Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis

The CReATe Consortium

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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.

Original languageEnglish (US)
Article numbere12595
JournalEMBO Molecular Medicine
Volume13
Issue number1
DOIs
StatePublished - Jan 11 2021

Keywords

  • amyotrophic lateral sclerosis
  • cognition
  • frontotemporal dementia
  • machine learning
  • polygenic score

ASJC Scopus subject areas

  • Molecular Medicine

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