Mitochondrial genome variants associated with Amyotrophic Lateral Sclerosis and their haplogroup distribution

Abstract

AbstractIntroduction/AimsAmyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial disfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS.MethodsHere we conducted a genome wide association study (GWAS) in mitogenomes of 1,965 ALS patients and 2,547 controls to test the hypothesis that mitogenome variants are associated with ALS.ResultsWe identified 51 mitogenome variants withp-values <10−7of which 13 variants have odds ratios (OR)>1, in genesRNR1,ND1,CO1,CO3,ND5,ND6andCYB, while 38 variants have OR<1 in genesRNR1,RNA2,ND1,ND2,CO2,ATP8,ATP6,CO3,ND3,ND4,ND5,ND6andCYB. The frequencies of haplogroups H, U and L, the most frequent in our ALS dataset, are the same in different onset sites (bulbar, limb, spinal and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U.DiscussionOur study shows that mitogenome variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy would have a potential basis for ALS treatment.