COMT and the beginning of Warrior/Worrier . . .
We're going to be releasing our COMT story soon. COMT is an important gene in the metabolism of neurotransmitters like dopamine and epinephrine. The GenEd COMT Story will tell you how your individual genotype at a specific location in COMT is important for dopamine metabolism and reward behaviors. As we work up to that release, we'll make blog posts about how GenEd builds a Story. Today's post is about the original description of the most famous SNP in COMT, rs4680. Rs4680 is a favorite SNP for companies that sell individualized genotyping reports. We've long suspected this is because of the great marketing tag that is almost always applied to COMT genotype at rs4680: "Warrior/Worrier". According to an excellent review article by Stein et al (1) David Goldman was their source for this wonderfully appealing dichotomy. Rather than repeat the excellent narrative found in the Stein et al paper, we're going to go back to the original peer-reviewed description of what would become the famous COMT SNP, rs4680 (2). Note that this paper, even after 20+ years in the literature, is still behind a paywall. Alas, this is not our problem to fix. Let's dissect what is freely available, the abstract. The authors assume we know enough about biochemistry to parse the acronym for COMT. COMT stands for Catechol O Methyl Transferase. "Catechol" is the chemistry word for molecules with a benzene ring and two hydroxyls. Benzene is a six carbon ring with alternating double bonds. Hydroxyls are the small molecule group -OH, an oxygen hooked to a hydrogen. The "O" is another chemistry term. In this context, it stands in for the Oxygen in one of the hydroxyls. "Methyl" is chemist-speak for a carbon with three hydrogens hooked to another molecule. "Transferase" is biochemist-speak for an enzyme-that-transfers or moves one part of a molecule to another. In the plainest English possible for this writer, COMT is the enzyme that transfers a methyl group to an oxygen on catechols. Why is transferring methyl groups to catechols important? Transferring a methyl group to a catecholamine like dopamine inactivates that catecholamine. As the authors point out, COMT doesn't just inactivate catecholamines like dopamine and epinephrine. COMT also inactivates drugs like L-DOPA. COMT's inactivating activity is variable between individual people. John Smith might have more active COMT than Joe Public. This is very important to people who might need L-DOPA. Depending on what studies you look at, it's probably also important for a host of other human diseases that involve catecholamine metabolism. This inter-individual variability in COMT was known before this paper. The authors major contribution was figuring out WHY there is variability between people in COMT activity. Note the date on reference 2. This study was done in the bad old days before gene sequencing was cheap and common. In the late 90s, biologists had to climb up snow-covered hills both ways to get to their PCR machines! Lachman et al developed an experiment that takes advantage of two common techniques in the pre-sequencing days of molecular biology: PCR and restriction enzymes. PCR is a technique for amplifying small amounts of a single chunk of DNA. Lachman et al PCRed "up" lots of COMT gene DNA from different people they already knew had different COMT enzyme activities. Restriction enzymes are tiny molecular machines built by bacteria to fight each other and viruses. Biologists in the dim recesses of time learned how to use these restriction enzymes to cut DNA in specific places. Restriction enzymes cleanly cut DNA in between exact sequences, making exactly two fragments of the PCRed gene. The restriction enzyme used by Lachman et al, Nla III, is one of these narrow specificity restriction enzymes. Think of Nla III as a pair of scissors that only cuts between two specific spellings of DNA letters, CATG and it's reciprocal GTAC: C A T G| |G T A C If you are lucky like the Lachman team in 1996, the location of your COMT mutation is between one of these two DNA words. Imagine Nla III sliding along the double helix, looking for its magical DNA letters. If the sequence is mutated, it doesn't cut! This effect is called a restriction fragment length polymorphism (RFLP) or "riflip". The Lachman group showed that one of these RFLPs is a misspelling of a part of the COMT gene. The more common G DNA base is misspelled as an A DNA base. This misspelling is propagated all the way to the COMT enzyme itself, resulting in a substitution of the more common amino acid valine (Val) for the amino acid methionine (Met) at position 158 in the COMT sequence. Swapping a bulky methionine for valine is roughly equivalent to asking your car to run on tires that are square instead of round. A car would move forward on square wheels, but it wouldn't be a very smooth ride. COMT enzymes with Val158 ("round tires") inactivate more catecholamines than COMT enzymes with Met158 ("square tires"). Before Lachman et al, no one knew exactly why there was so much variability in COMT activity. Their seminal work is the basis for everything we know about this particular mutation. We'll talk more about what catecholamine inactivation means for Warriors and Worriers in the next blog post. Be sure to follow along . . . 1. Stein DJ, Newman TK, Savitz J, Ramesar R (2006) Warriors versus worriers: The role of COMT gene variants. CNS Spectr 11(10):745–748. 2. Lachman HM, et al. (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6(3):243–50.