Evidence for Sub-Haplogroup H5 of Mitochondrial DNA as a Risk Factor for Late Onset Alzheimer's Disease

Santoro, Aurelia; Balbi, Valentina; Balducci, E.; Pirazzini, Chiara; Rosini, Francesca; Tavano, Francesca; Achilli, Alessandro; Siviero, Paola; Minicuci, Nadia; Bellavista, Elena; Mishto, Michele; Salvioli, Stefano; Marchegiani, Francesca; Cardelli, Maurizio; Olivieri, Fabiola; Nacmias, Benedetta; Chiamenti, Andrea Maria; Benussi, Luisa; Ghidoni, Roberta; Rose, Giuseppina; Gabelli, C.; Binetti, Giuliano; Sorbi, Sandro; Crepaldi, Gaetano; Passarino, Giuseppe; Torroni, Antonio; Franceschi, Claudio

doi:10.1371/journal.pone.0012037

Cited by 110 publications

(74 citation statements)

References 54 publications

(83 reference statements)

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“…Haplogroup distribution analysis did not reveal a disease susceptibility to mt-hgs; all major European mt-hgs were represented in the sample and no significant differences in their overall distribution were observed when compared with those reported for three Italian control samples (Table 1). [11][12][13] The frequencies of each mt-hg in patients and controls were then analyzed by applying the Bonferroni's adjustment for multiple comparisons and no statistically significant differences were observed.…”

Section: Resultsmentioning

confidence: 99%

Analysis of complete mitochondrial genomes of patients with schizophrenia and bipolar disorder

et al. 2011

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The present study aims at investigating the association between common and rare variants of mitochondrial DNA (mtDNA), and increased risk of schizophrenia (SZ) and bipolar disorder (BPD) in a cohort of patients originating from the same Italian population. The distribution of the major European mtDNA haplogroups was determined in 89 patients and their frequencies did not significantly differ from those observed in the Italian population. Moreover, 27 patients with high probability of having inherited the disease from the maternal side were selected for whole mitochondrial genome sequencing to investigate the possible presence of causative point mutations. Overall, 213 known variants and 2 novel changes were identified, but none of them was predicted to have functional effects. Hence, none of the sequence changes we found in our sample could explain the maternal component of SZ and BPD predisposition. Keywords: bipolar disorder; mtDNA variants; schizophrenia INTRODUCTION Schizophrenia (SZ) and bipolar disorder (BPD) are among the top ten causes of disability worldwide. 1 Despite extensive genetic and pharmacological studies, the etiology and pathophysiology of these mental disorders are still unknown, and the nuclear susceptibility loci identified so far can explain only a small fraction of the genetic component of these diseases. 2 The growing body of observations published in the last decade points to the involvement of mitochondria in the pathophysiology of psychiatric disorders, including SZ and BPD. 3 Several genetic studies reported association between these diseases and common mitochondrial DNA (mtDNA) polymorphisms defining ethnic-specific mitochondrial haplogroups. [4][5] Other analyses found new rare variants with a putative functional effect 6 and a global excess of synonymous substitutions in the dorsolateral prefrontal cortex of SZ patients. 7 Despite the great interest of these findings, the role of mtDNA in the pathogenesis of SZ/BDP remains unclear.The present study aims at investigating the association between common and rare variants of mtDNA and the increased risk of SZ/ BPD in a sample of patients originating from the same Italian population.

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Section: Resultsmentioning

confidence: 99%

Analysis of complete mitochondrial genomes of patients with schizophrenia and bipolar disorder

et al. 2011

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“…Mitochondrial haplogroups defined by common polymorphisms are known to be associated with the risk of a variety of diseases, including Leber's hereditary optic neuropathy (27), Alzheimer's disease (28), cardiovascular disease (29) and T2DM (14)(15)(16)(17). It was hypothesized that mitochondrial haplogroups confer the genetic predisposition to develop T2DM when an individual is exposed continuously to environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Effects of mitochondrial haplogroup N9a on type 2 diabetes mellitus and its associated complications

