Homozygosity analysis in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2 Mb were identified, and 3568 rare segments remained after filtering 'common' segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P=0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P=1 × 10(-5)), a greater proportion of cases harboured homozygosity (P=2 × 10(-5)), a longer average length of segment (P=1 × 10(-5)), a longer total genome coverage (P=1 × 10(-5)), and a higher rate of these segments overlapped with RefSeq gene regions (P=1 × 10(-5)), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9-4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS.