title: Homozygosity mapping in an Irish ALS case-control cohort describes local demographic phenomena and points towards potential recessive risk loci.
abstract: 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.
authors.affiliation: Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, College Green, Dublin 2, Ireland. Electronic address: mclaugr@tcd.ie.
authors.forename: Russell L
authors.initials: RL
authors.lastname: McLaughlin
authors.affiliation: Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, College Green, Dublin 2, Ireland. Electronic address: kennak@tcd.ie.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Kenna
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland. Electronic address: vajdaa@tcd.ie.
authors.forename: Alice
authors.initials: A
authors.lastname: Vajda
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland. Electronic address: mark.heverin@tcd.ie.
authors.forename: Mark
authors.initials: M
authors.lastname: Heverin
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland. Electronic address: suabyrne@gmail.com.
authors.forename: Susan
authors.initials: S
authors.lastname: Byrne
authors.affiliation: Department of Neurology, Royal Victoria Hospital, Belfast, Northern Ireland, United Kingdom. Electronic address: donaghy1a@hotmail.com.
authors.forename: Colette G
authors.initials: CG
authors.lastname: Donaghy
authors.affiliation: Beaumont Hospital, Dublin 9, Ireland; Cork University Hospital, Cork, Ireland. Electronic address: scronin@rcsi.ie.
authors.forename: Simon
authors.initials: S
authors.lastname: Cronin
authors.affiliation: Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, College Green, Dublin 2, Ireland. Electronic address: dbradley@tcd.ie.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bradley
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland. Electronic address: hardimao@tcd.ie.
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D003710:Demography; D005260:Female; D005808:Genes, Recessive; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D007494:Ireland; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D044465:White People / Q000235:genetics
keywords: ALS; Amyotrophic lateral sclerosis; Irish population; Panmixia; Population density; ROH; Runs of homozyosity