Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease.
BACKGROUND
Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD.


RESULTS
We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR=1.85, 95% CI:1.04-3.23) in particular for females (OR=2.19, 95% CI:1.06-4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p=0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p=0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls.


CONCLUSIONS
Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD.
Santoro
Aurelia
A
Department of Experimental Pathology, University of Bologna, Bologna, Italy. aurelia.santoro@unibo.it
Balbi
Valentina
V
Balducci
Elisa
E
Pirazzini
Chiara
C
Rosini
Francesca
F
Tavano
Francesca
F
Achilli
Alessandro
A
Siviero
Paola
P
Minicuci
Nadia
N
Bellavista
Elena
E
Mishto
Michele
M
Salvioli
Stefano
S
Marchegiani
Francesca
F
Cardelli
Maurizio
M
Olivieri
Fabiola
F
Nacmias
Benedetta
B
Chiamenti
Andrea Maria
AM
Benussi
Luisa
L
Ghidoni
Roberta
R
Rose
Giuseppina
G
Gabelli
Carlo
C
Binetti
Giuliano
G
Sorbi
Sandro
S
Crepaldi
Gaetano
G
Passarino
Giuseppe
G
Torroni
Antonio
A
Franceschi
Claudio
C
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010802:Phylogeny; D011110:Polymorphism, Genetic
D004272:DNA, Mitochondrial