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

Introduction/Aims Amyotrophic 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. Methods Here 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. Results We identified 51 mitogenome variants with p -values <10 −7 of which 13 variants have odds ratios (OR)>1, in genes RNR1 , ND1 , CO1 , CO3 , ND5 , ND6 and CYB , while 38 variants have OR<1 in genes RNR1 , RNA2 , ND1 , ND2 , CO2 , ATP8 , ATP6 , CO3 , ND3 , ND4 , ND5 , ND6 and CYB . 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. Discussion Our 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.