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.

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.

We identified 51 mitogenome variants with p-values 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.

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. Competing Interest Statement The authors have declared no competing interest. Funding Statement 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. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes None of the authors has any conflict of interest to disclose. Minor formatting of the abstract and correct a figure number in the Discussion. DATA AVAILABILITY STATEMENT All data produced in the present study are available upon reasonable request to the corresponding authors.