Machine learning in Alzheimer’s disease genetics

作者：Matthew Bracher‐Smith, Federico Melograna, Brittany Ulm, Céline Bellenguez, Benjamin Grenier‐Boley, Diane Duroux, Alejo Nevado‐Holgado, Peter Holmans, Betty M. Tijms, Marc Hulsman, Itziar de Rojas, Rafael Campos-Martín, Sven J. van der Lee, Atahualpa Castillo-Morales, Fahri Küçükali, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Jürgen Deckert, Steffi G. Riedel‐Heller, Lucrezia Hausner, Laura Molina‐Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann‐Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols‐Icardo, Fermín Moreno, Jordi Pérez‐Tur, María J. Bullido, Pau Pástor, Raquel Sánchez‐Valle, Victoria Álvarez, Merçé Boada, Pablo García‐González, Raquel Puerta, Pablo Mir, Luís Miguel Real, Gerard Piñol-Ripoll, José María García‐Alberca, Eloy Rodríguez‐Rodríguez, Hilkka Soininen, Sami Heikkinen, Alexandre de Mendonça, Shima Mehrabian, Latchezar Traykov, Jakub Hort, Martin Vyhnálek, Nicolai Sandau, Jesper Qvist Thomassen, Yolande A.L. Pijnenburg, Henne Holstege, John C. van Swieten, Inez Ramakers, Frans Verhey, Philip Scheltens, Caroline Graff, Goran Papenberg, Vilmantas Giedraitis, Julie Williams, Philippe Amouyel, Anne Boland, Jean‐François Deleuze, Gaël Nicolas, Carole Dufouil, Florence Pasquier, Olivier Hanon, Stéphanie Debette, Edna Grünblatt, Julius Popp, Roberta Ghidoni, Daniela Galimberti, Beatrice Arosio, Patrizia Mecocci, Vincenzo Solfrizzi, Lucilla Parnetti, Alessio Squassina, Lucio Tremolizzo, Barbara Borroni, Michael Wagner, Benedetta Nacmias, Marco Spallazzi, Davide Seripa, Innocenzo Rainero, Antonio Daniele, Fabrizio Piras, Carlo Masullo, Giacomina Rossi, Frank Jessen, Patrick G. Kehoe, Magda Tsolaki, Pascual Sánchez‐Juan, Kristel Sleegers, Martin Ingelsson, Mikko Hiltunen, Rebecca Sims, Wiesje M. van der Flier, Ole A. Andreassen, Agustı́n Ruiz, Alfredo Ramı́rez, EADB, Iris E. Jansen, Sven van der Lee, Víctor Andrade, María Victoria Fernández, Maria-Carolina Dalmasso, Luca Kleineidam, Shahzad Ahmad, Dag Aarsland, Amanda Cano, Carla Abdelnour, Emilio Alarcón‐Martín, Daniel Alcolea, Montserrat Alegret, Ignacio Álvarez, Nicola J. Armstrong, Tsolaki Anthoula, Ildebrando Appollonio, Marina Arcaro, Silvana Archetti, Alfonso Arias Pastor, Lavinia Athanasiu, Henri Bailly, Nerisa Banaj, Miquel Baquero, Ana Belén Pastor, Claudine Berr, Céline Besse, Valentina Bessi, Giuliano Binetti, Silvia Fostinelli, Sonia Bellini, Alessandra Bizarro, Rafael Blesa, Mercè Boada, Silvia Boschi, Paola Bossù, Geir Bråthen, Catherine Bresner, Henry Brodaty, Keeley J. Brookes, Dolores Buiza‐Rueda, Katharina Bürger, Vanessa Burholt, Miguel Calero, Geneviève Chêne, Ángel Carracedo, Roberta Cecchetti, Laura Cervera‐Carles, Camille Charbonnier, Caterina Chillotti, Simona Ciccone, Jurgen A.H.R. Claassen, Jordi Clarimón, Christopher Clark, Elisa Conti, Anaïs Corma‐Gómez, Guido Maria Giuffrè, Carlo Custodero, Delphine Daian, Efthimios Dardiotis, Jean‐François Dartigues, Peter Paul De Deyn, Teodoro del Ser, Nicola Denning, Janine Diehl‐Schmid, Mónica Díez-Fairén, Paolo Rossi, Srdjan Djurovic, Emmanuelle Duron, Sebastiaan Engelborghs, Jorge Blázquez, Michael Ewers, Fabrizio Tagliavini, Sune