Posts tagged genetics

Environmental factors like teacher quality and SES affect the full flowering of potential

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In some combinations of environments and genot...
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This should be a no-brainer: in an era when increasingly words like ‘gene-environment interaction‘ are bandied around, it would be self evident that for full flowering of a prototypical trait, the genotype has to get the right environmental inputs. In absence of the right environmental conditions, the genetic differences may be masked and the trait under consideration suffer from universal stunted growth, thus even different genotypes leading to same phenotype -that of survival trait. contrast this with the condition where the environment provides rich conditions for the flowering of the trait under consideration. Here the trait will be having maximal value and would be a thriving trait value. Here genotype differences , if any , would be accentuated and become visible as difference sin phenotype expression.

If the above is a bit abstract , take the concrete example of SES and the corresponding low environmental condition and its relation to IQ/brain/cognitive ability. In an impoverished environment differences due to genetics would be masked and everyone will have a low IQ/cognitive ability. As opposed to this in an enriched environment condition, not only the average IQ would be higher (a thriving condition), there would be more differences in the IQ of children/people concerned as the right environment will make it possible for genetic effects to come into play and determine the IQ/cognitive ability. The above is a bit paradoxical and counter-intuitive- one advocates environmental interventions only to see that effects of environment becoming less for the trait and effects due to genetics becoming more prominent as more and more conducive environment is provided. The rationale for providing the right enriched environment /high SES to all would thus be not to eliminate inequality (inequality would paradoxically be accentuated) ; but to raise the trait value to maximum possible under the right environmental and that perhaps is for the good of all.

I have debated this issue earlier in my low IQ and SES series of posts, but thought will comment on the same in light of two articles that I cam across recently. The first article is a bit old, but has the devastating effect of waking one form ones slumber as one realizes that low SES leads to brain effects in low SES children that are akin to those faced by normal children/people who suffer brain damage due to stroke etc. I came across this via this science daily release tweeted by someone today (forgot the source).

The second study is a brand new one , published just today (and I have just read the extract and accompanying Sci Am article). The study, using identical and fraternal twin studies, in essence found that children’s reading ability was largely genetic (82 % genetic component), but that teacher quality mattered a lot. The genotype was able to flower fully when teacher was high h=quality- not only the reading ability was better; differences were accentuated. In contrast, when teacher quality was low, environmental had a much stronger effect by leveling everyone to a smaller value. To quote from the article:

“When children receive more effective instruction, they will tend to develop at their optimal trajectory,” said study lead author Jeanette Taylor in a prepared statement. “When instruction is less effective, then children’s learning potential is not optimized and genetic differences are left unrealized.”

The researchers found that good instruction promoted stronger reading development. Without it, children were less likely to reach the potential conferred by their genes. “When teacher quality is very low, genetic variance is constricted, whereas, when teacher quality is very high, genetic variance blooms,” they report. While teacher quality appears to be an important contributor, other classroom factors, such as classmates and resources, might also influence reading ability, the researchers noted.

To me, the results are important, though self-evident. Hopefully they will seal the endless confusion on the matter and allow a more reasoned dialogue and intervention to happen where IQ and SES/enriched environment is concerned.

Taylor, J., Roehrig, A., Hensler, B., Connor, C., & Schatschneider, C. (2010). Teacher Quality Moderates the Genetic Effects on Early Reading Science, 328 (5977), 512-514 DOI: 10.1126/science.1186149
Kishiyama, M., Boyce, W., Jimenez, A., Perry, L., & Knight, R. (2009). Socioeconomic Disparities Affect Prefrontal Function in Children Journal of Cognitive Neuroscience, 21 (6), 1106-1115 DOI: 10.1162/jocn.2009.21101

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Model_1

Autism and Schizophrenia: proof from comparative genomics

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I have blogged extensively about the Autism and Schizophrenia as opposites on a continuum theory. I remember first putting this theory in words in an article 3 yrs back on the mouse trap titled Autism and Schizophrenia: the two cultures. That 2006 article, in turn, was inspired by Daniel Nettle’s 2005 article in Journal of Research in Personality where Nettle had also proposed the dichotomy and that paper helped crystallize my thoughts on the subject, a theory which I had been building on my own and now supported by someone like Nettle who I respect a lot. Important to note that at that time I was blissfully unaware of Badcock or Crespi and their work. It is to the credit of Badcock that he had published in 2006 his own theory of Autism and Schizophrenia as opposites on a continuum based on parental imprinting of genes and proposed a mechanism. Crespi I guess got involved in Badcocks’s efforts later on and gave it more experimental and theoretic grounding. I firts became aware of Badcock and Crespi’s work in early 2008.

The wider world became aware of the Autism/Schizophrenia dichotomy sometime in late 2008 (November 2008) . at that time too, I was a little disappointed because most of the coverage did not mention Daniel Nettle, who I think should be credited for this work and line of reasoning too. As a consolation, some reports did mention Chris Frith who has also been partly supporting the thesis.

I wanted to give a historical perspective, because I am sure the recent Crespi article would be grabbed on by mainstream media and the pioneers Chris Frith/Nettle perhaps overlooked- but to me they too are heroes for having come up with such profound early insights. this is not to discredit teh work of Badcock and Crespi- they are doing a thorough job of convincing the skeptics and delineating the exact mechanism and genetics involved.

While we are on the topic of historical perspective , let me also pat myself on the back. In May 2008, a study came out that de novo Copy Number Variations’s (CNVs) were quite high in schizophrenics and they are in the same region as that for autistics who also have high CNVs in the same region. While some took that result to imply that Schizophrenia and Autism are same and are not different, I persisted and proposed a mechanism, whereby they could still be opposites : To quote:

Now as it happens previous research has also found that CNVs are also found to a higher extent in autistics. Moreover, research has indicated that the same chromosomal regions have CNVs in both Autism and Schizophrenia. To me this is exciting news. Probably the chromosomal region (neurexin related is one such region) commonly involved in both schizophrenia and autism is related to cognitive style, creativity and social thinking. Qualitatively (deletions as opposed to duplications) and quantitatively (more duplications) different type of CNVs may lead to differential eruption of either Schizophrenia or Autism as the same underlying neural circuit gets affected due to CNVs, though in a different qualitative and quantitative way.

Now one and half year later Crespi et al report the results of their study which has found exactly the same- that is, if deletions in some locus lead to autism, duplications lead to schizophrenia and vice versa. That to me is clinching evidence of my thesis. Who says Science does not happen on blogs- I proposed something to flow as a consequence of theory and exactly the same thing is found as per the hypothesis. I feel vindicated and emotional to some extent. Loves labor has not been lost to deaf ears.

Let us then return to the new and latest study that has sort of proven that Autism and Schizophrenia are opposites, genetically. Crespi et al, report in the latest PNAS edition that comparative genomics leads to that conclusion. What Crespi et al did was look at theCNV s and the locus whee CNV in both Autism and Schizophrenia are involved and sure enough they found the pattern I had proposed. I’ll now quote from the abstract and the article extensively:

We used data from studies of copy-number variants (CNVs), singlegene associations, growth-signaling pathways, and intermediate phenotypes associated with brain growth to evaluate four alternative hypotheses for the genomic and developmental relationships between autism and schizophrenia: (i) autism subsumed in schizophrenia, (ii) independence, (iii) diametric, and (iv) partialoverlap. Data from CNVs provides statistical support for the hypothesis that autism and schizophrenia are associated with reciprocal variants, such that at four loci, deletions predispose to one disorder, whereas duplications predispose to the other. Data from single-gene studies are inconsistent with a hypothesis based on independence, in that autism and schizophrenia share associated genes more often than expected by chance. However, differentiation between the partial overlap and diametric hypotheses using these data is precluded by limited overlap in the specific genetic markers analyzed in both autism and schizophrenia. Evidence from the effects of risk variants on growth-signaling pathways shows that autism-spectrum conditions tend to be associated with upregulation of pathways due to loss of function mutations in negative regulators, whereas schizophrenia is associated with reduced pathway activation. Finally, data from studies of head and brain size phenotypes indicate that autism is commonly associated with developmentally-enhanced brain growth, whereas schizophrenia is characterized, on average, by reduced brain growth.These convergent lines of evidence appear most compatible with the hypothesis that autism and schizophrenia represent diametric conditions with regard to their genomic underpinnings, neurodevelopmental bases, and phenotypic manifestations as reflecting under-development versus dysregulated over-development of the human social brain.

Copy Number Data. Rare copy-number variants (CNVs) at seven loci, 1q21.1, 15q13.3, 16p11.2, 16p13.1, 17p12, 22q11.21, and 22q13.3 (Tables S1 and S2), have been independently ascertained and associated with autism and schizophrenia in a sufficient number of microarray-based comparative genomic hybridization (aCGH) and SNP-based studies to allow statistical analysis of the frequencies of deletions versus duplications in these two conditions (Table 1, Tables S3–S9). For five of the loci (1q21.1, 16p11.2, 16p13.1, 22q11.21, and 22q13.3), specific risk variants have been statistically supported for both autism and schizophrenia using case-control comparisons, which allows direct evaluation of the alternative hypotheses in Fig. 1. One locus (16p13.1) supports a model of overlap, and four loci support the reciprocal model, such that deletions are associated with increased risk of autism and duplications with increased risk of schizophrenia (16p11.2, 22q13.3), or deletions are associated with increased risk of schizophrenia and duplications with increased risk of autism (1q21.1, 22q11.21). For 1q21.1 and 22q11.21, contingency table analyses also indicate highly significant differences in the frequencies of deletions compared with duplications for the two disorders, such that schizophrenia is differentially associated with deletions and autism with duplications. By contrast, for 16p11.2 and 22q13.3 such analyses show that autism is differentially associated with deletions and schizophrenia with duplications.

Model_1

I cannot cut n paste the table, but a look at the table clears all doubts. They also look at gene association data and come to a similar conclusion ruling out model A (autism, subsumed in schizophrenia) or model B (autism and schizophrenia are independent of each other).

Models 1C (diametric) and 1D (overlapping) both predict broad overlap in risk genes between autism and schizophrenia, and do not necessarily predict an absence or paucity of genes affecting one condition but not the other. In theory, these models can be differentiated by using data on specific risk alleles for specific loci (such as single-nucleotide polymorphisms, haplotypes, or genotypes), which should be partially shared under the overlapping model but different under the diametric model. For the genes DAO, DISC1, GRIK2, GSTM1, and MTHFR, the same allele, genotype, or haplotype was associated with both autism and schizophrenia, and for the genes AHI1, APOE, DRD1, FOXP2, HLA-DRB1, and SHANK3, alternative alleles, genotypes, or haplotypes at the same loci appear to mediate risk of these two conditions (SI Text). For the other genes that have been associated with both conditions, heterogeneity in the genetic markers used, heterogeneity among results from multiple studies of the same genes, and the general lack of functional information preclude interpretation in terms of shared or alternative risk factors.

Models of autism as a subset of schizophrenia (Fig. 1A), and autism and schizophrenia as independent or separate (model 1B), can be rejected with some degree of confidence, but models involving diametric etiology (model 1C) or partial overlap (model 1D) cannot be clearly rejected. Taken together, most of the data and analyses described here appear to support the hypothesis of autism and schizophrenia as diametric conditions, based primarily on the findings that reciprocal variants at 1q21.1, 16p11.2, 22q11.21, and 22q13.3 represent statistically-supported, highly-penetrant risk factors for the two conditions (Table 1), and that for a number of genes, alternative alleles or haplotypes appear to mediate risk of autism versus schizophrenia.
Additional lines of evidence supporting the diametric hypothesis, from previous studies of autism and schizophrenia, include:

  • 1. Data showing notable rarity of familial coaggregation of autism with schizophrenia (38), in contrast, for example, to strong patterns of co-occurance within pedigrees of schizophrenia, schizoaffective disorder, and bipolar disorder (39).
  • 2. Psychiatric contrasts of Smith-Magenis syndrome with Potocki-Lupski syndrome (due to the reciprocal duplication at the Smith-Magenis locus), Williams syndrome with cases of Williams-syndrome region duplication, and Klinefelter syndrome with Turner syndrome, each of which tends to involve psychotic-affective spectrum phenotypes in the former syndrome, and autistic spectrum conditions in the latter (5, 40).
  • 3. Effects of autism and schizophrenia risk alleles on common growth-signaling pathways, such that autism has been associated with loss of function in genes, such as FMR1, NF1, PTEN, TSC1, and TSC2 that act as negative regulators of the PI3K, Akt, mTOR, or other growth-signaling pathways (41–45), whereas schizophrenia tends to be associated with reduced function or activity of genes that up-regulate the PI3K, Akt, and other growth-related pathways (46–49).
  • 4. Increased average head size, childhood brain volume, or cortical thickness in individuals with: (i) idiopathic autism (50–53), (ii) the autism-associated duplications at 1q21.1 (17) and 16p13.1 (32) and the autism-associated deletions at 6p11.2 (31), and (iii) autism due to loss of function (or haploinsufficiency) of FMR1 (54), NF1 (55), PTEN (56) and RNF135 (57). By contrast, reduced average values for brain size and cortical thickness, due to some combination of reduced growth and accelerated gray matter loss, have been demonstrated with notable consistency across studies of schizophrenia (58–62), and such reduced head or brain size has also been associated with the schizophrenia-linked CNVs at 1q21.1 and 22q11.21 (17, 63, 64), and with deletions of 16p13.1 (65).

I am more than pleased with these results. Badcock too is. You can read his comments here. What about you? What would it take to convince you? :-)

Crespi, B., Stead, P., & Elliot, M. (2009). Evolution in Health and Medicine Sackler Colloquium: Comparative genomics of autism and schizophrenia Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0906080106

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Sibling-correlation-422

IQ,SES and heritability

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A reader of this blog wrote to me recently regarding a series of posts I have written regarding IQ,SES and heritability, and I thought it would be good to share the comments with the rest of the mouse trap community and to delineate my position on the matter (and what I believe the studies show the relation is). First I’ll like to quote extensively from the comment (private mail):

Let me start with my belief that I think we share the same idea about IQ and its origins.
That is, genetics endows each and every person with a maximum IQ that can be achieved if and only if the environment is perfect for the development of this IQ.

Agreed!

Consequently, in identical twins, environment is the only cause of differences in IQ; IQ differences between persons that are not identical twins must be related to both environment and genes.

Sibling-correlation-422There are subtle nuances here. (no I’m not being pedantic, the importance of these will become clear in the course of this post). First if MZ twins are raised in the same family, they share the same genotype (A), they share the same ‘shared environment’ (C), so the difference is due to the non-shared environmental factor (E) only. In case of DZ twins raised in the same family, they share half the genotype (A), they share the same shared environment (C) and the difference in say IQ, is due to both genotype (A) and non-shared environmental factors (E). Twin studies with MZ and DZ twins (and in some cases siblings, half-siblings etc ) raised in the same family are used to tease apart the contribution of shared environmental factor, as opposed to genetics and non-shared environmental factors and can be used to find at a broad level if the trait is highly ‘genetically’ heritable (correlation between MZ>>DZ>>siblings), has high ‘shared environmental’ factors operating (MZ~DZ~sibling , but correlation still high) or is largely controlled by random non-shared environmental influences (low correlation in DZ/MZ/siblings). Please see accompanying Wikipedia figure.

Adoption studies are another method that is used to tease apart the shared environmental factors from genetic factors in calculating the heritability of a trait. Thus, even if correlation in MZ twin IQ is high, the effect could be due to shared environment factors (if say both MZ and DZ twin show similar correlation) , or it may be largely genetic (if MZ>>DZ when it comes to correlation between the trait in affected twins.

So it is necessary to qualify your statement: In identical twins, raised in the same family, , non-shared environment is the only cause of differences in IQ. IQ differences between persons that are not identical twins must be related to both shared environment , non-shared environment and genes.

I fully back up this citation:
“suffice it to say that I believe (and think that I have evidence on my side) that shows that in low SES conditions, a Low SES does not lead to full flowering of genetic Intelligence potential and is thus a leading cause of low IQ amongst low SES populations.”
In this case, I think that the problem starts only with your following comments; while you write “a leading cause”, I think that, by yourself, you mean “way more important than genetics”. If this is the case, would you explain to me why you think that?

Here goes. Consider a large sample of children in say low SES populations. IQ may be represented by a formula IQ= aA+cC+eE; where A reflects genotype, C shared environment and E non-shared environment. Here we are assuming no interaction of IQ with SES, so this equation (given values of a, c, e ) should hold for all SES data (both high as well as low SES cohort) . Unfortunately, life is not that simple, and one can not fit the same equation to low SES as well as high SES data set without changing the slopes of variables involved. Thus, Turkheimer and colleagues in two sets of studies have shown that there is an interaction of IQ and SES and there is direct affcet (SES mediated by s) and indirect interaction effects mediated via effects on A(a’), C(c’) and E(e’). Thus our equation becomes
IQ= sSES+(a+a’SES)A+(c+c’SES)C+(e+e’SES)E.
This equation, with suitable values of s, a, a’, c, c’, e and e’ now holds for all values of SES and IQ and the data fits nicely and can be interpreted. Remember that a+a’SES is sort of indicative of contribution of genetic factor to IQ and the proportion of variance due to genetic factor(at any given SES) can be found by squaring this and dividing this by sum of all other variances .
Var(A) =SQR(a+a?SES)
Similarly heritability or proportion of variance due to A :SQR(h)=SQR(a+a?SES)/(SQR(a+a?SES)*SQR(c+c?SES)*SQR(e+e?SES))

Turkheimer have plotted nice plot of their data which sows clearly that in LOW SES situations, the proportion of variance in IQ is largely due to shared environmental factors (C) , while in HIGH SES situations, the proportion of variance in IQ is largely due to genetic factors (A). the figures (in the free PDF available at Turkheimer’s side) is a must see to grasp the significance of this. I am quoting a bit from the paper:

Figure 3 shows the FSIQ variance accounted for by the three components, with 95% confidence intervals. In the most impoverished families, the modeled heritability of FSIQ is essentially 0, and C accounts for almost 60% of the variability; in the most affluent families, virtually all of the modeled variability in IQ is attributable to A.

Let us pause here and reflect on what this means. This means that in low SES families, IQ is independent of genotype and is mostly dependent on the SES status. Let us take some concrete examples. Say the mean IQ of low SES sample (income as a proxy for SES ranging from 1000-5000 rs p.a.; mean 2500 and variance 250)) is 80 with mean variance of 20. Thus, in this sample a typical child has IQ in range 80 +-20 or between 60 and 100. Suppose further that there are 5 alleles that confer differential advantage for IQ on a locus thus representing 5 genotypes, then having either of the genotype will essentially give us no predictive power to say whether the IQ of a particular sample is 80 or 60 or 100. Also, let us assume that there are 5 classes of C and they are highly correlated with SES. First class of C (is 1000-1500 SES range) and so on and so forth. Then knowing whjat kind of family (C) the child grew up in we could easily predict his IQ (if he is of class C where SES ranges from 1000-1500), his IQ is most probably 60. This is what I mean when I say that in low SES environments IQ is largely determined by environment and not by genetics. Now , I have taken a jump here and equated C with SES, but that is a justified leap in my opinion (more about that later).

What this also means is that given the right type of environment (say class C with SES in upper range of 3500-5000 rs p.a.) , all children (irrespective of their genotype (any 5 variants of genotype) can still achieve an IQ in the upper range , say 100 as the environment is the only predominant factor operating at this level and the impact of genetics is still not felt. Thus, if we do increase SES and provide the right C, then every child in this group can have mean IQ of 100.

Contrast this with the case at the upper end of the strata (SES). Here most of the variation in IQ is predominantly due to genetics (A) and shared environment C does not seem to play a big factor. Thus, knowing a genotype of a child has greater predictive power in this sample, than knowing his C (or family income or SES). Thus, evenif we provide a very enriched environment to all children (increase their C to the highest percentile), it would have no effect on increasing the mean IQ of the sample as now the IQ is mostly under genetic control.

This in a nutshell, is what I mean when I claim that low SES is the leading cause of low IQ in low SES families.

