Machine learning in Alzheimer's disease genetics.
Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models. ML approaches successfully captured all genome-wide significant genetic variants identified in the training set and 22% of associations from larger meta-analyses. They highlight 6 novel loci which replicate in an external dataset, including variants which map to ARHGAP25, LY6H, COG7, SOD1 and ZNF597. They further identify novel association in AP4E1, refining the genetic landscape of the known SPPL2A locus. Our results demonstrate that machine learning methods can achieve predictive performance comparable to classical approaches in genetic epidemiology and have the potential to uncover novel loci that remain undetected by traditional GWAS. These insights provide a complementary avenue for advancing the understanding of AD genetics.
Authors
Bracher-Smith Bracher-Smith, Melograna Melograna, Ulm Ulm, Bellenguez Bellenguez, Grenier-Boley Grenier-Boley, Duroux Duroux, Nevado Nevado, Holmans Holmans, Tijms Tijms, Hulsman Hulsman, de Rojas de Rojas, Campos-Martin Campos-Martin, der Lee der Lee, Castillo Castillo, Küçükali Küçükali, Peters Peters, Schneider Schneider, Dichgans Dichgans, Rujescu Rujescu, Scherbaum Scherbaum, Deckert Deckert, Riedel-Heller Riedel-Heller, Hausner Hausner, Molina-Porcel Molina-Porcel, Düzel Düzel, Grimmer Grimmer, Wiltfang Wiltfang, Heilmann-Heimbach Heilmann-Heimbach, Moebus Moebus, Tegos Tegos, Scarmeas Scarmeas, Dols-Icardo Dols-Icardo, Moreno Moreno, Pérez-Tur Pérez-Tur, Bullido Bullido, Pastor Pastor, Sánchez-Valle Sánchez-Valle, Álvarez Álvarez, Boada Boada, García-González García-González, Puerta Puerta, Mir Mir, Real Real, Piñol-Ripoll Piñol-Ripoll, García-Alberca García-Alberca, Rodriguez-Rodriguez Rodriguez-Rodriguez, Soininen Soininen, Heikkinen Heikkinen, de Mendonça de Mendonça, Mehrabian Mehrabian, Traykov Traykov, Hort Hort, Vyhnalek Vyhnalek, Sandau Sandau, Thomassen Thomassen, Pijnenburg Pijnenburg, Holstege Holstege, van Swieten van Swieten, Ramakers Ramakers, Verhey Verhey, Scheltens Scheltens, Graff Graff, Papenberg Papenberg, Giedraitis Giedraitis, Williams Williams, Amouyel Amouyel, Boland Boland, Deleuze Deleuze, Nicolas Nicolas, Dufouil Dufouil, Pasquier Pasquier, Hanon Hanon, Debette Debette, Grünblatt Grünblatt, Popp Popp, Ghidoni Ghidoni, Galimberti Galimberti, Arosio Arosio, Mecocci Mecocci, Solfrizzi Solfrizzi, Parnetti Parnetti, Squassina Squassina, Tremolizzo Tremolizzo, Borroni Borroni, Wagner Wagner, Nacmias Nacmias, Spallazzi Spallazzi, Seripa Seripa, Rainero Rainero, Daniele Daniele, Piras Piras, Masullo Masullo, Rossi Rossi, Jessen Jessen, Kehoe Kehoe, Magda Magda, Sánchez-Juan Sánchez-Juan, Sleegers Sleegers, Ingelsson Ingelsson, Hiltunen Hiltunen, Sims Sims, van der Flier van der Flier, Andreassen Andreassen, Ruiz Ruiz, Ramirez Ramirez, , Frikke-Schmidt Frikke-Schmidt, Amin Amin, Roshchupkin Roshchupkin, Lambert Lambert, Van Steen Van Steen, van Duijn van Duijn, Escott-Price Escott-Price
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