Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer's Disease in European Populations: Development and Validation.
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Akdeniz Bayram Cevdet, Bahrami Shahram, Hagen Espen, Fuhrer Julian, Fominykh Vera, Shadrin Alexey, Filiz Tahir Tekin, Athanasiu Lavinia, Grenier-Boley Benjamin, Bellenguez Céline, de Rojas Itziar, Küçükali Fahri, Schneider Anja, Kleineidam Luca, Rujescu Dan, Scherbaum Norbert, Deckert Jürgen, Riedel-Heller Steffi, Hausner Lucrezia, Molina-Porcel Laura, Grimmer Timo, Heilmann-Heimbach Stefanie, Moebus Susanne, Scarmeas Nikolaos, García-Alberca Jose María, Franco-Macías Emilio, Mir Pablo, Real Luis M, Rodriguez-Rodriguez Eloy, Royo Jose Luís, Sáez María Eugenia, Carracedo Ángel, de Munain Adolfo Lopez, Amer-Ferrer Guillermo, Calero Miguel, Medina Miguel, Garcia-Ribas Guillermo, Mendioroz Maite, Dols-Icardo Oriol, Moreno Fermin, Pérez-Tur Jordi, Bullido María J, Álvarez Victoria, Soininen Hilkka, Heikkinen Sami, de Mendonça Alexandre, Mehrabian Shima, Traykov Latchezar, Hort Jakub, Vyhnalek Martin, Sandau Nicolai, Thomassen Jesper Qvist, Luo Jiao, Pijnenburg Yolande A L, Tesi Niccolo, van Swieten John, Giedraitis Vilmantas, Williams Julie, Nicolas Gael, Debette Stephanie, Amouyel Philippe, Grünblatt Edna, Popp Julius, Bossù Paola, Galimberti Daniela, Rossi Giacomina, Arosio Beatrice, Mecocci Patrizia, Squassina Alessio, Tremolizzo Lucio, Borroni Barbara, Nacmias Benedetta, Seripa Davide, Rainero Innocenzo, Daniele Antonio, Piras Fabrizio, Masullo Carlo, Kehoe Patrick Gavin, Frikke-Schmidt Ruth, Ghidoni Roberta, Ruiz Agustín, Fernandez Victoria, Sánchez-Juan Pascual, Sleegers Kristel, Ingelsson Martin, Hiltunen Mikko, Sims Rebecca, Ramirez Alfredo, Broce Iris J, Haavik Jan, Selbæk Geir, Knapskog Anne-Brita, Saltvedt Ingvild, Bergh Sverre, Aakhus Eivind, Kirsebom Bjørn-Eivind, Watne Leiv Otto, Rongve Arvid, Årsland Dag, Djurovic Srdjan, Stordal Eystein, Toft Mathias, Scheffler Katja, Fladby Tormod, Lambert Jean-Charles, Dale Anders, Frei Oleksandr, Andreassen Ole
Аннотация
METHODS: We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model. We developed a PHS model building on 720 genetic variants, including Apolipoprotein E (APOE) ε2 and ε4 alleles. We used Elastic Net-regularized Cox regression approach to develop the PHS model.
RESULTS: The new PHS model (EADB720) improved prediction accuracy compared to alternative models in European populations, with the Odds Ratio OR80/20 from the highest quintile of risk (80th risk percentile and above) to the lowest quintile of risk (20th risk percentile and below) varying between 5.10 and 13.15 within the range of age of onset from 65 - 85 years. Our model also improved risk stratification across ε3/3 individuals of European ancestry (OR80/20 ranges from 1.95 to 3.52). It was also successfully validated in independent datasets (HUSK, DemGene and ADNI) by achieving OR80/20 up to 10.00 in each independent dataset.
CONCLUSION: Our EADB720 model significantly improves the accuracy of age-associated risk of AD across European populations (pval<0.03). Accurately predicting the age of onset of AD is of large clinical importance to implementing new AD medication and early intervention in clinical settings.