Analysis of FGGY as a risk factor for sporadic amyotrophic lateral sclerosis.

A genome-wide association study (GWAS) using pooled DNA samples from 386 sporadic ALS patients and 542 controls from the USA, identified genetic variation in FGGY (FLJ10986) as a risk factor, as well as 66 additional candidate SNPs. Considering the large number of hypotheses that are tested in GWAS, independent replication of associations is crucial for identifying true-positive genetic risk factors for disease. The primary aim of this study was to study the association between FGGY and sporadic ALS in large, homogeneous populations from northern Europe. Genotyping experiments were performed using Illumina Beadchips, Sequenom iPLEX assays and Taqman technology on large case-control series from The Netherlands, Belgium, Sweden and Ireland (total: 1883 sporadic ALS patients and 2063 controls). No significant association between sporadic ALS and the six previously reported associated SNPs in FGGY was observed: rs6700125 (p=0.56), rs6690993 (p=0.30), rs10493256 (p=0.68), rs6587852 (p=0.64), rs1470407 (p=0.28) and rs333662 (p=0.44). Screening of the additional candidate loci did not yield significant associations either, with the lowest p-value in joint analysis for rs7772593 (p=0.14). We concluded that common genetic variation in FGGY is not associated with susceptibility to sporadic ALS in genetically homogeneous populations from northern Europe

Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration.

Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P=1.96 x 10(-9)). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: -0.49, P=1.83 x 10(-12) (start codon morpholino) and -0.46, P=4.05 x 10(-9) (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P=0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS