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Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease.
Friday,2016-09-16 10:58 America/Los_Angeles — zdrager
| Title | Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. |
| Publication Type | Journal Article |
| Year of Publication | 2016 |
| Authors | Chouraki, V, Reitz, C, Maury, F, Bis, JC, Bellenguez, C, Yu, L, Jakobsdottir, J, Mukherjee, S, Adams, HH, Choi, SHoan, Larson, EB, Fitzpatrick, A, Uitterlinden, AG, De Jager, PL, Hofman, A, Gudnason, V, Vardarajan, B, Ibrahim-Verbaas, C, van der Lee, SJ, Lopez, O, Dartigues, J-F, Berr, C, Amouyel, P, Bennett, DA, van Duijn, C, DeStefano, AL, Launer, LJ, Ikram, AM, Crane, PK, Lambert, J-C, Mayeux, R, Seshadri, S |
| Corporate/Institutional Authors | International Genomics of Alzheimer’s Project |
| Journal | J Alzheimers Dis |
| Volume | 53 |
| Issue | 3 |
| Pagination | 921-32 |
| Date Published | 2016 Jun 18 |
| ISSN | 1875-8908 |
| Abstract | <p>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.</p> |
| DOI | 10.3233/JAD-150749 |
| Alternate Journal | J. Alzheimers Dis. |
| PubMed ID | 27340842 |
| PubMed Central ID | PMC5036102 |
| Grant List | AG012100 / AG / NIA NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States N01 HC085079 / HC / NHLBI NIH HHS / United States N01 HC085080 / HC / NHLBI NIH HHS / United States N01 HC085081 / HC / NHLBI NIH HHS / United States N01 HC085082 / HC / NHLBI NIH HHS / United States N01 HC085083 / HC / NHLBI NIH HHS / United States N01 HC085086 / HC / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States R01 AG008122 / AG / NIA NIH HHS / United States R01 AG015819 / AG / NIA NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States R01 AG017917 / AG / NIA NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 AG027058 / AG / NIA NIH HHS / United States R01 AG030146 / AG / NIA NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01 AG037212 / AG / NIA NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States U01 AG006781 / AG / NIA NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States U01 HG004610 / HG / NHGRI NIH HHS / United States U01 HG006375 / HG / NHGRI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States |