Before I rest, some objections might be readily apparent to a keen observer. First is the assumption inherent that SES and C are the same. I would like to propose here a new shared and universal sub-threshold environmental factor and would like to elaborate with a couple of examples. Let us say that those below poverty level do not have access to iodized salt and are thus prone to goiter and also mysteriously to low IQ as there is a module of brain (5 diff alleles at a particular locus leading to differences in abilities using this module) that needs iodine for its flowering and in absence of iodine, none of the alleles have any effect whatsoever- the module itself does not develop, so there are no questions of differences in ability or IQ due to differences in genotype etc. Now, given this state of affairs and also the fact that low SES families do not have access to iodine, when IQ is measured (then because of absence of this factor X), all children in this proband will have an IQ that does not measure abilities of this module (say this module adds 20 points of IQ) and thus all of them will have an IQ less by 20 points than was actually possible.Say the mean IQ measured is 80. Given the fact that some of the higher SES within this low SES group may have partial and sporadic access to iodine , the variance will be entirely environmental and no genetic variance would be found with some people having IQ close to 100 , who are in relatively upper start and have decent access to iodine. Contrast this the higher SES proband all of whom have access to iodized salt and thus can use their additional 20 points advantage on IQ tests. It would not be surprising if most of the variation here was genetic based on factor X allele) rather than due to income level or SES.

Another example to ruminate on is another universal and shared sub-threshold factor like having a golf course in the house. Let us assume that within higher SES group, this environmental enrichment factor plays a role, with some lower strata of higher SES (the middle class) not able to afford a golf course, while the higher higher SES strata (the upper class) abvle to afford a golf course and expose their children to them . Further, suppose that there is a module in the brains and genes switched on only if exposure to golf course takes place. Then within this higher SES group, what we will observe is that though the genetics plays a good role (due to factor X-iodine: remember, which is available to all in this group) ; still there would also be variation due to environment (golf course exposure) and that a full 20 points more can be added to all people of this group (with mean IQ 100 raising their IQ to 120), if all were exposed to a golf course and a intelligence-module-dependent-on-golf-course-exposure was allowed to develop. And on the higher end of IQ (and SES) what we would find is that most of the variance now is genetic (due to this golf-course module coming into play), while at the lower end, most of the variance is still environmental within this ‘high’ SES group.

If the above seems far fetched this is exactly what Turkheiemrs et al found in their follow up study focusing on mid to high SES children. I quote from it (again the pdf has beautiful figures and you should see them) :

Figure 2 illustrates the relations between income and genetic and shared environmental proportions of variance, as implied by the parameters estimated in Model 3. Genetic influences accounted for about 55% of the variance in adolescents’ cognitive aptitude and shared environmental influences about 35% among higher income families. Among lower income families, the proportions were in the reverse direction, 39% genetic and 45% shared environment. Although the shared environmental proportion of variance decreased with income, shared environmental variance per se did not decrease. The interactive effect was driven entirely by the increase in genetic variance. Genetic variance in cognitive aptitude nearly doubled from 4.41 in families earning less than $5000 annually to 8.29 in families earning more than $25,000 annually.

Our investigation supports our hypothesis that the magnitude of genetic influences on cognitive aptitude varies with socioeconomic status. This partially replicates the results presented by Turkheimer et al. (2003); however, no shared environmental interaction effects were demonstrable in the current study. Genetic influences accounted for about 55% of the variance in adolescents’ cognitive aptitude and shared environmental influences about 35% among higher income families. Among lower income families, the proportions were in the reverse direction, 39% genetic and 45% shared environment. This pattern is similar to the pattern seen in Turkheimer et al. (2003), although less marked.

So, I want you to pause here and grasp the significance of this- at every level of IQ-SES, there may be threshold factor that giverns whether IQ modules flower to full potential and this is the putative mechanism that leads to SES causing low or high IQ directional and causal relation. At each level, as the threshold factors become available,. more and more IQ starts coming under genetic control, but , and this is important, for jumps in IQ to take place , increasing SES (removing the sub-threshold conditions) is VERY important.

I mean “not following up on the ‘a leading cause’”, because in a later post, you write:
“Now, I have shown elsewhere that low SES causes low IQ”
Here, there is no mention of any other possible cause besides the environment anymore.

Yes, because as shown very strongly by Turkeihems and team , at low SES, shared environment/SES is the putative mechanism and genetics has no/negligible role to play. So for low SES, low SES causes low IQ. period.

in another post, you write
“A series of studies that I have discussed earlier, clearly indicate that in the absence of good socioeconomic conditions, IQ can be stunted by as large as 20 IQ points. ”
This same post also contained this citation “Children of well-off biological parents reared by poor/well -off adopted parents have Average IQ about 16 point higher than children of poor biological parents”
In my opinion, the latter would indicate the approximate range of genetic IQ differences for the samples in this study, while the former would indicate the approximate maximal environmental gain that can be hoped for in the environments that were encountered in these studies.

No they don’t. They talk about different SES groups, so as shown findings from one cannot be extrapolated to the other. In the low SES group, there is no genetic variation. We can thus not conclude that that (16 points diff.) is the ‘average’ genetic component taken the entire sample together. what one can say is that if mean IQ of high SES children was 100, the mean IQ of low SES children was 84 . Period. The difference is likely due to the fact, that the module X has not developed in low SES people (more later) .

