Is DNA methylation the key?

Very cool paper in PLoS Genetics this week reporting alterations in DNA methylation in PSP.  It’s from Giovanni Coppola’s lab at UCLA, with Yun Li as first author and collaborators from UCSF.  They used Illumina probes to profile DNA methylation genome-wide in WBCs.  The result was that in PSP, MAPT showed more methylation than controls or subjects with FTD.  But the same was true for three other genes near MAPT: KIAA1267, ARHGAP27 and DND1.  All lie within the H1 haplotype block, an inversion spanning 1.8 Mb and 48 genes at 17q21.31.

A new statistical technique called “causal inference” suggested that something in the H1 haplotype caused the differential methylation, which in turn caused the PSP phenotype.  They conclude that a quantitative trait locus for methylation exists within the H1 haplotype, but that differential methylation is a characteristic of H1 independent of the presence of PSP.

A supplemental experiment looking for differences in gene expression correlating with methylation changes came up empty, unfortunately.

So now we have evidence that the pathogenetic mechanism of the H1 haplotype is differential methylation of MAPT and/or nearby genes.  Work by others has suggested that H1 operates, rather, by increasing MAPT expression, but that observation is not consistently replicated.  Either way, we still have to explain what else is necessary to the etiology of PSP.  After all, H1 is present in 95% of subjects with PSP aut also in a majority of the rest of the population.

Do any geneticists out there have any special insights to share?

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