Tag Archives: whole genome sequencing

Seek and ye shall find

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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.

Near-term genetic PSP-ology

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Remember the Human Genome Project?  It cost about $3 billion and took 13 years (1990 to 2003) – and that was with 20 labs around the world working in parallel.  A commercial lab can now sequence your whole genome in a few days for about $600.  Now the problem is how to recognize a “abnormal” result and what to do with that information.  We all have mutations that our parents don’t, and most of those have no health implications.  The problem is knowing which ones do.  This makes it medically and ethically tricky to interpret the results of a whole-genome sequence. 

Until that knowledge base improves, whole-genome sequencing will probably be useful mainly in assaying for known mutations in well-studied genes.  It is also possible to roughly predict the health implications of a never-before-seen mutation in a well-studied gene by working out the amino acid substitution that would result in the protein being encoded.  Then, using the physical and chemical principles of protein structure and function, one could roughly predict how that amino acid substitution might affect the function of the protein.  But that’s still an inexact science.  Besides, a lot of the genome doesn’t encode proteins at all – it has regulatory functions, which sometimes involves encoding small stretches of RNA that in turn regulate protein production.

So, with those challenges in mind, here’s a bit of speculation as to what might be in store, near-term, for genetic testing in the routine clinical care of PSP.  Thanks go to my friend and colleague Alex Pantelyat, MD of Johns Hopkins for his input.

  • Once effective treatments for PSP arrive, we may find that people with different variants in the gene encoding tau (or other gene) respond differently to specific medications.  This might be especially true for treatments targeting the process where the information in the DNA is encoded into proteins (called “transcription”).  Right now, short stretches of DNA or RNA called “antisense oligonucleotides” (ASOs) that interfere with the encoding of the normal form of tau are in clinical trials.  As you’d imagine, this risks side effects caused by a lack of normal tau protein.  But if we knew what gene mutation was causing PSP in an individual, an ASO could be specifically tailored for it. 
  • It will become standard practice for clinical trials of any sort of treatment to be designed for people with, or without, specific gene variants.  Or if a trial doesn’t try to restrict enrollment in that way, it will at least do the sequencing at the time of enrollment and apply the genetic information retrospectively to check if the treatment works in people with specific gene variants. 
  • As discussed in my last post, variants in the LRRK2 gene help determine the duration of survival of people with PSP, though they don’t affect the risk of developing the disease to begin with. There are bound to be other genes with similar effects.  Sequence data from such genes could be useful to people with PSP and their families in preparing for the future financially and emotionally.
  • The last point, about prognostic genetic markers, is about single-gene variants.  But the same point could apply to combinations of variants in multiple genes where no single variant has a measurable effect. 
  • Using a battery of gene variants as a high-accuracy diagnostic test for PSP (as opposed to prognosticating a rate of progression or what symptoms might develop next) seems unlikely to come to pass, as the list of genes already linked to PSP probably are the most informative ones, and they are insufficient as a diagnostic test.  But if that list is coupled with other non-genetic tests such as MRI, PET and blood tests for tau or neurofilament light chain, a highly accurate test battery could result. 

Beyond the $600 lab fee are the bills for the necessary interpretation and counseling, which add about $2,000.  While the lab fee has been declining because of technological improvements, the other services are provided by human beings and are only likely to rise.  Insurance companies, Medicare and Medicaid don’t presently cover any of this unless it’s for someone with cancer or a very ill newborn.  I assume this is because we don’t yet have enough use for the data in terms of alterations in management.  But what are the financial implications if my above predictions come true and actionable uses do become available?  PSP is a rare disease, but what if similar uses of whole-genome sequencing are developed for Alzheimer’s, atherosclerosis, depression and the many other diseases where genetic variants, or combinations thereof, affect disease risk or prognosis?   Even if we manage to reform the medical payment in the US and improve access to that system for those presently under-served, who will provide all that counseling? And who will respond to patients’ demands for preventive treatment? And who will pay for that treatment? Scary.