Amyotrophic Lateral Sclerosis (ALS) is a progressive, fatal, and non-reversible disease. It is the third most common neurodegenerative disease and the most frequent, adult-onset, motor neuron disease. Although familial and sporadic forms are observed, twin studies 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 associated with ALS, variants in mitochondrial genomes (mitogenomes) have not yet been associated with ALS. Here we conducted a genome wide association study (GWAS) in mitogenomes of 1,965 ALS patients and 2,547 controls. We identified 51 mitogenome variants with p-values <10-7of 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 frequency of haplogroups H, U and L, the most frequent in our ALS dataset, in the most severe, bulbar onset, versus limb, spinal and axial onsets shows that the proportion of Bulbar onset is the same in these haplogroups as compared to the other onset sites. Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U. Our study suggests that mitogenome variants (SNVs) could be included in routine genetic testing for ALS and that mitochondrial replacement therapy would have a potential basis for ALS treatment.

The authors have declared no competing interest.

This work was supported by grants to M. R. S. B. (FAPESP 2014/25602-6, FAPESP 2013/07838-0 and CNPq 303912/2017-0) and NIH grants to J. R. B. (#). All NYGC ALS Consortium activities are supported by the ALS Association (ALSA, 19-SI-459) and the Tow Foundation. J.H.C. was supported by a PhD fellowship from CAPES, I.M.S. was supported by an MSc fellowship from CAPES.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ALS samples were collected and analyzed under the Pennsylvania State University - College of Medicine Internal Review Board (IRB) protocol PRAMS00040532 last reviewed and approved on May 10, 2018. The New York Genome Center (NYGC) ALS sequence data has been determined by the Internal Review Board (IRB) on 7/23/2015.

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All data produced in the present study are available upon reasonable request to the corresponding authors.