Machine learning in Alzheimer’s disease genetics
Abstract
Abstract 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.
Article Details
Authors (331)
Matthew Bracher-Smith
Federico Melograna
Brittany Ulm
Céline Bellenguez
Benjamin Grenier-Boley
Diane Duroux
Alejo J. Nevado
Peter Holmans
Betty M. Tijms
Itziar de Rojas
Rafael Campos-Martin
Atahualpa Castillo
Fahri Küçükali
Oliver Peters
Anja Schneider
Martin Dichgans
Dan Rujescu
Norbert Scherbaum
Jürgen Deckert
Steffi 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
Fermin Moreno
Jordi Pérez-Tur
María J. Bullido
Pau Pastor
Victoria Álvarez
Pablo Mir
Luis M. Real
Gerard Piñol-Ripoll
Eloy Rodriguez-Rodriguez
Hilkka Soininen
Sami Heikkinen
Alexandre de Mendonça
Shima Mehrabian
Jakub Hort
Martin Vyhnalek
Nicolai Sandau
Jesper Qvist Thomassen
Yolande A. L. Pijnenburg
Henne Holstege
John van Swieten
Inez Ramakers
Frans Verhey
Philip Scheltens
Caroline Graff
Goran Papenberg
Vilmantas Giedraitis
Julie Williams
Philippe Amouyel
Anne Boland
Jean-François Deleuze
Gael Nicolas
Carole Dufouil
Florence Pasquier
Olivier Hanon
Stephanie Debette
Edna Grünblatt
Julius Popp
Roberta Ghidoni
Daniela Galimberti
Beatrice Arosio
Patrizia Mecocci
Vincenzo Solfrizzi
Lucilla Parnetti
Alessio Squassina
Lucio Tremolizzo
Barbara Borroni
Benedetta Nacmias
Marco Spallazzi
Davide Seripa
Innocenzo Rainero
Antonio Daniele
Fabrizio Piras
Carlo Masullo
Giacomina Rossi
Frank Jessen
Patrick Kehoe
Tsolaki Magda
Kristel Sleegers
Martin Ingelsson
Mikko Hiltunen
Rebecca Sims
Wiesje van der Flier
Ole A. Andreassen
Agustin Ruiz
Alfredo Ramirez
Iris Jansen
Sven van der Lee
Victor Andrade
Victoria Fernandez
Maria-Carolina Dalmasso
Luca Kleineidam
Shahzad Ahmad
Dag Aarsland
Amanda Cano
Carla Abdelnour
Emilio Alarcón-Martín
Daniel Alcolea
Montserrat Alegret
Ignacio Alvarez
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
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 Bûrger
Vanessa Burholt
Miguel Calero
Geneviève Chene
Ángel Carracedo
Roberta Cecchetti
Laura Cervera-Carles
Camille Charbonnier
Caterina Chillotti
Simona Ciccone
Jurgen A. H. R. Claassen
Jordi Clarimon
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 Diez-Fairen
Paolo Dionigi Rossi
Srdjan Djurovic
Emmanuelle Duron
Sebastiaan Engelborghs
Josep Blázquez
Michael Ewers
Tagliavini Fabrizio
Sune Fallgaard Nielsen
Lucia Farotti
Chiara Fenoglio
Marta Fernández-Fuertes
Catarina B. Ferreira
Evelyn Ferri
Bertrand Fin
Peter Fischer
Tormod Fladby
Klaus Fliessbach
Juan Fortea
Tatiana M. Foroud
Silvia Fostinelli
Nick C. Fox
Emlio Franco-Macías
Ana Frank-García
Lutz Froelich
Jose María García-Alberca
Pablo García-González
Sebastian Garcia-Madrona
Guillermo Garcia-Ribas
Ina Giegling
Giaccone Giorgio
Oliver Goldhardt
Antonio González-Pérez
Giulia Grande
Emma Green
Tamar Guetta-Baranes
Annakaisa Haapasalo
Georgios 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 Koivisto
Johannes Kornhuber
Mary H. Kosmidis
Carmen Lage
Erika J. Laukka
Alessandra Lauria
Jenni Lehtisalo
Ondrej Lerch
Alberto Lleo
Adolfo López de Munain
Seth Love
Malin Löwemark
Lauren Luckcuck
Juan Macías
Catherine A. MacLeod
Wolfgang Maier
Francesca Mangialasche
Spallazzi Marco
Marta Marquié
Rachel Marshall
Angel Martín Montes
Carmen Martínez Rodríguez
Simon Mead
Medical Research Council Prion Unit at University College London, University College London Institute of Prion Diseases
Miguel Medina
Alun Meggy
Silvia Mendoza
Manuel Menéndez-González
Merel Mol
Laura Montrreal
Kevin Morgan
Markus M. Nöthen
Tiia Ngandu
Børge G. Nordestgaard
Robert Olaso
Adelina Orellana
Michela Orsini
Maria Capdevila
Alessandro Padovani
Caffarra Paolo
Marta Martinez-Lucas
Pierre Pericard
Juan A. Pineda
Claudia Pisanu
Thomas Polak
Danielle Posthuma
Josef Priller
Raquel Puerta
Olivier Quenez
Inés Quintela
Alberto Rábano
Marcel J. T. Reinders
Peter Riederer
Claudia Olivé
Arvid Rongve
Irene Rosas Allende
Maitée Rosende-Roca
Jose Luis Royo
Elisa Rubino
María Eugenia Sáez
Paraskevi Sakka
Ingvild Saltvedt
Fernando García-Gutierrez
María Bernal Sánchez-Arjona
Florentino Sanchez-Garcia
Pascual Sánchez-Juan
Raquel Sánchez-Valle
Sigrid B. Sando
Michela Scamosci
Elio Scarpini
Martin Scherer
Matthias Schmid
Jonathan M. Schott
Geir Selbæk
Alexey A. Shadrin
Olivia Skrobot
Alina Solomon
Sandro Sorbi
Oscar Sotolongo-Grau
Annika Spottke
Eystein Stordal
Andrea Miguel
Lluís Tárraga
Niccoló Tesi
Anbupalam Thalamuthu
Tegos Thomas
Latchezar Traykov
Anne Tybjærg-Hansen
Andre Uitterlinden
Abbe Ullgren
Ingun Ulstein
Sergi Valero
Christine Van Broeckhoven
Jasper Van Dongen
Jeroen van Rooij
Rik Vandenberghe
Jean-Sebastian Vidal
Maria Gabriella Vita
Jonathan Vogelgsang
Michael Wagner
David Wallon
Leonie Weinhold
Gill Windle
Bob Woods
Mary Yannakoulia
Miren Zulaica
Mohsen Ghanbari
Perminder Sachdev
Karen Mather
Mohammad Arfan Ikram
Ruth Frikke-Schmidt
Najaf Amin
Department of Psychiatry, Erasmus University Medical Center
Gennady Roshchupkin
Jean-Charles Lambert
Kristel Van Steen
Cornelia van Duijn
Valentina Escott-Price