Homozygosity mapping in an Irish ALS case-control cohort describes local demographic phenomena and points towards potential recessive risk loci

•Runs of homozygoisty (ROHs) mapped in Irish ALS case-control cohort•ROHs are longer and more frequent in Irish individuals than in British.•ROHs are correlated with local population density and ancestral mobility.•ROHs are longer and more frequent in ALS cases than controls.•Matching homozygous haplotypes reveals several candidate recessive genes.

Runs of homozygosity are common in European populations and are indicative of consanguinity, restricted population size and recessively inherited traits. Here, we map runs of homozygosity (ROHs) in an Irish case-control cohort for amyotrophic lateral sclerosis (ALS), a devastating neurological condition with high heritability yet only partially established genetic cause. We compare the extent of homozygosity in the Irish cohort with a large British cohort and observe that ROHs are longer and more frequent in the Irish population than in the British, and that extent of ROHs is correlated with demographic factors within the island of Ireland. ROHs are also longer and more frequent in ALS cases compared to population-matched controls, supporting the hypothesis that recessively inherited loci play a pathogenic role in ALS. Comparing homozygous haplotypes between cases and controls reveals several potential recessive risk loci for ALS, including a genomic interval spanning ARHGEF1, a compelling ALS candidate gene.