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  1. Zhongbo Chen,
  2. Kuang Lin,
  3. Aleksey Shatunov,
  4. Ashley Jones,
  5. Ammar Al-Chalabi
  1. Department of Clinical Neuroscience, IPPN, King's College London


Background Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. We examined the phylogenetics of ALS-susceptibility genes from our previously-published genome-wide association study (GWAS).

Methods We examined the association between ALS-susceptibility genes and hybridisation from the Neanderthal genome using a modified gene set enrichment analysis (GSEA). These gene sets comprise thirteen candidate regions for Neanderthal to non-African human gene flow [UCSC Genome Browser]. We ranked the ascending p-values of 442,057 GWAS SNPs and simulated the distribution 100,000 times. The resulting empirical p-value, comparing observed with expected mean rank, identified which gene sets are over-represented at the top of the rank list. Bonferroni corrections for multiple testing were applied.

Results 6,402 imputed GWAS SNPs fell into the thirteen gene sets. We found that the regions on chromosomes 6 and 9 accrued the lowest observed mean ranks (8,594 and 7,096 respectively) and were not different from expected mean ranks after simulation for those regions – empirical p-values before Bonferroni correction were 0.086 for chromosome 6 and 0.071 for chromosome 9.

Discussion Using GSEA to evaluate European ALS GWAS data in the context of pre-defined gene sets refutes the theory that ALS-susceptibility loci may have arisen from Neanderthal to non-African modern human gene flow.

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