Neurology -- Correspondence for Eerola et al., 61 (7) 1000-1002

Correspondence published:

Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD.: Daniel G Healy, Patrick Abou-Sleiman, Shushant Jain, Kourosh R . Ahmadi and Nicholas W. Wood (17 December 2003)

Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD. 17 December 2003

Daniel G Healy,
Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N3BG.
Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N3BG.,
Patrick Abou-Sleiman, Shushant Jain, Kourosh R . Ahmadi and Nicholas W. Wood
Send Correspondence to journal:
Re: Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD.

d.healy{at}ion.ucl.ac.uk Daniel G Healy, et al.

We read with interest the report by Eerola et al [1]that demonstrates lack of association between a DJ-1 promoter polymorphism and PD. The authors also claim that their “observations indicate strong linkage disequilibrium (LD) across the gene” and that they provide “compelling evidence that common variation within DJ-1 does not act as a risk factor for PD”. However, their evidence represents an oversimplification of LD architecture and its potential in common trait mapping.
This study assesses LD with three polymorphisms; two promoter polymorphisms separated by 28 base pairs and a polymorphism in intron 5. However these cover only the first eight kb of a 22 kb gene and therefore no attempt has been made to estimate the LD structure of almost two thirds of the DJ-1 gene.
When quantifying LD across a gene, it is widely accepted that r2 performs considerably better than D', as D' overestimates the strength of LD. [2] In this report D' and not r2 is utilized. Furthermore DJ-1 LD is estimated in an out-bred American population, but applied to a relatively homogeneous Finnish population. The minor allele frequencies at these loci are not provided, which if discordant between populations, would also result in an erroneous overestimation of the strength of LD.
The authors report a D' LD measure of 0.76 between alleles of the promoter and of intron 5. However contrary to what has been stated, this suggests considerable historical recombination between these loci, which represents the only portion of DJ-1 where LD was measured.
Finally, even if DJ-1, when fully evaluated, does have strong LD across it, the background haplotype diversity would also require assessment before concluding, as this report does, that “it is therefore unlikely that analysis of further polymorphisms would produce a positive association in this series”. One approach that does capture information from all common DJ-1 variation involves haplotype tagging. This strategy determines a subset of SNPs, known as tagging SNPs, that can be predicted to maintain a consistently high r2 value with all other common SNPs, thereby capturing haplotype diversity and indicating that these tags could be used in an association study with only moderate power loss relative to direct assays of all common SNPs. [3]
While this report has found no association between a promoter polymorphism and DJ-1, further work is required before making claims about the rest of this gene.
References
1.) Eerola J, Hernandez D, Launes J et al. Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD. Neurology. 2003; 61: 1000-1002.
2.) Wall JD, Pritchard JK. Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet. 2003; 4: 587-597.
3.) Weale ME, Depondt C, Macdonald SJ et al. Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping. Am J Hum Genet. 2003; 73: 551-565.