Mitochondrial DNA haplogroups and amyotrophic lateral sclerosis

Mitochondrial dysfunction has been implicated in the pathophysiology of sporadic amyotrophic lateral sclerosis (ALS). One group [1] (but not others [2]) reported deficient mitochondrial respiration in ALS cybrids when compared to controls sharing the same nuclear background but containing different mtDNA, suggesting that inherited genetic variants of mtDNA contribute to the pathophysiology of ALS. In keeping with this, mtDNA haplogroup I was significantly more common in 222 Italian ALS patients than in 151 control subjects [3]. We sought to confirm these findings in a larger UK cohort.

We studied three groups. Group 1: 102 neuropathologically confirmed cases of ALS and 179 controls confirmed at autopsy. Group 2: 402 cases of definite or probable ALS cases according to El Escorial criteria and 344 sequential live births from the same geographic region. Group 3: 493 UK population controls (UK MRC 1958 cohort).

There was no difference in the overall mtDNA haplogroup distribution between the neuropathologically proven cases of ALS and controls (P = 0.0629, Table 1). Fisher’s exact test for the individual haplogroups revealed a higher frequency of haplogroup V in the ALS cases compared to controls (P = 0.02), which did not reach statistical significance after Bonferroni correction for the multiple haplogroups under comparison (P = 0.22). Whilst this study was adequately powered to exclude a major haplogroup effect, there was limited power to detect a disease association with the less common haplogroups, including haplogroup I. We therefore compared a larger independent group of ALS cases to controls (group 2). Again, there was no significant difference in the overall haplogroup distribution. Fisher’s exact test did not reveal a significant association between haplogroup V (P = 0.84) and haplogroup I (P = 0.63), but the frequency of haplogroup W was significantly less in the ALS cases than in controls (P = 0.04).