Confusion about g2019s, LRRK2, and Parkinson’s Disease still circulates after the vacuous media blitz about Sergey’s blog. Here’s an except of a conversation from the 23andMe private member forums.

Not included is Paul Wick’s note: “I guess the only question in my mind for 23andMe from a regulatory perspective is at what point this is diagnostic vs educational; I know it’s a different kettle of legal fish in the latter case. ”

Indeed. However, g2019s is not used to make nor confirm clinical diagnosis of Parkinson’s Disease, so I think this still counts as “education.” (I so hate that word.) Personally? Assuming 23andMe makes the appropriate medical care available, I’d love to see them report diagnostic mutations.

PaulWicks asks:
LRRK2 mutations?

A patient with Parkinson’s Disease (PD) posted today on the PD board of PatientsLikeMe that Google founder Sergey Brin has tested positive for LRRK2, a mutation that is implicated in some cases of inherited PD. See the original blog here: http://too.blogspot.­com/­When I look at my raw data I can see some listings next to LRRK2 but I need some more help to interpret that data; how can I tell what is / isn’t pathogenic?

Cheers
Paul Wicks
R&D Director @ PatientsLikeMe.com

Andrew Yates responds:
LRRK2 mutations?

Hey Paul,

First, see http://www.helixgene­.org/press/g2019s­ for a simple fast-fact press release about the g2019s mutation and Parkinson’s Disease.

“tested positive for LRRK2″ is a misnomer, what you mean is “tested positive for a variation of LRRK2.” The distinction is important, bare with me:

LRRK2 is a gene that everybody has. Everybody would test positive for LRRK2.

Actually, the test is for a single SNP^[1] in the gene LRRK2 called g2019s. I see you’re R&D;, so in computer code, the test evaluates:

if (YourGenome[39020469][0] == A
       || YourGenome[39020469][1] == A)

What does this mean? LRRK2 describes the protein “dardarin.” Think of a protein as a string of amino acids. This “bit flip” in your DNA changes the amino acid glycine at position 2019 to amino acid serine in dardarin. As code, this is like:

if (YourGenome[39020469][0] == A
       || YourGenome[39020469][1] == A) then
    dardarin[2019] = serine
else
    dardarin[2019] = glycine
endif

Note: g2019s is an abbreviation for “replace (g)lycine @ position 2019 with (s)erine”

What does THIS mean? It’s thought that g2019s mutated dardarin increases the protein MAPK’s activity, and this gain of function mutation leads to neuron death. That’s why g2019s is autosomal dominant: you only need one copy of the mutation to increase function and to create a toxic effect.^[2]

This is only a test for one very specific change in LRRK2. There are at least 30 known SNPs leading to 20 known amino acid substitutions mutations for LRRK2, though most of these have not been as well studied or are as medically relevant as g2019s. But a mutation can be be anywhere on the gene and cause all sorts of subtle and complex effects depending on other proteins and the environment…

Editorial

So, as you can see, this is a very complex system with many minutia that aren’t well understood. While I thought Sergey’s post was quite good, it’s _extremely irritating_ to see this sloppily reported in the media (like the NYTs) leading to significant medical misinformation at worst and general confusion at best. This is complex and important medical information, and if a NYT tech reporter^[3] with a comp sci degree from Stanford completely bungles elementary bayesian reporting because he copy-pasted the first percentage out of a press release and link cited a blog so he could go home early for the weekend… then we have a lot of work to do. Why not just read “MSN Health’s “Top Ten Mutations That Could Change Your Life?” Enraging.

I can tell you that the genomic medical community is PISSED, and it’s not even 23andMe’s fault. As far as I can tell, 23andMe’s g2019s test and report are very good. But, the medical community only knows what they’ve read in the NYTs because they don’t have 23andMe accounts. All they know is “Holy Crap! the NYTs says that 23andMe says that you could have an up to an 80% risk of Parkinson’s disease! Those huckster criminals!” Clearly, that’s not what 23andMe or Sergey’s “Too” actually says, but that’s the cost of standard of media reporting about genomics today.

[1] SNP, or single nucleotide polymorphism. “single nucleotide” means one DNA letter is changed, and “polymorphism” means a known variant that’s found in at least 1% of a population.

[2] It’s thought that this mutation makes dardarin more active because serine can be phosphorylated and glycine can’t be, and this helps the dardarin change shape such that ATP can better access its active site. Dardarin adds phosphate to other proteins including the protein MAPK, and this in turn makes MAPK too active. This is not my expertise, so any corrections or elaborations are welcome.

[3] Miguel Helft and his editor, Damon Darlin