Looking back, I can now see that they based their predictions on the promise of some new technologies that they felt sure would be confirming – the cracking of the genome and non-invasive functional neuroimaging. We’ve long known that many mental illness run in families [see too big a hurry…]. So with modern genetic sequencing techniques, they felt it was only a matter of time before the genetic bases of some mental illnesses would be handed to them on a platter by the herd of researchers looking for the answers. Likewise, we all know that the brain is the seat of matters mental. Being able to study the brain in action with the fMRIs would surely yield a cornucopia of confirmations. So the bet wasn’t so risky after all. All they had to do was wait. It was in the bag. And with luck, the neurochemists might come up with a biomarker or two that sealed the deal. No more turtle science. The hares had arrived!
by Maciej Trzaskowski, Philip S. Dale, and Robert PlominJournal of the American Academy of Child and Adolescent Psychiatry. 2013 52:1048-1056.
OBJECTIVE: Twin studies of behavior problems in childhood point to substantial genetic influence. It is now possible to estimate genetic influence using DNA alone in samples of unrelated individuals, not relying on family-based designs such as twins. A linear mixed model, which incorporates DNA microarray data, has confirmed twin results by showing substantial genetic influence for diverse traits in adults. Here we present direct comparisons between twin and DNA heritability estimates for childhood behavior problems as rated by parents, teachers, and children themselves.METHOD: Behavior problem data from 2,500 UK-representative 12-year-old twin pairs were used in twin analyses; DNA analyses were based on 1 member of the twin pair with genotype data for 1.7 million DNA markers. Diverse behavior problems were assessed, including autistic, depressive, and hyperactive symptoms. Genetic influence from DNA was estimated using genome-wide complex trait analysis [GCTA], and the twin estimates of heritability were based on standard twin model fitting.RESULTS: Behavior problems in childhood-whether rated by parents, teachers, or children themselves-show no significant genetic influence using GCTA, even though twin study estimates of heritability are substantial in the same sample, and even though both GCTA and twin study estimates of genetic influence are substantial for cognitive and anthropometric traits.CONCLUSIONS: We suggest that this new type of "missing heritability," that is, the gap between GCTA and twin study estimates for behavior problems in childhood, is due to nonadditive genetic influence, which will make it more difficult to identify genes responsible for heritability.
Discover BlogsBy NeuroskepticOctober 8, 2013
A paper just published reports that there are: No Genetic Influence for Childhood Behavior Problems From DNA Analysis. This is pretty big. Using a powerful approach called GCTA, King’s College London researchers Maciej Trzaskowski and colleagues found no evidence that genetics can explain differences in children’s behavioural and conduct difficulties.
First some background. ‘Missing heritability‘ refers to the fact that genetics has mostly failed to find common genetic variants that are associated with ‘complex traits’ like personality, mental disorer and intelligence. This is surprising because these traits are largely heritable – meaning that they run in families, and that identical twins [with all their DNA in common] tend to be more similar than non-identical ones [with only half]. But if they’re heritable then, by definition, there must be genes behind that. But with a few minor exceptions, over a decade of studies drew blanks. Hence the heritability is missing in our DNA, unaccounted for.
Yet geneticists finally struck gold – or seemed to – with a new technique called genome-wide complex trait analysis [GCTA]. Instead of looking at each variant individually, GCTA quantifies how genetically similar any two people are as a whole. GCTA has shown that the more genetically similar people are, the more similar they tend to be in terms of complex traits. Hooray – the missing heritability is… well, it’s still missing, but at least we know it’s out there, in small pieces scattered across the genome.
But this good news only applies to some complex traits, according to Trzaskowski et al. It doesn’t hold for child behaviour. In the TEDS sample of British twins, the authors conducted a simultaneous twin and GCTA study. During childhood these twins were assessed for IQ, height, weight, and a range of ‘behaviour problems’ including symptoms of autism, hyperactivity, psychopathy, conduct disorder and more.
The results of the twin study said that all of the traits were moderately heritable [roughly 0.5 on the scale of 0 to 1]. But while GCTA confirmed a large genetic influence on the intelligence traits, height and weight, it found no genetic influence on the behaviour measures: The difference between the two sets of traits is stark:
The same picture was seen whether it was parents [shown here], teachers, or the children themselves rating their behavioural symptoms. So, some of the missing heritabilities have been located [if not pinned down], but others are more missing than ever. Trzaskowski call it a “new kind of missing heritability” but I wonder if the name “mystery heritability” is more appropriate in relation to these behavioural problems. What’s going on?
The authors say that GCTA can only detect additive genetic effects, and can’t detect nonlinear interactions between genes. But the trouble is, the twin data just aren’t consistent with the idea that nonadditive effects explain any of these traits. However, Trzaskowski then suggest that the results make sense if we assume that twin studies substantially overestimate the heritability of behaviour problems [but not intelligence].
This might be because behaviour problems are just questionnaire ratings of traits, which are essentially subjective and prone to bias [e.g. by parents who assume that their identical twins ‘must be identical’ and rate them as such], while intelligence tests, although not perfect, are less easily fudged.This account does leave room for some genuinely heritability, but only a little.
It says to me that what looks like inherited complex behavior, indeed by all reports is at least partially inherited complex behavior, does not fit the genetic concepts of our current thinking – and isn’t likely to fit in the near future. I see it as confirmation, here in Dr. Insel’s Decade of Discovery, that we don’t yet know what we think we know about the inheritance or the hypothesized biological substrate of human behaviors. And we are anything but a year and a half away from the long yearned for Decade of Translation:
Although I have always thought Dr. Insel’s Clinical Neuroscience call was at best premature and more likely way overstated, I don’t post this just to rub his nose in that map. Time has already done that quite well. I mention it because valuable NIMH resources are still being squandered on the obsession with Translation in general – a frantic hurry-up to legitimize psychiatry’s biology. That’s not what the NIMH is for. That’s not what psychiatry is for either. We know a lot more about caring for mentally ill people than we’re doing right now – things forgotten in the current climate. This study is just one of many pieces of evidence that says priorities need re-evaluating and resources need re-allocating.
If there’s one blog post that Dr. Insel needs to take another look at, it’s Director’s Blog: Balancing Immediate Needs with Future Innovation from January 2012. How many more studies does he need to see that say fund free-range basic research and look at the very real problems of right now with new glasses instead of chasing the now very tired dreams of he and his cronies? If he can’t escape the rut he’s in, he needs to find somewhere else to be in his rut. His version of just-around-some-corner-future-innovation has failed the test of time.
If it has neither been the Decade of Discovery nor the Decade of Translation, what should we call this time? I think that it’s already on Dr. Insel’s slide. Realistically, we’re still in the time of Trial and Error. And rather than lamenting or denying that fact, it is incumbent on us to absolutely insure that our Trials [our Clinical Trials] are the best they can be. This is the Time of Clinical Trial Reform and our current task is to insure that we do that thoroughly. It’s exactly what we’re supposed to be doing right now…