Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis

Abstract

We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons

“…Of interest, UNC13A is the human orthologue of C. elegans unc-13, and UNC13A has recently been identified as a modifier disease progression in ALS patients [32][33][34] . Thus, we hypothesized that signalling from the motor neurons via unc-13 and unc-31 may affect the toxicity of mutant ALS proteins.…”

“…unc-13 is evolutionarily conserved and the human orthologue UNC13A also has roles in the regulation of neurotransmitter release at neuromuscular junctions 47 . Directly relevant to ALS, several research groups have uncovered UNC13A as a potential susceptibility gene for ALS [32][33][34]48 . Thus, UNC13A may be a modifier of disease survival and could be a target for therapeutic development.…”

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

“…5,6 Genome-wide association studies in sporadic and familial ALS demonstrated highly significant association with single-nucleotide polymorphisms (SNPs) across a 170-Kb region at 9p21.2. [7][8][9][10][11] A massive GGGGCC hexanucleotide repeat expansion mutation (HREM) has recently been identified within intron 1 of C9ORF72 as the pathogenic mutation responsible for familial and sporadic ALS and FTD in these cases. 12,13 Here we describe HREM mutation frequencies in ALS in five European populations.…”

Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes

“…Thoracic Transcription factor for corticofugal neuron subtype development (Daoud, et al, 2011,Lai, et al, 2008 VPS54 Thoracic Retrograde transport of proteins from prevacoules to late Golgi (Meisler, et al, 2008) ZFP64 Thoracic May be involved in transcriptional regulation (Schymick, et al, 2007) DCTN1 Lumbar Endoplasmic-reticulum-to-Golgi transport, and axonogenesis (Munch, et al, 2004,Puls, et al, 2003 PON1 Lumbar Hydrolyses the toxic metabolites of organophosphorus Insecticides (Saeed, et al, 2006) PVR Lumbar Transmembrane glycoprotein from the immunoglobulin superfamily (Saunderson, et al, 2004) SLC1A2 Lumbar Transports glutamate from the synaptic extracellular space (Lin, et al, 1998,Meyer, et al, 1999 UNC13A Lumbar Vesicle maturation during exocytosis (Chiò, et al, 2009,Daoud, et al, 2010,Shatunov, et al, 2010,van Es, et al, 2009 …”