What is the future of PD Genetics?

What will be the impact of the $1000 genome on PD genetics and what are the roadblocks to success?

Sequencing technology is moving forward at an incredible pace - "next gen" technologies are being called "now-gen" technologies and one genomic run on an illumina GAIIx or SOLID system can produce 50gbases of sequence. The promise is enormous, one can imagine using these approaches to rapidly find mutations that took years to find before,  to identify rare risk alleles, and perhaps most excitingly begin to understand the genetic similarities across disparate disorders.  There are also lots of unanswered questions and roadblocks - what samples should we prioritize, how do we standardize results from different platforms and runs and perhaps most importantly - how do we analyze such data. The $1000 genome is great, but not if it costs $50,000 to analyze.

Can we presently understand gene and environment interactions? Will new technologies reveal the interface between genetics and the environment?

I think that in essence the answer to this is "not very well" - but that there's lots of promise. Perhaps having a definite genetic risk profile (eg having LRRK2 mutations) and prospective epidemiology is the way to go. I suspect that epigenetics may be a valuable place to look for chronic effects of environment on the biological system.

What would you do with a billion dollars earmarked for genetic research?

I would start a phenotyping factory. Yearly, prospective deep phenotyping of 100,000 60 year olds at centers around the US; the aged population is one that is enriched for disease and a population that will grow within the US incredibly over the next 20 years. Complete phenotyping, including biometrics, scans, clinical observation etc, coupled with the application of genomics, epigenomics, metabolomics and proteomics would yield a wealth of information on diseases and traits associated with aging.

• Can we presently understand gene and environment interactions? Will new technologies reveal the interface between genetics and the environment?

No, we don’t understand gene-environment interaction yet, and yes, new technology will help.  In our group alone, we are now able to explore gene-environment interactions on the whole-genome scale, scan the genomes of PD patients and the fly PD model for targets of environmental interaction and therapeutic development, and develop patient and genotype specific adult stem cells to test environmental compounds for their interaction with disease susceptibility.  None of  these would have been possible 5 years ago.  Although there is no hesitation on my part that new technologies have been hugely beneficial, I do have one gripe.  The speed by which technology is evolving has created a maddeningly fast-paced research atmosphere.  Look at genome-wide studies that are popping up around the world:  it is like an assembly line, same study designs, same software, same everything.  You can’t deviate from the boiler plate because you won’t get funded, and if you take time to be creative or inquisitive during your data analysis, you will miss your embargo.  All that said – I am extremely optimistic that we will soon start learning a lot about the interface between genetics and environment.

• Is there a role for somatic mutation in Parkinson's disease?

I have been thinking about somatic mutations in PD for a long time but I don’t know how to go about it.  Here is my angle.  Many groups have noted that in familial PD age at onset is often earlier in younger generations.  We have turned our dataset upside down and cannot find any artifact that could explain it.  Moreover, in sporadic cases, the older the mother was when the patient was born, the earlier the age at onset of PD for the patient.  I am thinking accumulation of somatic mutations in the germ line as the mother ages; maybe in the mitochondria, maybe nuclear.  Say there is a threshold for mutation load at which point PD manifests; mutations are somatic, it will be a matter of time before one hits the threshold.  The clock starts ticking in the mother, or maybe even in the grandmother.  You can tie this in with gene-environment interaction, and come up with environmentally induced somatic mutations accumulating over time. 

What are the ethical considerations as we approach a more complete understanding of the genetic and epigenetic architecture of PD?

Disclosure:  My comments are my opinion and do not reflect those of the NY State Department of Health IRB, which I am a member of.   Personally, I think this ethics thing is way out of proportion.  Not to jinx ourselves; in 20 years of genetic research with human subjects and over 6000 research participants, we have not had a single adverse event, including ethics complaints.  Professionally, ethical considerations will be the same as they have always been.  The CITI online IRB training pretty much covers it for the investigators.  What is missing is guidelines and education at the other end – the public, which includes the research subjects, politicians, insurance companies, employers, and the general public.  We, the researchers, can help educate the research subjects.  Many of us send out research-update letters, hold public talks, etc.  As for the rest of the public, it gets political.  But with Obama in the white house and Collins heading up NIH, I think we are good.  Now if MJFF and NINDS want to line up behind our leaders and plan programs to educate policy makers, I would volunteer on the spot.

