This week, our knowledge of the genetics of PSP has more than doubled.  First, as usual, some background:

Like many other complex conditions like atherosclerosis, schizophrenia and most cancers, PSP does run in families a bit more often than expected by chance.  But as in those diseases, the familial tendency is too weak to produce the classic dominant or recessive pattern associated with a single, strongly-acting gene variant as in Huntington’s, Tay-Sachs or sickle cell anemia. Besides, adding up the risks from the known PSP-related genes wouldn’t explain the incidence of the disease in the population, rare though it is.  That has prompted the theory that some unidentified external exposure or experience also has to play a role. 

Over the past 25 years or so, a number of gene variants have been found to confer slight risks for developing PSP.  The first-discovered and still the most important, called the “H1 haplotype,” is a complex set of variants in region of chromosome 17 that includes MAPT, the gene encoding the tau protein. Another four variants on other chromosomes were published in 2011 by CurePSP’s PSP Genetics Consortium. 

In the years since, nine other variants were added piecemeal by other researchers. Those first 14 were all discovered using a technique called “marker association,” which only identifies a region of about 100 genes where the culprit gene would be located.  The gene from those 100 that’s reported as a “hit” is generally the one with the best statistical association with the marker along with a scientifically rational reason to be associated with the disease under study.  A more finely-grained search would actually work out the sequence of the genetic code, comparing people with PSP to those without PSP.  That wasn’t practical back in 2011, but now it is.  It’s called “whole-genome sequencing” or WGS.

The new list of gene variants has been found by an international WGS collaboration that grew out of the original CurePSP-supported team.  They used DNA samples from 1,718 people with PSP, of whom 1,441 were autopsy-confirmed, and 2,944 samples from people without PSP as controls.  The leaders are at the University of Pennsylvania and UCLA, but 26 other research institutions in nine countries contributed.

They confirmed five of the six previously-identified variants (the sixth came very close) and added seven new ones. They also elucidated new details of the cluster of variants in the H1 region.  Most remarkably, they confirmed a previous, smaller study showing that PSP reverses the relationship of Alzheimer’s disease with the ApoE gene on chromosome 19.  In AD, the epsilon 4 variant of ApoE is over-represented relative to controls and the epsilon-2 variant is under-represented, while in PSP, it turns out that those proportions are reversed despite the fact that both AD and PSP are tauopathies.

So far, the research article is only posted on medRxiv (“med archive”), a website for manuscripts not yet through the peer review process at a journal.  (But my brain’s blogging center couldn’t restrain itself.)  The next steps for the authorship team are to gather online comments on the manuscript from other scientists and to submit the resulting revision to a regular journal.  There, the peer review may dictate other changes.  The next scientific step will be to figure out what the mutations are doing wrong, determine to what extent the variants increase or decrease the amount of the protein they encode (called “expression studies”), and look for proteins encoded by those genes (or for proteins they interact with) that might be modulated by drugs.

As far as I can tell, even the newly expanded list of risk variants doesn’t explain enough of the overall cause of PSP to be used as a diagnostic panel.  But it’s a start in that direction.

My canned lecture on PSP includes a slide on the two dozen or so most important scientific milestones in PSP research since the disease was first described in 1963.  This paper is going there.  As I learn more about the publication progress and clinical implications of this work, I’ll keep you all apprised.