCP;
Rab K. Prinjha, PhD;
Jill C. Richardson, PhD;
Ann Saunders, PhD;
Andrew J. Slater, BSc;
Peter H. St. George-Hyslop, MD, FRCPC;
Sandra W. Stinnett, MSc;
Jina E. Swartz, MD, PhD;
Rachel L. Taylor, BSc;
John Wherrett, MD;
Julie Williams, PhD;
David P. Yarnall, PhD;
Rachel A. Gibson, PhD;
Michael C. Irizarry, MD, MPH;
Lefkos T. Middleton, MD;
Allen D. Roses, MD
Arch Neurol. 2008;65(1):45-53. Published online November 12, 2007 (doi:10.1001/archneurol.2007.3).
Objective To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs.
Design Case-control study with replication.
Setting Memory referral clinics in Canada and the United Kingdom.
Participants The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England.
Main Outcome Measures Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments.
Results Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P < .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2).
Conclusions Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.
Author Affiliations: GlaxoSmithKline, Research Triangle Park, North Carolina (Drs H. Li, L. Li, St. Jean, Hosford, Ehm, Saunders, Yarnall, Irizarry, and Roses, Messrs Briley, Kelly, and Slater, and Mss Johnson, King, and Stinnett); GlaxoSmithKline, Harlow, England (Mss Wetten, Upmanyu, Hammond, and Taylor, Drs Surh, Barnes, Plumpton, Prinjha, Richardson, Swartz, Gibson, and Middleton, and Mr Goodgame); Division of Geriatric Medicine, Parkwood Hospital (Dr Borrie) and Department of Cognitive Neurology, St Joseph's Hospital (Dr Kertesz), London, Ontario, Canada; GlaxoSmithKline Inc, Mississauga, Ontario, Canada (Mss Coletta and Dhalla and Dr Pryse-Phillips); Clinique de Neurologie, Trois-Rivières, Quebec, Canada (Dr Delisle); Division of Neurology, University of British Columbia, Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada (Drs Feldman and Hsiung); Memory Clinic (Dr Fornazzari) and University Health Network (Drs Keren, St. George-Hyslop, and Wherrett), University of Toronto, Toronto, Ontario, Canada; McGill Centre for Studies in Aging, Verdun, Quebec, Canada (Dr Gauthier); Clinical Trials Unit, SCO Health Service, University of Ottawa, Ottawa, Ontario, Canada (Drs Guzman and Loy-English); Medical Research Council Neuropsychiatric Genetics Group, School of Medicine, Cardiff University, Cardiff, Wales (Drs Hollingworth, Owen, and Williams); and Medical Research Council Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry (Dr Lovestone) and GlaxoSmithKline Research and Development, Clinical Imaging Centre, and Department of Clinical Neurosciences, Imperial College, Hammersmith Hospital (Dr Matthews), London, England.
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