• What would you do with a billion dollars earmarked for genetic research?

If I had a billion dollars, I would use half of it to find the brightest, most creative, free-thinking people from around the world, young and old, must be well-educated but not necessarily in medicine or genetics.  I would take any extraordinary mind, be it a philosopher or rocket scientist.  I would give them the money they need to free themselves from all obligations and concerns for a year. I will even send them to their happy place.  And I would ask them to solve Parkinson’s disease.  The other half of the money I would use to implement what they come up with.  

I think these are great questions and look forward to reading responses from others in the community. Here is my take from a 'funder' perspective (although much of this is my own personal opinion and so should not be considered official MJFF position):

Impact of cheap genome sequencing

Clearly there will be an explosion of data and I agree with the other posters to this discussion thread that handling all of those data will not be easy. From a funder perspective, what would make it more compelling to support such efforts I think is in making sure that these analyses are done in a prioritized and consortium-style approach rather than as a bunch of competing individual $50,000 grant requests from labs all wanting to analyze the same dataset. It would be great to see the genetics community work together in a unified fashion on this. (I know that is starting to happen, so kudos to those leading that charge.) I also agree about needing some strategy about who the best populations should be for applying these new technologies in order to maximize the genetic and ultimately disease insight a study will provide.

One thing I’ve wondered about for how to handle large genetic datasets (especially if moving to looking at gene-gene interactions) is whether the distributed computing approaches pioneered by groups like the Seti@home effort could be valuable. Let all the armchair geneticists at home contribute to the cause!

Gene-Environment interactions

This has been a tough question to address. MJFF has supported a few projects in this area in the past (e.g., see work from Drs. Lorene Nelson, Haydeh Payami and Bill Langston). And more recently we’re working with various investigators to look at people carrying LRRK2 mutations (work from Drs. Bressman et al and Farrer et al); some of that work will seek to examine potential environmental factors that might modify LRRK2-associated PD. One of the challenges in my mind seems to be that, unlike genomics where technology is growing leaps and bounds, environmental factors don’t really have the same level of technological advancement. Is there an environmental version of a ‘genome-wide association study’? Can we use Google maps to overlay where people with PD have lived with exposure data on smoking statistics, pesticide exposures, etc., to generate potential cluster maps? (I know this sort of approach is being used by investigators in California.) From funder perspective, again, this is a challenging area given high costs of performing epidemiological studies. But use of innovative technologies and approaches that can increase bang for the buck could be one way to make such studies easier to swallow.

Somatic Mutations and PD

I leave this one to the experts, but if mutations differ depending on which tissue you look at, that obviously creates a much more complex picture of disease than we expected. Again, is this something that can be looked at more comprehensively rather than in piecemeal fashion? Where would you even start?

Ethics of emerging genetic information age?

I tend to fall in the camp of wanting to know more about my genetic (and I guess epigenetic) make-up. I’ve even paid to have my own SNPs done through commercial services. But that’s me and I know many others have no interest in knowing or worry about how such information will be used. Clearly, strong and protective legislation is one part of the need here to make sure that people who choose to know more about their genes do not suffer discrimination. But a bigger issue is really about education in my opinion: how to inform people enough about what these genetic/epigenetic factors actually mean? It’s easy when it comes to defining genes that contribute to your hair color or ability to make your tongue do that weird folding thing. But when it comes to defining risk for disease, it enters a real problem area. And in the age of healthcare reform here in the US where paying for unnecessary medical tests is one of the big reasons for high healthcare costs, having everyone rush to their doctor with their genome in hand is something we will have to deal with.

What to do with a $1billion for genetic research?

