Associação de variantes do genoma mitocondrial à esclerose lateral amiotrófica e sua distribuição em haplogrupos
Arquivos
Data
2021-08-11
Autores
Campos, João Henrique Coelho 
Orientadores
Briones, Marcelo Ribeiro da Silva
Tipo
Tese de doutorado
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Resumo
A esclerose lateral amiotrófica (ELA) é uma doença progressiva, fatal, irreversível e incurável. É a terceira doença neurodegenerativa mais comum e a mais frequente entre as doenças dos neurônios motores que se iniciam na idade adulta. Embora existam formas familiares e esporádicas, estudos com gêmeos revelam que mesmo as formas esporádicas possuem um componente genético significativo. Até o momento, variantes em 37 genes nucleares foram associadas à ELA. Embora a disfunção mitocondrial tenha sido associada à doença, variantes nos genomas mitocondriais (mitogenomas) ainda não foram associadas à ELA. Neste estudo, realizamos uma análise de associação ampla do genoma (GWAS) em mitogenomas de 1.965 pacientes com ELA e 2.547 controles. Identificamos 51 variantes no mitogenoma com p-valor < 10-7, das quais 13 têm Odds Ratios (OR) >1 e 38 têm OR <1. A distribuição dessas variantes é consistentemente diferente nos haplogrupos mitocondriais. Os escores de risco poligênico (PRS) indicam que, devido a diferentes combinações de variantes com OR >1 e OR <1, cada haplogrupo pode ser considerado um fator de risco (por exemplo, haplogrupos K, M, V e parte do H) ou um fator de proteção (por exemplo, haplogrupos A, B, D e F). Além disso, o GWAS intra-haplogrupo revelou variantes únicas associadas à ELA nos haplogrupos L e U. Os escores de risco poligênico dos casos de início bulbar são mais altos em comparação com os de início apendicular, de membros e espinhal nos haplogrupos H e L. Este estudo sugere que as variantes no mitogenoma (SNVs) podem ser incluídas nos testes genéticos de rotina para ELA, e que a terapia de reposição mitocondrial possui uma base potencial para o tratamento da doença.
Amyotrophic Lateral Sclerosis (ALS) is a progressive, fatal, irreversible, and incurable neurodegenerative disease. Although both familial and sporadic forms of ALS are observed, twin studies have demonstrated a significant genetic component even in sporadic forms. To date, variants in 37 nuclear genes have been associated with ALS, whereas mitochondrial genomes (mitogenomes) have not yet been linked to the disease, despite the association of mitochondrial dysfunction with ALS. In this study, a genome-wide association study (GWAS) was conducted on the mitogenomes of 1,965 ALS patients and 2,547 controls. A total of 51 mitogenome variants with p-values <10-7 were identified, of which 13 had Odds Ratios (OR) >1, while 38 had OR <1. The distribution of these variants consistently differed across mitochondrial haplogroups. Polygenic Risk Scores (PRS) indicated that, due to different combinations of OR >1 and OR <1 variants, each haplogroup could be either a risk or protective factor for ALS. For example, haplogroups K, M, V, and partially H were considered risk factors, while haplogroups A, B, D, and F were protective factors. Furthermore, ALS-associated variants were revealed in haplogroups L and U in the intra-haplogroup GWAS. Notably, polygenic risk scores of bulbar onset cases were higher compared to appendicular, limb, and spinal onsets in haplogroups H and L. The findings suggest that mitogenome variants (SNVs) could be included in routine genetic testing for ALS, and that mitochondrial replacement therapy may have potential as an ALS treatment.
Amyotrophic Lateral Sclerosis (ALS) is a progressive, fatal, irreversible, and incurable neurodegenerative disease. Although both familial and sporadic forms of ALS are observed, twin studies have demonstrated a significant genetic component even in sporadic forms. To date, variants in 37 nuclear genes have been associated with ALS, whereas mitochondrial genomes (mitogenomes) have not yet been linked to the disease, despite the association of mitochondrial dysfunction with ALS. In this study, a genome-wide association study (GWAS) was conducted on the mitogenomes of 1,965 ALS patients and 2,547 controls. A total of 51 mitogenome variants with p-values <10-7 were identified, of which 13 had Odds Ratios (OR) >1, while 38 had OR <1. The distribution of these variants consistently differed across mitochondrial haplogroups. Polygenic Risk Scores (PRS) indicated that, due to different combinations of OR >1 and OR <1 variants, each haplogroup could be either a risk or protective factor for ALS. For example, haplogroups K, M, V, and partially H were considered risk factors, while haplogroups A, B, D, and F were protective factors. Furthermore, ALS-associated variants were revealed in haplogroups L and U in the intra-haplogroup GWAS. Notably, polygenic risk scores of bulbar onset cases were higher compared to appendicular, limb, and spinal onsets in haplogroups H and L. The findings suggest that mitogenome variants (SNVs) could be included in routine genetic testing for ALS, and that mitochondrial replacement therapy may have potential as an ALS treatment.
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Citação
CAMPOS, João Henrique Coelho. Associação de variantes do genoma mitocondrial à esclerose lateral amiotrófica e sua distribuição em haplogrupos. 2021. 418 f. Tese (Doutorado em Microbiologa e Imunologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP). São Paulo, 2021.