Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer’s Disease
Year: 2016
Type: article
Study design: Observational Study
Abstract: Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI = [1.13-1.21] per standard deviation increase in GRS; p-value = 2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI = [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI = [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex = 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.
Source: Journal of Alzheimer s Disease
DOI: 10.3233/jad-150749
Authors: Vincent Chouraki, for the International Genomics of Alzheimer’s Project, Christiane Reitz, Fleur Maury, Joshua C. Bis, Celine Bellenguez, Lei Yu, Johanna Jakobsdottir, Shubhabrata Mukherjee, Hieab H. Adams, Seung Hoan Choi, Eric B. Larson, Annette Fitzpatrick, Andre G. Uitterlinden, Philip L. de Jager, Albert Hofman, Vilmundur Gudnason, Badri Vardarajan, Carla Ibrahim-Verbaas, Sven J. van der Lee, Oscar Lopez, Jean-François Dartigues, Claudine Berr, Philippe Amouyel, David A. Bennett, Cornelia van Duijn, Anita L. DeStefano, Lenore J. Launer, M. Arfan Ikram, Paul K. Crane, Jean-Charles Lambert, Richard Mayeux, Sudha Seshadri
Institutions: Boston University, Framingham Heart Study, Columbia University, Inserm, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, Approches épidémiologiques et moléculaires intégratives visant à améliorer la compréhension des maladies chroniques liées au vieillissement, LabEx DISTALZ, University of Washington, Rush University Medical Center, Rush University, Icelandic Heart Association, Erasmus MC, Kaiser Permanente Washington Health Research Institute, Brigham and Women's Hospital, University of Iceland, University of Pittsburgh, Université de Bordeaux, Bordeaux Population Health, Université de Montpellier, Neuropsychiatrie : Recherche Epidemiologique et Clinique, National Institutes of Health, National Institute on Aging
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease, Institut National de la Santé et de la Recherche Médicale, National Institutes of Health, Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences
Awards: G1002540797, G1072871761, G1177103769, G1194337659, G1220223050, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1309605592, G1332411685, UC Davis Alzheimer's Disease Core Center, G1353455142, G1379949353, THE AGES STUDY - THE REYKJAVIK STUDY OF HEALTHY AGING FOR THE NEW MILLENUM, G1602633198, CORONARY HEART DISEASE AND STROKE, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, Epidemiology of Biomarkers of Risk and Progression in LOAD, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2194386449, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G232264632, G232440474, G2391884931, G247538147, G250924255, G2621534636, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G278200998, G2878691739, G297113894, G3045517347, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, Prospective meta-analyses of drug-gene interactions: CHARGE GWAS consortium, G3220743633, UCLA Clinical and Translational Science Institute, G3342163884, G3405256882, G3478357739, G36433118, G3677674694, G3743240706, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, Predictors of Alheimers Disease in Mild Cognitive Impairment, G4000272535, G4429312988, Risk Factors, Pathology, and Clinical Expressions of AD, G5164707915, G5479317095, G581887176, CHS Events Follow-up Study, Epidemiology of Familial Late-Onset Alzheimer's Disease, G6226795708, Genetic Discovery and Application in a Clinical Setting Continuing a Partnership, The Framingham Heart Study, G6680420078, CHS-Transition Phase, G716312657, G7176672723, G7880223742, G828200374, Risk Factors, Pathology, and Clinical Expressions of AD, G8900867631, Diabetes Research Center (DRC), National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), G950304953, G983864884
OpenAlex ID: W2465169012