%0 Journal Article
%A Harvey, Calum
%A Weinreich, Marcel
%A Lee, James A K
%A Shaw, Allan C
%A Ferraiuolo, Laura
%A Mortiboys, Heather
%A Zhang, Sai
%A Hop, Paul J
%A Zwamborn, Ramona A J
%A van Eijk, Kristel
%A Julian, Thomas H
%A Moll, Tobias
%A Iacoangeli, Alfredo
%A Al Khleifat, Ahmad
%A Quinn, John P
%A Pfaff, Abigail L
%A Kõks, Sulev
%A Poulton, Joanna
%A Battle, Stephanie L
%A Arking, Dan E
%A Snyder, Michael P
%A Veldink, Jan H
%A Kenna, Kevin P
%A Shaw, Pamela J
%A Cooper-Knock, Johnathan
%T Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis.
%J Heliyon
%V 10
%N 3
%@ 2405-8440
%C London [u.a.]
%I Elsevier
%M DKFZ-2024-00284
%P e24975
%D 2024
%X Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38317984
%2 pmc:PMC10839612
%R 10.1016/j.heliyon.2024.e24975
%U https://inrepo02.dkfz.de/record/287630