A receptor for dopamine and a mismapped mutation

Right or wrong, the word "dopamine" always conjures up images in my head of rats pushing levers over and over again, working desperately hard to send shots of dopamine into their tiny little rodent brains.

Dopamine, like many other neurotransmitters (chemicals that send signals in the brain), works by binding to proteins on the surface of brain cells and sending a signal to the cell. There are five different subtypes of receptors for dopamine (D1-D5) with somewhat different activities (1) and drugs that bind to these receptors are known to have potent effects on brain activity and behavior (1).

With that knowledge in hand, it seems reasonable to expect that genetic differences that change the number of dopamine receptors or the structure of the receptor itself, could contribute to differences in the way people behave.

This has been a topic of intense investigation over the past decade or so. It turns out that there are many papers in PubMed discussing studies that have been done to understand if a particular genetic difference, called "TaqI DRD2" is associated with a variety of behavorial issues and personality traits. A quick PubMed search with the query "Taq1 DRD2" found 129 papers looking at traits varying between novelty-seeking, methamphetamine addiction, smoking, quitting smoking, impulsiveness, obesity, alcohol dependence; it's simply amazing. We try to blame this receptor for everything we can.

I didn't read all those papers, but in scanning the abstracts, most of the authors discuss their results in the context of a larger picture in our understanding of dopamine and the function of the dopamine receptors.

But what if the genetic difference that is being studied isn't in the dopamine receptor?

This is the question I stumbled on last December and wrote about earlier this week (here and here).

I found that the Taq1 DRD2 polymorphism doesn't map in the dopamine D2 receptor at all. It maps in a different gene as you can see in the image below (I made this by editing the map I got from the UCSC genome browser). The arrows show that ANKK1 and the DRD2 genes are transcribed in the opposite directions and the rs numbers identify polymorphisms. Red numbers indicate a change in the amino acid sequence, green, no change, and blue ones map in untranslated sections of the mRNA. I put a box around the SNP that's otherwise known as the Taq1 DRD2 polymorphism.

This Taq1 A polymorphism changes a single base, number 2231 in the mRNA, from a gene called ANKK1, that encodes a protein called "ankyrin repeat." This base change causes some people to have a lysine at amino acid 713 in the kinase domain of the ankryrin protein and others to have a glutamic acid. How this structural change influences the function of the ankryin protein is still unknown.

The frequency of this change varies greatly depending on ethnicity. In Europe, 80% of the people described in dbSNP have the glutamic acid form, and 20% have both. In the Asian samples, it's a different story. Most people have both forms, 20% have only the glutamic acid form, and about 24% only have the lysine form. The frequency of the lysine form in the African samples falls between the two groups.

Okay - so it's pretty clear that this genetic change is NOT located in the DRD2 gene, it's in the ANKK1 gene.

Does it matter?

It does seem that the information about the new gene location has been slow to percolate through the community. As I wrote yesterday, many of the citations in the Gene database are found associated with the wrong gene (DRD2 and not ANKK1). When I used the query "TaqI DRD2 AND 2005:2008[Entrez Date]", with PubMed, I found 37 papers where when I searched with "ANKK1," I only found 10. Most of the DRD2 papers discuss the polymorphism in terms of the the dopamine 2 receptor and the lower number of receptors. One paper was even published in July 2008, from authors at Harvard Medical School. Even at Harvard, it seems, authors can miss getting the memo about the gene change (2).

To be fair, some commenters have noted, even though the polymorphism maps somewhere else, it could still change the levels or properties of the DRD2 receptor. If that were true, then everyone would still be right about the role of dopamine, and at least some of the genetic associations.

Is there evidence to show that the TaqI base changes the number of D2 receptors?

Let's look at the data. I really didn't find much, but here's what I found.

1998 Pohjalainen, et. al. (2) I can't get the article very easily, so I can't tell how many people they tested or look at the data, but here's what they say:

A statistically significant reduction in D2 receptor availability reflecting an alteration in receptor density was observed in the A1/A2 genotype group compared to the A2/A2 group.

1999 Jonssen et.al. (3) with 56 subjects found:

In agreement with some previous studies the
presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine receptor density (t=2.58, P=0.01).

1998 Laruelle, et.al. (4) 70 subjects

In conclusion, the results of this study failed to replicate the previously reported association between A1 allele and lower D2 receptor expression.

Does this polymorphism cause a decrease in the number of dopamine D2 receptors?

I don't know. We have two papers that say there's a decrease, one that says there isn't, and no one seems to have done any biochemistry since 1999.

Is there an association between ANKK1 behavioral traits and is there a benefit to knowing where the TaqI polymorphism really maps?

It would seem so. It also seemed that when I scanned the papers using "ankk1" it seemed that the people who knew the right gene name (5) also performed more sophisticated studies, and looked at haplotype associations, linkage disequilibrium, and more subjects than the other studies I found. At a quick glance, it seems that the researchers are "in the know" as far as the correct map position, may be "in the know" in other ways, too.

References:
1. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects
Siegel, George J.; Agranoff, Bernard W.; Albers, R. Wayne; Fisher, Stephen K.; Uhler, Michael D., editors, Philadelphia: Lippincott,Williams & Wilkins ; c1999

2. Pohjalainen T, Rinne JO, Någren K, Lehikoinen P, Anttila K, Syvälahti EK, Hietala J. "The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers." 1998 Mol Psychiatry. May;3(3):256-60.

3. Jönsson EG, Nöthen MM, Grünhage F, Farde L, Nakashima Y, Propping P, Sedvall GC. "Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers." Mol Psychiatry. 1999 May;4(3):290-6.

4. Laruelle M, Gelernter J, Innis RB. "D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene." Mol Psychiatry. 1998 May;3(3):261-5.

5.B.-Z. Yang, H. R. Kranzler, H. Zhao, J. R. Gruen, X. Luo, J. Gelernter (2007). Association of haplotypic variants in DRD2, ANKK1, TTC12 and NCAM1 to alcohol dependence in independent case control and family samples Human Molecular Genetics, 16 (23), 2844-2853 DOI: 10.1093/hmg/ddm240.