McLaughlin Russell L, Kenna Kevin P, Vajda Alice, Heverin Mark, Byrne Susan, Donaghy Colette G, Cronin Simon, Bradley Daniel G, Hardiman Orla
Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, College Green, Dublin 2, Ireland.
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.
Genomics. 2015 Apr;105(4):237-41. doi: 10.1016/j.ygeno.2015.01.002. Epub 2015 Jan 23.
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.
纯合子连续区域在欧洲人群中很常见，表明存在近亲通婚、有限的种群规模以及隐性遗传性状。在此，我们在一个爱尔兰肌萎缩侧索硬化症（ALS）病例对照队列中绘制了纯合子连续区域（ROH），ALS是一种具有高遗传性但遗传病因仅部分明确的毁灭性神经系统疾病。我们将爱尔兰队列中的纯合性程度与一个大型英国队列进行比较，观察到爱尔兰人群中的ROH比英国人群中的更长且更频繁，并且ROH的程度与爱尔兰岛内的人口统计学因素相关。与人群匹配的对照相比，ALS病例中的ROH也更长且更频繁，这支持了隐性遗传位点在ALS中起致病作用的假设。比较病例和对照之间的纯合单倍型揭示了几个潜在的ALS隐性风险位点，包括一个跨越ARHGEF1的基因组区间，ARHGEF1是一个引人注目的ALS候选基因。
