@article{09be404a1b6642ff93136de0e63bbfce,
title = "Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis",
abstract = "Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.",
keywords = "amyotrophic lateral sclerosis, cognition, frontotemporal dementia, machine learning, polygenic score",
author = "{The CReATe Consortium} and Katerina Placek and Michael Benatar and Joanne Wuu and Evadnie Rampersaud and Laura Hennessy and {Van Deerlin}, {Vivianna M.} and Murray Grossman and Irwin, {David J.} and Lauren Elman and Leo McCluskey and Colin Quinn and Volkan Granit and Statland, {Jeffrey M.} and Burns, {Ted M.} and John Ravits and Andrea Swenson and Jon Katz and Pioro, {Erik P.} and Carlayne Jackson and James Caress and Yuen So and Samuel Maiser and David Walk and Lee, {Edward B.} and Trojanowski, {John Q.} and Philip Cook and James Gee and Jin Sha and Naj, {Adam C.} and Rosa Rademakers and Wenan Chen and Gang Wu and {Paul Taylor}, J. and McMillan, {Corey T.}",
note = "Funding Information: The following authors declare the following conflicts of interest: C.T.M. receives financial support from Biogen and has provided consulting for Axon Advisors. M.B. reports grants from National Institutes of Health, the ALS Association, the Muscular Dystrophy Association, the Centers for Disease Control and Prevention, the Department of Defense, and Target ALS during the conduct of the study; personal fees from Mitsubishi Tanabe Pharma, AveXis, Prilenia, Genentech, and Roche outside the submitted work. In addition, M.B. has a provisional patent entitled “Determining Onset of Amyotrophic Lateral Sclerosis” and serves as a site investigator on clinical trials funded by Biogen and Orphazyme. All other authors declare no competing interests. Funding Information: The CReATe Consortium (U54NS092091) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the National Center for Advancing Translational Sciences (NCATS) Office of Rare Diseases Research (ORDR). Additional research support was provided by the National Institutes of Health (NS106754, AG017586, NS092091, AG054060). The genomics sequencing was funded by St. Jude Children?s Research Hospital American Lebanese Syrian Associated Charities (ALSAC), with additional support from the ALS Association for biorepository and sequencing costs (grants 17-LGCA-331 and 16-TACL-242). Funding Information: The CReATe Consortium (U54NS092091) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the National Center for Advancing Translational Sciences (NCATS) Office of Rare Diseases Research (ORDR). Additional research support was provided by the National Institutes of Health (NS106754, AG017586, NS092091, AG054060). The genomics sequencing was funded by St. Jude Children{\textquoteright}s Research Hospital American Lebanese Syrian Associated Charities (ALSAC), with additional support from the ALS Association for biorepository and sequencing costs (grants 17‐LGCA‐331 and 16‐TACL‐242). Publisher Copyright: {\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2021",
month = jan,
day = "11",
doi = "10.15252/emmm.202012595",
language = "English (US)",
volume = "13",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "1",
}