Regarding the former, yes I agree that that is the maximum gain that one can hope for if all children of low SES were given the right environment (raised to high SES). Put another way, if mean IQ of poor/low SES children is 84 , then given the right conditions the mean of the low SES children can be raised to 104 (greater than high SES children’s mean :-).

As both of them do cover the same IQ range (10-20), the logical consequence for a broad statement on IQ and genetics seems therefore to be, that these studies may say that overall, IQ changes can be expected to be determined to approximately equal parts by genetics and environment, with environment being responsible for a typically larger part in low SES families, and genetics playing a relatively larger part in high SES families.

Agreed partially, but that glosses over the fact of sub-threshold universal shared environments and the fact that the role of genetic and environmental component varies with SES, an therefore an ideal statement would be IQ is under gentic controltolarge extent, but that gentics needs threshold environments to flower and thus the importance of environment component- not in explaining variance , but by its direct effect on IQ enabling/flowering.

This same post also contained this citation “Children of well-off biological parents reared by poor/well -off adopted parents have Average IQ about 16 point higher than children of poor biological parents”
In my opinion, the latter would indicate the approximate range of genetic IQ differences for the samples in this study, while the former would indicate the approximate maximal environmental gain that can be hoped for in the environments that were encountered in these studies.
As both of them do cover the same IQ range (10-20), the logical consequence for a broad statement on IQ and genetics seems therefore to be, that these studies may say that overall, IQ changes can be expected to be determined to approximately equal parts by genetics and environment, with environment being responsible for a typically larger part in low SES families, and genetics playing a relatively larger part in high SES families.
There also is this citation:
“The normal observation that identical twins belonging to well-off/middle class families have IQ rates similar as compared to fraternal twins, thus indicates that for children from well-off background (biological/adopted), the IQ (observed phenotype) is mostly due to genetic factors (underlying genotype) and environmental factors are not a big determinant.

The paradoxical observation that identical twins belonging to poor families have IQ rates as varying as compared to fraternal twins, should indicate that for children from poor background (biological/adopted), the IQ (observed phenotype) is mostly due to environmental factors and genetic factors (the underlying genotype ) are not a big determinant.”

These are extremely nice observations. I would be interested in the conclusions one might be tempted to draw from them. Reading the latter part of this sentence, one might come to the following conclusion (conclusion 1): “if in low-SES families the variations in IQ are largely determined by environmental factors, then providing a positive environment for the development of IQ would increase the IQ levels in these families impressively (up to 20 points; but, this is an up to value, means would be more interesting).”
While I completely agree with this thinking, one might also be tempted to draw the conclusion that (conclusion 2) “As IQ variations in low-SES families are largely due to environment, providing an IQ-stimulating environment in low-SES families might completely eliminate the IQ differences between low-SES families and high-SES families”
At the least, a non-cautious reader might understand your words as such. I am not sure whether you think that way or not. I would like to hear your opinion on that. I think that this citation “Children of well-off biological parents reared by poor/well -off adopted parents have Average IQ about 16 point higher than children of poor biological parents” provides an argument that precludes conclusion 2. It would rather say that (conclusion 3), ” providing a perfect IQ-stimulating environment for low-SES families as encountered in these studies, one should think that their offspring would achieve an IQ level that is 16 points lower than that of the offspring of high-SES families.”
I would like to hear your opinion on my conclusion 3.

I agree with conclusion 1. I also agree with conclusion 2 (not based on political correctness, but hard data). The paper on which these figures are based can be found here. The mean IQ of high SES persons is 113.5 and the mean IQ of low SES children is 98.00, thus a difference of ~16 points. The variation in IQ of high SES children raised in high SES families is 12.25; as shown this variance is likely due to genetics (say hundred percent is due to genetics); then changing the SES within the given range should have no effect on average IQ and it would remain 119 (for this high +/high+ group). On the other hand, the variance in low SES, reared by low SES families is 15.41 and mean is 92.40;thus if all were given enriched environment, their mean IQ would become 92.4+ 15.4 = ~ 108 . We still have a 10 point difference which can be accounted for by the fact that genetics had not come into play for low SES , low SES group yet and as genetics enters and increases the variance due to genetic flowering,, their IQ would be in the same league as high IQ/High IQ children.

So definitely the conclusion 3 is flawed- the difference would not be close to 16 points, but negligible, as the 16 points nowhere measures gentic difference in abilities, but reflects the genetic factor not yet active in low SES, due to improper environmental exposure.

I think that this is a rather important conclusion, as it tells us something about the differences in IQ that can be expected to exist between distinct population stratums (don’t know whether this is an appropriate word for what I try to say; I hope you understand what I mean).
If this is the ballpark of figures that we can expect between low-and high SES IQ differences, this would have important effects on future IQ-distributions. Population-wide stability of IQ-performance, if measured in a saturated environment (maximum stimulation of all members of society), can then only be achieved if all stratums of society have the same number of offspring per individuum. If low-SES families have more children, we have to expect that the 16-point lower IQ will decrease the whole-population IQ.
Here, the 16 points only apply to the sample as measured in your example; the true value of the saturated stratum-dependent-IQ together with stratum-dependent birthrates will determine the shift of the saturated IQ-distribution for the generations to come.