(Disclosure: MJFF does not currently have a billion dollars for genetic research, so don’t ask!)

I like the suggestions of developing a larger more comprehensive genotyping/phenotyping strategy to collect an ultimate and growing mega-dataset that can address many of the basic questions we’ve been trying to answer but to date have only been able to use relatively smaller numbers of genetic markers and sample sizes. It’s a long-term effort but would give back data of real value. Of course, choosing the best population to do this with (e.g., based on age or family history as other post-ers suggested) will be something that the field will need to prioritize but I guess if we hit the $1000 or less genome threshold, a billion dollars gives you a lot of genomes to play around with. Some of this money would presumably be needed to develop the tools and pay the data analyzers as well, but I say again that there might be creative and cost-effective ways to allow data analysis to happen on a broader and perhaps individually cheaper scale.

An interesting article in the New York Times discussing a recent case where a Federal Judge invalidated gene patents held by the company Myriad Genetics. The legal precedent could open up the possibility of other gene patents being invalidated. If we're talking about the future of PD genetics in this discussion thread, one has to wonder whether the intellectual property surrounding genetic findings will alter just as much as the technologies used to identify genes. What sort of impact would this have? Does it open up ability to generate more tools and models based on genetics findings without the need to worry about who owns which patent? Or does it stifle ability of companies to translate and develop novel strategies based on genetic findings? Or will it have no impact at all? I'd be curious to hear from those of you who have either patented PD-associated genes or have come across legal barriers around patented genes that have blocked you from pursuing a particular line of research?

There is increasing interest in using the power of electronic medical records (EMR) for research purposes.  Two recent papers (Denny et al., Bioinformatics. 2010 Mar 24; Ritchie et al., American Joiurnal of Human Genetics 2010 Mar 31) highlight the power of this approach.  In both cases the authors used an EMR-based biobank (BioVU) that has connected a deidentified version of the clinical health record to a DNA sample.  BioVU currently has ~82,000 samples.  Denny et al demonstrate that such a biobank can be mined to identify novel clinical phenotypes for specific genes.  In other words, they look at a SNP in one gene and test it against hundreds of phenotypes to identify novel associations (essentially a phenotype-wide association study, or PheWAS).  Ritchie et al. demonstrate that such a biobank can be successfully used to generate phenotypic data useful for research purposes.  As a proof of principle, they tested 5 known GWAS associations for five different diseases and showed that electronic data algorithms can successfully extract "clean" phenotypes from the clinical medical record, and confirm known genetic associations.

There are a growing number of such biobanks around the country and the world.  Our ability to quickly generate large datasets of PD cases and controls, with potentially very rich additional phenotypic information, can greatly speed our research efforts.  Rather than taking months or years to develop and recruit sufficient datasets, these datasets may already exist and just need to be pulled from the biobank, perhaps in just weeks.

Interesting flurry of news in the last week or so about the US drugstore Walgreens initially deciding to offer at-home genetic test kits, the US FDA investigating and the store ultimately deciding to hold off offering the kits. Given that consumer-targeted genetic testing is becoming more common these days, I'm curious as to what the best approach to this should be? Clearly, there is consumer demand for this sort of testing (both on the medical and ancestry side) so simply banning these tests from store (or online) shelves seems near-sighted. However, there is a clear and reasonable appreciation that many people who might seek these tests do not fully understand the information they receive or that much of it is likely not very predictive of anything at this stage. From a research perspective, though, is this an opportunity for engaging the public in genetics more broadly? What can the research community do to take advantage of this advance in not only technology but also public interest?

(For full disclosure, The MJFF has worked with the consumer genetics company 23andMe to look at novel ways of engaging the public in web-based clinical and genetic research efforts.)

Some recent news that the company Population Diagnostics Inc. is receiving federal NIH funding to develop further its approach to identifying rare causal genetic variants associated with PD. I'm curious if anyone knows more about this company's approach and whether other groups are starting to focus more on this rare variant idea for PD? Is this the next appropriate step for the field?