Avtor/Urednik		Rheenen, Wouter van; van der Spek, Rick A. A.; Bakker, Mark K.; Van Vugt, Joke J. F. A.; Hop, Paul J.; Rogelj, Boris; Koritnik, Blaž; Zidar, Janez; Ravnik-Glavač, Metka; Glavač, Damjan
Naslov		Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Tip		članek
Vol. in št.		Letnik 53, št. 12
Leto izdaje		2021
Obseg		str. 1636‐1648
ISSN		1061-4036 - Nature genetics
Jezik		eng
Abstrakt		Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenera- tive spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
Proste vsebinske oznake		amiotrofična lateralna skleroza nevronsko specifična biologija genetska arhitektura amyotrophic lateral sclerosis neuron-specific biology genetic architectures