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Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.

Author information

Affiliations

  • 1. Center for Medical Bioinformatics, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, Brazil.
      Authors
    • Briones MRS 1
    • Antoneli FM 1
    (2 authors)
  • 2. Graduate Program in Microbiology and Immunology, Federal University of São Paulo, São Paulo, São Paulo, Brazil.
      Authors
    • Campos JH 2
    • Santos IM 2
    (2 authors)
  • 3. Department of Neurology and Neurosurgery, Federal University of São Paulo, São Paulo, São Paulo, Brazil.
      Authors
    • Ferreira RC 3
    (1 author)
  • 4. Department of Biochemistry, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
      Authors
    • Schneper L 4
    • Broach JR 4
    (2 authors)

ORCIDs linked to this article

Show all (7)

Muscle & Nerve, 09 Aug 2024, 70(4):862-872
https://doi.org/10.1002/mus.28230 PMID: 39126144 

This article is based on a previously available preprint.
Free full text available after 01 Oct 2025

Abstract 

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 dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS.

Methods

We conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls.

Results

We identified 51 mitogenome variants with p values <10-7, of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had 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 data set, were 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 single nucleotide 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 has the potential to serve as a basis for ALS treatment.

Full text links 

Read article at publisher's site: https://doi.org/10.1002/mus.28230

References 

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    Funding 

    Funders who supported this work.

    ALS Association (2)

    CAPES

      CNPq (1)

      Conselho Nacional de Desenvolvimento Científico e Tecnológico (1)

      Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

        FAPESP (2)

        Fundação de Amparo à Pesquisa do Estado de São Paulo (2)

        NIH

          NLM NIH HHS (1)

          National Institutes of Health

            Tow Foundation