Do you agree with this point of view?

To use a very strong and negative connotation word, the above smacks of eugenics. And I wont comment further on this. Each according to his own philosophy, but beware that science does not support your conclusions. Instead of population controlling the poor, please try to elevate their vicious loop of undeserved poverty, low IQ and harmful stigma.

Turkheimer, E., Haley, A., Waldron, M., D’Onofrio, B., & Gottesman, I. (2003). Socioeconomic status modifies heritability of iq in young children Psychological Science, 14 (6), 623-628 DOI: 10.1046/j.0956-7976.2003.psci_1475.x

Harden, K., Turkheimer, E., & Loehlin, J. (2006). Genotype by Environment Interaction in Adolescents’ Cognitive Aptitude Behavior Genetics, 37 (2), 273-283 DOI: 10.1007/s10519-006-9113-4

Capron, C., & Duyme, M. (1989). Assessment of effects of socio-economic status on IQ in a full cross-fostering study Nature, 340 (6234), 552-554 DOI: 10.1038/340552a0

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The epigenetics of Autism: Oxytocin factor and implications for schizophrenia

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ResearchBlogging.org
Autism is a hard disorder to nail down genetically- single nucleotide polymorphisms (SNPs) or even multiple locus genetic effects are not able to account for the large genetic component to the disorder. In recent times, Copy number variations (CNVs) has come to the forefront of Autism research , suggesting that microdeletions, duplications etc may account for some cases. Another new , till now unsuspected mechanism that has recently been implicated in autism is epigenetic mechanism of increased methylation in promoter regions that has the effect of silencing/reducing the expression of genes involved to a certain extent. The recent study by Gregory et al, is just such a step in the right direction, which will hopefully bring us closer to the truth.

The study is available in full at BMC Medicine site and is accompanied by a must read commentary that explains a lot of things and puts the finding in context.

In a nutshell, the study authors used CNV determining methods to discover that a deletion of OXTR (oxytocin receptor) gene was presnet in an autistic subject and was not de novo , but the deletion was inherited from his mother. One of the affected siblings of the autistic subject, who too was autistic, on the other hand did not have a deletion, but had increased methylation of the OXTR. this led the study authors to revisit their genomics data and look at adta across all autistic subjects and controls and discover that indeed, in other autistics too the OXTR had increased methylation. Then they looked for expression of OXTR in peripheral blood cells and temporal cortex and found that indedd in autistics, as compared to controls, there was reduced expression of OXTR. This strongly suggest that the epigentic changes that lead to autism (the efffect of OXTR suppression) happen quite early in the devlopmenet and might happen in utero.

Before I elaborate on my take home from the study, there are some excerpts (as I know you didn’t read the originals)

Classic autism comprises a spectrum of behavioral and cognitive disturbances of childhood development. The core autism phenotype includes deficits in social interaction, language development and patterns of repetitive behaviors and/or restricted interests. The population prevalence of the spectrum of autism disorders is estimated to range between 1/300 [1] to 1/100 (http://www.nschdata.org/), with a male: female ratio of 4:1 [2,3]. The disorder has been shown to be highly heritable with the relative risk for siblings being approximately 2% to 8%, much higher than that of the general population [4]. To date, only a small percentage of autism cases (<10%) have been ascribed to single gene disorders such as fragile X syndrome, tuberous sclerosis [5] and Rett syndrome [6]. Numerous approaches including genetic linkage, genome-wide association, candidate gene association and gene expression analysis have been used to identify the additional genes
implicated in the development of autism [7,8]. However, the heterogeneous nature of autism and autism spectrum disorders has limited their success.

An additional approach to identify genes involved in autism is to characterize copy number variants (CNVs), that is, chromosomal deletions and duplications, that are known to be present within at least 5% of individuals with idiopathic autism [9]. Autism CNVs have been shown to involve almost all chromosomes [10,11], with the most frequently observed alteration localizing to chromosome 15q11-13 [12-23]. A number of different methods have been used to characterize autism related CNVs, including but not limited to, cytogenetic Gbanding [14,23,24], metaphase fluorescence in situ hybridization (FISH) [22], Southern blotting [18], loss of heterozygosity (LOH) analysis [15-17,19], quantitative polymerase chain reaction (PCR) [25] and, more recently, genotyping and representational oligonucleotide microarray analysis (ROMA) [26].
Here we describe the use of genome-wide tilepath microarrays and array comparative genomic hybridization (CGH) to identify CNVs in a dataset of 119 unrelated probands from multiplex autism families [27]. The genomic profiles of our autism dataset were compared to the array CGH profiles of 54 phenotypically normal individuals, to previously published CNVs present within the database of genomic variants [28] and to the Autism Chromosome Rearrangement Database (http://projects.tcag.ca/autism/). The most significant finding thus far from our analysis is a heterozygous deletion of the oxytocin receptor gene (OXTR) (MIM accession no.: 167055) in an individual with autism and his mother with putative obsessive-compulsive disorder (OCD). We further investigated the relationship between OXTR and autism by carrying out epigenetic analysis of the promoter region of OXTR. We show that the gene is hypermethylated in independent cohorts with autism as compared to controls, in both peripheral blood mononuclear cells (PBMCs) and the temporal cortex. Additionally, our analysis of expression levels of OXTR in the temporal cortex shows decreased levels of expression in individuals with autism as compared to controls matched for age and sex.

