1. Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease
- Author
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Annette L. Fitzpatrick, P. Amouyel, Richard Mayeux, Johanna Jakobsdottir, Hieab H.H. Adams, Anita L. DeStefano, Badri N. Vardarajan, Chouraki, de Jager Pl, David A. Bennett, Jean-François Dartigues, Shubhabrata Mukherjee, Seung Hoan Choi, M. A. Ikram, Christiane Reitz, Eric B. Larson, Oscar L. Lopez, Fleur Maury, Jean-Charles Lambert, Sudha Seshadri, Lei Yu, van der Lee Sj, Albert Hofman, van Duijn C, J. C. Bis, Gudnason, L. J. Launer, A.G. Uitterlinden, Carla A. Ibrahim-Verbaas, Paul K. Crane, Céline Bellenguez, Claudine Berr, Epidemiology, Internal Medicine, and Neurology
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Apolipoprotein E4 ,Genome-wide association study ,Neuropsychological Tests ,Polymorphism, Single Nucleotide ,Risk Assessment ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Statistics ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Genetic testing ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Psychiatric Status Rating Scales ,Framingham Risk Score ,medicine.diagnostic_test ,business.industry ,Proportional hazards model ,General Neuroscience ,Hazard ratio ,General Medicine ,Psychiatry and Mental health ,Clinical Psychology ,030104 developmental biology ,Meta-analysis ,Educational Status ,Female ,Geriatrics and Gerontology ,business ,Risk assessment ,030217 neurology & neurosurgery ,Cohort study ,Genome-Wide Association 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 APOE epsilon 4. 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 IGAPGWAS 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 (Delta-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 = 2.86x10(-16)). This association was stronger among persons with at least one APOE epsilon 4 allele (HRGRS = 1.24; 95% CI = [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI = [1.08-1.18]; p(interaction) = 3.45x10(-2)). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE epsilon 4, and education (Delta-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 APOE epsilon 4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.
- Published
- 2016