RT Journal Article
SR Electronic
T1 Enrichment of rare protein truncating variants in amyotrophic lateral sclerosis patients
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 307835
DO 10.1101/307835
A1 Sali M.K. Farhan
A1 Daniel P. Howrigan
A1 Liam E. Abbott
A1 Andrea E. Byrnes
A1 Claire Churchhouse
A1 Hemali Phatnani
A1 Bradley N. Smith
A1 Simon D. Topp
A1 Evadnie Rampersaud
A1 Gang Wu
A1 Joanne Wuu
A1 Amelie Gubitz
A1 Joseph R. Klim
A1 Daniel A. Mordes
A1 Sulagna Ghosh
A1 CReATe Consortium, FALS Consortium, ALSGENS Consortium
A1 Kevin Eggan
A1 Rosa Rademakers
A1 Jacob L. McCauley
A1 Rebecca Schüle
A1 Stephan Züchner
A1 Michael Benatar
A1 J. Paul Taylor
A1 Mike A. Nalls
A1 Bryan Traynor
A1 Christopher E. Shaw
A1 David B. Goldstein
A1 Matthew B. Harms
A1 Mark J. Daly
A1 Benjamin M. Neale
YR 2018
UL http://biorxiv.org/content/early/2018/04/25/307835.abstract
AB To discover novel genetic risk factors underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry matched controls. We observed a significant excess of ultra-rare and rare protein-truncating variants (PTV) among ALS cases, which was primarily concentrated in constrained genes; however, a significant enrichment in PTVs does persist in the remaining exome. Through gene level analyses, known ALS genes, SOD1, NEK1, and FUS, were the most strongly associated with disease status. We also observed suggestive statistical evidence for multiple novel genes including DNAJC7, which is a highly constrained gene and a member of the heat shock protein family (HSP40). HSP40 proteins, along with HSP70 proteins, facilitate protein homeostasis, such as folding of newly synthesized polypeptides, and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of degraded proteins can occur leading to aberrant protein aggregation, one of the pathological hallmarks of neurodegeneration.