Analysis of European mitochondrial haplogroups with Alzheimer disease risk

[Edward]

Van der Walt, J. M., Dementieva, Y. a, Martin, E. R., Scott, W. K., Nicodemus, K. K., Kroner, C. C., … Pericak-Vance, M. a. (2004). Analysis of European mitochondrial haplogroups with Alzheimer disease risk[/url]. Neuroscience Letters, 365(1), 28–32. doi:10.1016/j.neulet.2004.04.051

"We examined the association of mtDNA variation with Alzheimer disease (AD) risk in Caucasians (989 cases and 328 controls) testing the effect of individual haplogroups and single nucleotide polymorphisms (SNPs). Logistic regression analyses were used to assess risk of haplogroups and SNPs with AD in both main effects and interaction models. Males classified as haplogroup U showed an increase in risk (OR = 2.30; 95% CI, 1.03-5.11; P = 0.04) of AD relative to the most common haplogroup H, while females demonstrated a significant decrease in risk with haplogroup U (OR = 0.44 ; 95% CI, 0.24-0.80; P = 0.007). Our results were independent of APOE genotype, demonstrating that the effect of mt variation is not confounded by APOE4 carrier status. We suggest that variations within haplogroup U may be involved in AD expression in combination with environmental exposures or nuclear proteins other than APOE."

Moderator note - I deleted the link to the Dropbox-hosted paper because our copyright infringement policy prohibits it. Members in jurisdictions for which access to Sci-Hub is legal may want to search for the paper at sci-hub.bz.

[circular]

Thanks! I have wondered about this for a long time! Would love to see the whole study and how other mtDNA gaps fared.

[GenePoole0304]

Got enough to start exploring

http://familypedia.wikia.com/wiki/Haplo ... 28mtDNA%29

[Russ]

Very intrigued by this line of thinking. Makes sense that if mitochondrial disfunction is a possible cause that mitochondrial DNA might have an effect. Checked 23andMe and my Dad (APOE 3/4) who suffered from another form of neurodegeneration was indeed a U5. I am an X2 which is much rarer but is correlated with reduced risk (Table 2) but with low confidence (p=.54).

Uploading paper here for others...

Moderator note - I deleted the attached paper (doi:10.1016/j.neulet.2004.04.051) because our copyright infringement policy prohibits it. Members in jurisdictions for which access to Sci-Hub is legal may want to search for the paper there.

[rep]

I cannot view the paper Russ linked. It says I do not have the permissions required. Can anyone else view it? I would love to read it.

[rep]

Never mind. I found the full paper through Google! Thanks anyway.

[rep]

Helpful Student's Guide to Statistics - useful for interpreting studies such as the one above

http://www.students4bestevidence.net/a- ... -tutorial/

[rep]

What are we to believe? One says one thing, another says another.

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Int J Alzheimers Dis. 2011; 2011: 709061.
Published online Feb 22, 2011. doi: 10.4061/2011/709061
PMCID: PMC3056451
May “Mitochondrial Eve” and Mitochondrial Haplogroups Play a Role in Neurodegeneration and Alzheimer's Disease?

Elena Caldarazzo Ienco,1 Costanza Simoncini,1 Daniele Orsucci,1 Loredana Petrucci,1 Massimiliano Filosto,2 Michelangelo Mancuso,1,* and Gabriele Siciliano1

By studying an Italian sample of subjects, Carrieri et al. [77] hypothesized that K and U haplogroups may act by neutralizing the effect of the major AD risk factor ApoE ε4 allele. However, this association was not confirmed recently by a collaborative study performed by Elson et al. [78], in which the authors analyzed the complete mtDNA coding region sequences from more than 270 AD patients and normal controls. The authors described no statistically significant association between haplogroup and disease status. They also observed that for both synonymous and nonsilent changes, the overall numbers of nucleotide substitutions were the same for the AD and control sequences.

Regarding our experience, in our laboratory we did not find any evidence for an etiological role of haplogroups in AD risk [56]. We studied the frequency of the European mtDNA haplogroups in a clinically well-defined group of 209 unrelated patients and 191 controls, both with clear Tuscan origin (in order to minimize the risk of false associations between gene markers and disease). The frequency of haplogroups was not significantly different between the two groups. Furthermore, there was no significant difference between genders as far as mtDNA haplogroups distribution in both AD patients and control groups is concerned.

[rep]

And then there is this one:

Neurology. Apr 3, 2012; 78(14): 1038–1042.
doi: 10.1212/WNL.0b013e31824e8f1d
PMCID: PMC3317529
No consistent evidence for association between mtDNA variants and Alzheimer disease

G. Hudson, PhD,* R. Sims, PhD,* D. Harold, PhD, J. Chapman, PhD, P. Hollingworth, PhD, A. Gerrish, PhD, G. Russo, PhD, M. Hamshere, PhD, V. Moskvina, PhD, N. Jones, BSc, C. Thomas, BSc, A. Stretton, BSc, P.A. Holmans, PhD, M.C. O'Donovan, PhD, M.J. Owen, PhD, J. Williams, PhD,‡ and P.F. Chinnery, PhD, FMedSci‡, On behalf of the GERAD1 Consortium

Among other things, they state:

Our findings fail to replicate previous studies reporting associations with either single genetic variants or specific mtDNA haplogroups.

How can we explain the previous findings? The strict maternal inheritance of mammalian mtDNA and the associated lack of intermolecular recombination renders mtDNA genetic association studies particularly vulnerable to a population stratification effect.11 This increases the chance of detecting a false-positive disease association.12 In addition, given that the size of any genetic effect is likely to be small, a reliable association study requires a very large sample size to deliver a consistent result.13

Although our findings show that the evidence linking inherited mtDNA variants to AD is not compelling, the relative contribution of specific mtDNA variants could vary in different ethnic groups, possibly through an interaction with environmental factors and different nuclear genes.14 In practice, this means that the specific mtDNA variants that fail to show an association with disease in this study could be associated with disease in a different ethnic population.

[circular]

Rep, I think you answered your own question:

"How can we explain the previous findings? The strict maternal inheritance of mammalian mtDNA and the associated lack of intermolecular recombination renders mtDNA genetic association studies particularly vulnerable to a population stratification effect.11 This increases the chance of detecting a false-positive disease association.12 In addition, given that the size of any genetic effect is likely to be small, a reliable association study requires a very large sample size to deliver a consistent result.13"

I suspect if there's any medically relevant connection it will take a massive dataset and very strong study design. I found it interesting, while apparently totally meaningless in the context these current studies, to learn that K is an offshoot of U which showed an association between AD and men with U mtDNA. The AD in my family (women) is mtDNA haplogroup K.