These data suggest that OXTR and the oxytocin signaling pathway play an important role in the etiology of autism and autism spectrum disorders and implicate epigenetic misregulation of OXTR in this complex disease.

Epigenetic control of autism susceptibility is a recent concept and most certainly a topic of great interest in the field. Over the past decade, researchers have uncovered suggestive links between epigenetics and autism, for example, autism is associated with duplications of 15q11-13 (especially maternally inherited), an imprinted region in the genome where DNA methylation status has been linked to Prader-Willi syndrome (PWS) and Angelman syndrome (AS) [66]; mutation within a gene that encodes a methyl-DNA-binding protein (MECP2, (MIM accession no.: 300005)) is the causative agent of Rett syndrome [67]; and mutation of this same gene has been associated with both autism and AS populations [55]. Nagarajan et al. have shown that 79% of autism cases have a decrease in MECP2 expression in the frontal cortex and that an increase in aberrant DNA methylation correlates with this decrease in MECP2 expression [68]. These data implicate epigenetic dysregulation as a mechanism for the development of autism and justify the examination of DNA methylation of autism candidate genes, such as OXTR identified in this study.

Now from the accompanying (more accessible) commentary:

The article by Gregory et al. published this month in BMC Medicine, reports on genomic and epigenetic alterations of OXTR, the gene encoding the receptor for oxytocin. The involvement of this gene was suggested by its deletion in an autistic patient. The subsequent analysis of a group of unrelated autistic subjects did not show an OXTR deletion, but rather hypermethylation of the gene promoter, with a reduced mRNA expression.

These findings address two major points of the current debate on the etiology and pathogenesis of autism: the role of oxytocin, known to be involved in modeling human behavior, and the possible involvement of epigenetic mechanisms. The nature of this epigenetic dysregulation is unknown but, if proved to be true, might explain the failure to identify sequence alterations in a host of candidate genes. Practical implications of these findings may be forthcoming, however not before extension and validation on a larger scale have confirmed their value.
..
The second issue raised by Gregory et al. deals with the epigenetic inhibition of OXTR expression in ASD. Such epigenetic modification, at least as reported so far, does not seem to be sequence based but rather of a different, as yet unknown nature. This might explain why researchers have been looking for decades for genetic mutations in ASD and yet have found almost none. An epigenetic mechanism would justify the ‘unusual’, non-Mendelian familial aggregations of ASD. In this respect, even the family with OXTR deficiency reported by Gregory et al. shows an unusual genotype-phenotype correlation, in that the same phenotype is caused by alterations of the same gene but due to different molecular defects (deletion versus hypermethylation).

Also, the possibility that in most ASD patients there might be an epigenomic instability is of interest in consideration of the fact that it has been shown that the epigenetic status in early fetal development can be reprogrammed by maternal behavior in a reversible way [34]. Therefore, other environmental factors, yet to be discovered, might also be able to reprogram the epigenotype of the embryo.

I hope the fact that epigenetic changes may happen during pregnancy line of reasoning does not lead to the harmful and without-any-basis vaccination is cause of autism arguments. On the other hand I had covered earlier how Autism is more likely if mother was exposed to valproate during pregnancy or the child soon after birth. What if valproate is instrumental in an epigenetic fashion in leading to more or less methylation and gene expression. It is well known that valproate and valporic acid is given as treatment for psychosis/bipolar. In a similar vein, I am inclined to stick my neck out and claim that in schizophrenics/psychotics , the OXTR should be more expressed : perhaps more methylation, duplications etc . However I am checked in my musings by these studies that claim that negative symptoms of schizophrneia may be associated with reduced oxytocin activity in the brain. Yet, all said and done I would like to see a study that analyzes for epigenetic mechanisms in schizophrneia especially at the OXTR locus. Although the negative symptoms like social withdrawal of schizophrenia may lead to the opposite hypothesis regarding schizophrenia and oxytocin correlation, I am inclined to believe that schizophrenics (at least those suffering from positive symptoms predominantly) are too much oxytocin guided , trusting and socially too much involved in others type of people.

Gregory, S., Connelly, J., Towers, A., Johnson, J., Biscocho, D., Markunas, C., Lintas, C., Abramson, R., Wright, H., Ellis, P., Langford, C., Worley, G., Delong, G., Murphy, S., Cuccaro, M., Persico, A., & Pericak-Vance, M. (2009). Genomic and epigenetic evidence for oxytocin receptor deficiency in autism BMC Medicine, 7 (1) DOI: 10.1186/1741-7015-7-62
Gurrieri, F., & Neri, G. (2009). Defective oxytocin function: a clue to understanding the cause of autism? BMC Medicine, 7 (1) DOI: 10.1186/1741-7015-7-63
Hat tip to @Boraz for tweeting about this study.

This post was chosen as an Editor's Selection for ResearchBlogging.org

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