sábado, 12 de febrero de 2011

Simplemente la gente que tiene TDAH tiene un mapa genético diferente.

Susan Smalley, Ph.D., is a professor in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, Semel Institute for Neuroscience and Human Behavior and director of its Mindful Awareness Research Center. Dr. Smalley's work has a dual focus: the genetics of attention-deficit hyperactivity disorder and the use of techniques of mindfulness in promoting well-being.

Susan Smalley

Q: Many people notice that attention-deficit hyperactivity disorder, or A.D.H.D., seems to run in families. Is it very strongly inherited?

A: It is; the heritability of A.D.H.D. is 76 percent.

Q: Does that mean that 76 percent of all cases of A.D.H.D. are inherited?

A: No — heritability is different: it's looking at the variability in the population at a particular point in time. If you think about height and you lined everybody up in the population, you could see a nice, kind of a bell-shaped curve, with very tall people at one extreme and very short people at the other extreme, and the majority of people falling in this middle place, around the average. That bell-shaped curve is the distribution of variability of height in the population.

Now, if you could measure people's genes that contribute to height, we know that 60 to 80 percent of the variability in height is due to genetic differences. That's heritability — the proportion of the total variance that's due to genes. How much of the variance in A.D.H.D. is due to genetics? That's where that 76 percent comes from.

Q: So the heritability of A.D.H.D. rivals that of height? We typically think of height as being very strongly inherited.

A: The heritability of A.D.H.D. is very high; that's a very high number, 76 percent. When we look at other psychiatric conditions — things like depression — it's more on the order of 50 percent. Autism tends to be one of the highest; it's around 90 percent.

Q: Have we located any of the specific genes that contribute to A.D.H.D.?

A: We're still at the level of trying to find the genes that might play a role in A.D.H.D. That work has yielded several likely genes that are involved in A.D.H.D., but none of them has a big effect. We were saying 76 percent of the variance is genetic. These are genes that contribute to maybe 2 percent, 5 percent — very small, small amounts.

But it's very likely that the genes that are involved in A.D.H.D. are going to be many, many more than we've identified to date, and a lot of research groups, including our own, have been actively looking throughout the whole genome for genes that might have a bigger role. It's kind of like looking for a needle in a haystack. Those are the genome-wide approaches, genome-scan approaches, to A.D.H.D.

Q: How does the genome-scan approach work?

A: There are two approaches to searching for these genes. A candidate-gene approach is when you know a gene, and you go in and you directly say, "Does this gene contribute to A.D.H.D.?" You have to have the gene; you've got to know what it is and how to look at differences in that gene. That's where we've found the handful that have played a role so far.

But the majority of discoveries for disease-gene relationships haven't really emerged from that approach. They're more often found by using the genome-wide approach — by saying, "O.K., there're 30,000 genes in the genome. Let's sample little pieces of DNA throughout the whole genome that we can study in pairs of siblings, for example, with A.D.H.D., or in relatives that we can study. Do they share a particular piece of DNA more often than you'd expect by chance?" If so, then the piece of DNA they share is going to be located really near the risk gene.

Using that approach, you don't have a clue where the gene might be, but you actively search everywhere. And my analogy is, finding a gene is about equivalent to finding a contact lens at Disneyland — sort of the ratio of the size of the gene to the size of all your DNA, or the genome. Finding a contact lens in Disneyland: that would be pretty hard. But it wouldn't be so hard if we had a really good map, and a technique for saying, "O.K., the chance that you've lost it in Space Mountain is much larger than the chance that you lost it on Tom Sawyer Island, right?"

Q: Does that type of map exist?

A: Yes. That's what a genome-wide strategy does: it samples all [areas] across the whole Disneyland park with a grid, a map. You study people who have A.D.H.D., asking which pieces of DNA they have in common among the 300,000 pieces of DNA that span the whole genome. They can be used as a marker map, to study differences in the population. It helps us locate the likely candidate gene. You still don't have the gene; you just know its location. Marker maps help you map the most likely position, in the whole genome, for a gene that contributes to A.D.H.D.