F. Nielsen, Lucia Farotti, Chiara Fenoglio, Marta Fernández‐Fuertes, Catarina B. Ferreira, Evelyn Ferri, Bertrand Fin, Peter Fischer, Tormod Fladby, Klaus Fließbach, Juan Fortea, Tatiana Foroud, Silvia Fostinelli, Nick C. Fox, Emlio Franco-Macías, Ana Frank, Lutz Froelich, José María García‐Alberca, Pablo García‐González, Sebastián García‐Madrona, Guillermo García‐Ribas, Ina Giegling, Giaccone Giorgio, Oliver Goldhardt, Antonio González-Pérez, Giulia Grande, Emma Green, Tamar Guetta‐Baranes, Annakaisa Haapasalo, Georgios M. Hadjigeorgiou, Harald Hampel, John Hardy, Annette M. Hartmann, Ganna Leonenko, Janet Harwood, Seppo Helisalmi, Michael T. Heneka, Isabel Hernández, Martin J. Herrmann, Per Hoffmann, Clive Holmes, Raquel Huerto Vilas, Marc Hulsman, Geert Jan Biessels, Charlotte Johansson, Lena Kilander, Anne Kinhult Ståhlbom, Miia Kivipelto, Anne M. Koivisto, Johannes Kornhuber, Mary H. Kosmidis, Carmen Lage, Erika J. Laukka, Alessandra Lauria, Jenni Lehtisalo, Ondřej Lerch, Alberto Lleó, Adolfo Lopez de Munain, Seth Love, Malin Löwemark, Lauren Luckcuck, Juan Macı́as, Catherine Macleod, Wolfgang Maier, Francesca Mangialasche, Spallazzi Marco, Marta Marquié, Iain Marshall, Ángel Martín Montes, Carmen Martínez Rodríguez, Simon Mead, Miguel Ángel Medina, Alun Meggy, Silvia Mendoza, Manuel Menéndez‐González, Merel O. Mol, Laura Montrreal, Kevin Morgan, Markus M. Nöthen, Tiia Ngandu, Børge G. Nordestgaard, Robert Olaso, Adelina Orellana, Michela Orsini, María Luisa Sarrate Capdevila, Alessandro Padovani, Paolo Caffarra, Marta Martinez-Lucas, Pierre Péricard, Juan A. Pineda, Claudia Pisanu, Thomas Polak, Daniëlle Posthuma, Josef Priller, Raquel Puerta, Olivier Quenez, Inés Quintela, Alberto Rábano, Marcel Reinders, Peter Riederer, Clàudia Olivé, Arvid Rongve, Irene Rosas Allende, Maitée Rosende‐Roca, José Luís Royo, Elisa Rubino, María Eugenia Sáez, Paraskevi Sakka, Ingvild Saltvedt, Fernando García‐Gutiérrez, María Bernal Sánchez‐Arjona, Florentino Sánchez-García, Pascual Sánchez‐Juan, Raquel Sánchez‐Valle, Sigrid B. Sando, Michela Scamosci, Elio Scarpini, Martin Scherer, Matthias Schmid, Jonathan M. Schott, Geir Selbæk, Alexey Shadrin, Olivia Anna Skrobot, Alina Solomon, Sandro Sorbi, Óscar Sotolongo‐Grau, Annika Spottke, Eystein Stordal, Andrea Miguel, Lluís Tárraga, Niccoló Tesi, Anbupalam Thalamuthu, Thomas Tegos, Latchezar Traykov, Anne Tybjærg-Hansen, André G. Uitterlinden, Abbe Ullgren, Ingun Ulstein, Sergi Valero, Christine Van Broeckhoven, Jasper Van Dongen, Jeroen van Rooij, Rik Vandenberghe, Jean‐Sébastien Vidal, Maria Gabriella Vita, Jonathan Vogelgsang, Michael Wagner, David Wallon, Leonie Weinhold, Gill Windle, Bob Woods, Mary Yannakoulia, Miren Zulaica, Mohsen Ghanbari, Perminder S. Sachdev, Karen A. Mather, M. Arfan Ikram, Ruth Frikke‐Schmidt, Najaf Amin, Gennady V. Roshchupkin, Jean‐Charles Lambert, Kristel Van Steen, Cornelia M. van Duijn, Valentina Escott‐Price · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61650-z · 被引用次数：14 · 研究领域：Genetic Associations and Epidemiology、Bioinformatics and Genomic Networks、Gene expression and cancer classification

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.