Machine learning suggests polygenic contribution to cognitive dysfunction in amyotrophic lateral sclerosis
Preprint
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
All Related Versions
- Published version: EMBO Molecular Medicine, 13 (1), e12595.
This publication has 72 references indexed in Scilit:
- Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort studyThe Lancet Neurology, 2012
- Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALSNeuron, 2011
- A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTDNeuron, 2011
- A harmonized classification system for FTLD-TDP pathologyActa Neuropathologica, 2011
- Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosisActa Neuropathologica, 2010
- Dementia induces correlated reductions in white matter integrity and cortical thickness: A multivariate neuroimaging study with sparse canonical correlation analysisNeuroImage, 2010
- Transactive Response DNA-Binding Protein 43 Burden in Familial Alzheimer Disease and Down SyndromeArchives of Neurology, 2009
- Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathiesActa Neuropathologica, 2009
- TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysisThe Lancet Neurology, 2008
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature, 1993