Association studies on human mitochondrial DNA: Methodological aspects and results in the most common age-related diseases

Raule, Nicola; Sevini, Federica; Santoro, Aurelia; Altilia, Serena; Franceschi, Claudio

doi:10.1016/j.mito.2006.11.013

Cited by 48 publications

(48 citation statements)

References 94 publications

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“…This is the first reported association with a major haplogroup. Some earlier studies reported no associations with major haplogroups, but suffered from small sample sizes, particularly for certain haplogroups [18]. The association with haplogroup J was supported by a study in a white Brazilian population, which also found an association with haplogroup T [19].…”

Section: Introductionmentioning

confidence: 79%

Family-based mitochondrial association study of traits related to type 2 diabetes and the metabolic syndrome in adolescents

et al. 2009

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Aims/hypothesis There has been much focus on the potential role of mitochondria in the aetiology of type 2 diabetes and the metabolic syndrome, and many casecontrol mitochondrial association studies have been undertaken for these conditions. We tested for a potential association between common mitochondrial variants and a number of quantitative traits related to type 2 diabetes in a large sample of >2,000 healthy Australian adolescent twins and their siblings, many of whom were measured on more than one occasion. Methods To the best of our knowledge, this is the first mitochondrial association study of quantitative traits undertaken using family data. The maternal inheritance pattern of mitochondria means established association methodologies are unsuitable for analysis of mitochondrial data in families. We present a methodology, implemented in the freely available program Sib-Pair for performing such an analysis.Results Despite our study having the power to detect variants with modest effects on these phenotypes, only one significant association was found after correction for multiple testing in any of four age groups. This was for mt14365 with triacylglycerol levels (unadjusted p=0.0006). This association was not replicated in other age groups. Conclusions/interpretation We find little evidence in our sample to suggest that common European mitochondrial variants contribute to variation in quantitative phenotypes related to diabetes. Only one variant showed a significant association in our sample, and this association will need to be replicated in a larger cohort. Such replication studies or future meta-analyses may reveal more subtle effects that could not be detected here because of limitations of sample size.

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Section: Introductionmentioning

confidence: 79%

Family-based mitochondrial association study of traits related to type 2 diabetes and the metabolic syndrome in adolescents

et al. 2009

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“…More than 90% of European mtDNAs belong to nine haplogroups (H, V, U, K, J, T, W, I and X), which are highly specific for Western Eurasia [20]. Specific mtHgs might reflect functional differences in energy metabolism and were therefore linked with human diseases like neurodegenerative disorders [21] or cancer [22]. Polymorphisms in mtDNA might also represent modifier factors as has been shown in Leber's hereditary optic neuropathy (LHON) where mtHgs contribute to the phenotypic expression of mtDNA mutations [23-25].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial haplogroup U is associated with a reduced risk to develop exfoliation glaucoma in the German population

Wolf

Gramer²,

Müller‐Myhsok

et al. 2010

BMC Genet

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BackgroundVarious lines of evidence demonstrate the involvement of mitochondrial dysfunction in the pathogenesis of glaucoma. Therefore, mitochondrial DNA is a promising candidate for genetic susceptibility studies on glaucoma. To test the hypothesis that mitochondrial haplogroups influence the risk to develop glaucoma, we genotyped 12 single-nucleotide polymorphisms that define the European mitochondrial DNA haplogroups in healthy controls and two German patient cohorts with either exfoliation glaucoma or the normal tension subgroup of primary open angle glaucoma.ResultsMitochondrial haplogroup U was significantly under-represented in patients with exfoliation glaucoma (8.3% compared with 18.9% in controls; p = 0.004).ConclusionsPeople with haplogroup U have a lower risk to develop exfoliation glaucoma. Our results substantiate the suggestion that mitochondrial alterations have an impact on the etiology of glaucoma.

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“…Previous conflicting studies of disease associations with mtDNA have been suggested to be the result of insufficient power 48 , insufficient stratification respect to sex, age, geographical background 49 or population admixture 50 , or the use of small areas of recruitment risking "occult" founder effects 51 . The fact that careful control, as here, of these factors and the 2GLD, results in none of eight previously SZ associated mtDNA SNPs being associated with SZ in the very large Danish iPSYCH cohort, suggests that previously reported associations could indeed be spurious findings due to cryptic population stratification.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

Hagen

Gonçalves

Hedley

et al. 2017

Preprint

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Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. A reanalysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 normal Danes and 2,538 schizophrenia patients, revealed marked inter-allelic differences in haplogroup affiliation and nuclear ancestry, genogeophraphic affinity (GGA). This bi-genomic linkage disequilibrium (2GLD) could entail population stratification. Only two mitochondrial SNPs, m.15043A and m.15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation. The extensive 2GLD documented is a major concern when interpreting historic as well as designing future mtDNA association studies.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/149070 doi: bioRxiv preprint first posted online 3 Genetic variants in mitochondrial DNA (mtDNA) -and in nuclear genes coding for mitochondrial function -have been associated with disease 1-3 . More than 300 variants 4,5 in mtDNA and genes involved in mitochondrial function 6 have been reported to cause mitochondrial disease which is clinically characterised by complex metabolic, neurological, muscular and psychiatric symptoms 7,8 .SNPs in mtDNA and mitochondrial haplogroups (mtDNA hgs), which are evolutionarily fixed SNP sets with a characteristic geographical distribution, have been proposed as potential disease modifiers 8 . This has been reported in neurological degenerative diseases such as Alzheimer's disease 9-12 and Parkinson's disease 12-14 , metabolic diseases and cancers 15 , as well as psychiatric diseases, notably schizophrenia (SZ) and bipolar disease [16][17][18] .Association studies of mtDNA variants and disease have been difficult to replicate 8 . However, the definition of a methodological paradigm for association studies with mtDNA variants 19 implicitly assumes that mtDNA variants are independent of the nuclear genome. In a recent Danish study on mtDNA haplogroups and their nuclear ancestry or nuclear genogeographical affinity (GGA), we demonstrated a marked difference in nuclear ancestry between individual haplogroups 20 . This means that mtDNA hgs entail population stratification also at the level of gDNA. The effect of such a stratification on disease association, will depend on the admixture structure of the particular population, the population history, epidemiology and genetic epidemiology of the disease, as well as the number of persons included in the study. The extensive fine-scale heterogeneity of gDNA and significant admixture documented in the UK 21 and Europe 22 further increase the risk of spurious false positive associations, if the mtDNA/gDNA interaction is not corrected phenomenon for in association studies.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The co...

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Association studies on human mitochondrial DNA: Methodological aspects and results in the most common age-related diseases

Cited by 48 publications

References 94 publications

Family-based mitochondrial association study of traits related to type 2 diabetes and the metabolic syndrome in adolescents

Family-based mitochondrial association study of traits related to type 2 diabetes and the metabolic syndrome in adolescents

Mitochondrial haplogroup U is associated with a reduced risk to develop exfoliation glaucoma in the German population

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

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