My lab has found strong, strong support for particular places on four chromosomes — Chromosome 5, Chromosome 6, Chromosome 16 and Chromosome 17 — that have a very high chance of having a gene that contributes a bigger effect to A.D.H.D., maybe 5 to 10 percent of the variance. There are other groups that are doing the same kind of work, and the sad part is, they're not all coming up with the same four positions. They're finding evidence on Chromosome 9, Chromosome 11 — different positions. So that probably means that there are going to be a lot of genes that contribute to A.D.H.D.

Q: How does environment interact with genes in A.D.H.D.?

A: My biggest insight into A.D.H.D. is to think of it as a kind of a neural map, a neural network, a template, if you will, of brain organization that is just not the average brain organization in the population. It's more of the extreme on this normal bell-shaped curve, the extreme end of a normal distribution. It has to do with different areas of the brain, and all of those brain neural networks are bumping up against different kinds of cultures, different kinds of school systems, etc. The degree of impairment is a function of all of those things, and no one thing alone.

We understand that the predisposition to getting a diagnosis of A.D.H.D. has a lot to do with what kind of genetic complement you're born with, and then how that genetic complement interacts with the environment throughout early development. Prenatal exposure to cigarettes, for example, may impact the genes differently when you have a genetic predisposition to A.D.H.D.. Several studies have shown that maternal smoking in pregnancy increases risk for hyperactivity-impulsivity later in life, and a recent study suggests that that effect may be greater if the fetus has a certain genotype.

Postnatally, there may be differences in childhood as well. We have interesting research showing that in families where there's a lot of conflict in the home, a lot of arguing, that has a very negative impact on kids with A.D.H.D. in terms of leading to greater impairment, greater problems.

Q: Is this where your work in mindfulness comes in?

A: Our lab studies families that have two affected kids with A.D.H.D., and then we evaluate the parents for A.D.H.D. as well. In those studies, we've found that at least half of the families have one parent affected with A.D.H.D.. We've had a great opportunity to study families that are heavily loaded with genes for A.D.H.D., and we've found a lot of interesting things. Some kids don't have a lot of psychiatric issues, or as many problems academically, or cognitively. Other families have tons of problems. What is accounting for this variability?

When we studied that, conflict in the home seemed to be really important. Having a lot of conflict made families suffer much, much more than having little conflict. So A.D.H.D. alone doesn't cause the problem, because all these families have pretty much the same constellation of A.D.H.D. Something else is going on.

So another whole hat that I wear is trying to look at tools to help people cope with stress. Can meditation be useful — mindfulness-type practices? Can those be taught and used in families or schools that kids might find themselves in to help build resiliency, help reduce stress? Can that help parents cope? We know that can reduce conflict in general, so would it be useful in families that have kids with A.D.H.D.?

We're just starting to understand what the gene-by-environment interaction is in A.D.H.D. that unfolds as we develop. Then the question is, what can we do to minimize the impairment associated with A.D.H.D. and maximize the strengths? What are the strengths of having that genetic predisposition, of being at that end of the distribution?

Q: What advice would you offer parents of children with A.D.H.D.?

A: Finding their child's strengths is really important. There's a negative impact of seeing the world differently. Anybody who's at the extreme of anything — I don't care if you're just really, really tall — you bump into a world that isn't so tall, and it's impairing. It's not easy being green; we've all got some green dimension to figure out.

So I think it helps for families to understand the genetics, but it also helps to hone in on what are the strengths, and how best to manage the weaknesses. That's the approach that we take — to recognize that the way you're wired, you can learn to find tools to help manage that brain wiring so it's more compatible with the world around you. Sometimes that requires medications, and that's O.K.; sometimes it doesn't, and that's O.K. Be very open to finding the best way to manage it for your child at this particular point in time
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