Niu

Zhang

Wang

et al. 2015

Experimental and Therapeutic Medicine

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Abstract.A case-control study was conducted with the aim of identifying the predominant haplogroups associated with type 2 diabetes mellitus (T2DM) and its complications. In addition, the role of N9a in T2DM risk and complications was analyzed. Sequencing of the entire mitochondrial DNA was conducted in 235 patients and 244 controls in cohort 1, and six haplogroups (F, B4, D4, D5, M8a and N9a) associated with T2DM were classified. The frequency of N9a was further determined in cohort 2 (440 patients and 244 controls) and examined in two combined cohorts, including 675 patients with T2DM and 649 non-diabetic controls. Multivariate logistic regression analysis and association analysis were performed to investigate the association between genotypes, T2DM and diabetic nephropathy. M8a [P=0.011; odds ratio (OR), 3.49; 95% confidence interval (CI), 1.26-9.69] and haplogroup N9a (P=0.023; OR, 2.60; 95% CI, 1.11-6.05) were associated with an increased risk of T2DM. The frequency of N9a was higher in T2DM patients compared with that in the controls (6.2% vs. 4.3%) and associated with a mild risk (P=0.10; OR, 1.51; 95% CI, 0.92-2.49). N9a was significantly associated with an increased risk of diabetic nephropathy (P=0.024; OR, 2.15; 95% CI, 1

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“…Increased prevalence of mitochondrial haplogroups H and T has been noted in individuals affected with late-onset sporadic AD [100][101][102]. Specifically, sub-haplogroup H5 (common in Southeast Europe) was associated with > 2-fold increased risk for AD in European populations independently of APOE4 status [101]. Concomitant carriership of haplogroup H is associated with earlier onset of neurological symptoms in carriers of the CAG repeat that is expanded in Huntington's disease [103].…”

Section: Breath Of Life (And Death) -Increased Atp Production Is Assomentioning

confidence: 99%

“…In carriers of haplogroup H the risk for some of the complications of diabetes type 2 (diabetic retinopathy and neuropathy) is significantly increased [99]. Increased prevalence of mitochondrial haplogroups H and T has been noted in individuals affected with late-onset sporadic AD [100][101][102]. Specifically, sub-haplogroup H5 (common in Southeast Europe) was associated with > 2-fold increased risk for AD in European populations independently of APOE4 status [101].…”

Section: Breath Of Life (And Death) -Increased Atp Production Is Assomentioning

confidence: 99%

APOE4, oxidative stress and decreased repair capacity - a no-brainer. Faulty lipid metabolism and increased levels of oxidative damage may be risk factors in the pathogenesis of late-onset dementia

Nayyar

Chakalova²

2015

Biodiscovery

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Keywords: Late-onset disease, dementia, APOE, mitochondrial DNA, individual repair capacity.Abbreviations: AD -Alzheimer's disease, APOE -apolipoprotein E, ATP -adenosine triphosphate, BER -base excision repair, CAA -cerebral amyloid angiopathy, CNS -central nervous system, FTD -frontotemporal dementia, HD -Huntington's disease, IMT -intimamedia thickness, IRC -individual repair capacity, MCI -mild cognitive impairment, MND -motor neuron disease, NER -nucleotide excision repair, NMDA -N-methyl-D-aspartate, PD -Parkinson's disease, PDAPP -PDGF promoter expressing amyloid precursor protein, ROS -reactive oxygen species; SOD -superoxide dismutase, VCI -vascular cognitive decline.* Corresponding Authors: Ashima Nayyar, email: a.nayyar@abertay.ac.uk Conflict of Interests:No potential conflict of interest was disclosed by any of the authors. AbstractDementia is very common in the elderly and its incidence increases in an age-dependent fashion. Alzheimer's disease and vascular cognitive decline are the most common cases of dementia in the elderly. Amyloid burden and increased levels of oxidative damage have been implicated to play significant roles in the pathogenesis of late-onset dementia. In this paper we propose that there are three major genetic factors that may modulate the risk for dementia in later life: carriership of APOE variant alleles, carriership of mitochondrial DNA of haplogroups associated with ineffective oxygen utilisation (specifically, haplogroup H) and carriership of genetic polymorphisms conferring subtly deficient DNA repair. All three factors are quite common in the European populations. Each of these three factors may not have significant effect on the phenotype when taken separately, but when combined in the same genotype, the effects may be cumulative. Further studies are needed in order to elucidate the genotype-phenotype relationships and provide a reliable basis for assessment of the genetic risk for sporadic late-onset dementia. Lifestyle alterations and therapies targeted at decreasing the oxidative burden to aging cells and tissues may decrease the risk for neurological decline in later life.

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Evidence for Sub-Haplogroup H5 of Mitochondrial DNA as a Risk Factor for Late Onset Alzheimer's Disease

Cited by 110 publications

References 54 publications

Analysis of complete mitochondrial genomes of patients with schizophrenia and bipolar disorder

Analysis of complete mitochondrial genomes of patients with schizophrenia and bipolar disorder

Effects of mitochondrial haplogroup N9a on type 2 diabetes mellitus and its associated complications

APOE4, oxidative stress and decreased repair capacity - a no-brainer. Faulty lipid metabolism and increased levels of oxidative damage may be risk factors in the pathogenesis of late-onset dementia

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