August 16, 2004
Gene Variants Influence Schizophrenia, Cognitive Abilities

A variant in the GRM3 glutamate receptor gene may increase the risk for schizophrenia while simultaneously lowering cognitive ability.

Glutamate is a key neurotransmitter long thought to play a role in schizophrenia. The gene identified in this study makes the glutamate receptor (GRM3) which is responsible for regulating glutamate in synapses spaces in between brain cells where chemicals like glutamate transfer information from cell to cell. The amount of glutamate remaining in the synapse may have a downstream impact on cognition.

...

GRM3 alters glutamate transmission, brain physiology and cognition, increasing the risk for schizophrenia. To pinpoint the section of the gene responsible for these changes, scientists are exploring a region where the gene may differ by one letter at a location called SNP4. The normal variation is spelled with either an 'A' the more common of the two or a 'G'. Patients with schizophrenia are more likely to inherit an 'A' from either parent, indicating the 'A' variant slightly increases risk. The 'A' variant is also associated with the pattern of traits linked with the disorder. This was true in patients, their healthy siblings, and normal volunteers.

In the study, people with an 'A' variant have differences in measures of brain glutamate. In a postmortem study of brain tissue, the 'A' variant was associated with lower levels of the chemical that promotes gene expression for the protein responsible for regulating the level of glutamate in the cell. N-acetylaspartate, a measure of cell health evaluated through the use of MRI spectroscopy, was lower in 'A' participants. 'A' carriers had poorer performance on several cognitive tests of prefrontal and hippocampal function than people with the 'G' variant. The 'G' marker was associated with relatively more 'efficient' processing in the prefrontal cortex. Those who inherit the 'G' variant scored higher on verbal and cognitive tests than those who have two of the 'A' variant. Scientists think the less common 'G' variant may exert a protective effect against the disease.

People with schizophrenia and their healthy siblings share the inefficient brain physiology, and cognition patterns, which suggests a link to genetic risk, though the disease itself is most likely caused by a combination of genetic and environmental factors. The gene seems to affect the mechanism of memory encoding only as there was no genotype effect seen during retrieval in the memory tests.

What I find more interesting than the link to schizophrenia risk is that these two genetic variants differ in their impact on normal cognitive function. GRM3 SNP4 looks like it will turn out to be one of the locations in the human genome which have variations that produce different levels of intelligence. In the next 10 years expect to see the identification of dozens and perhaps even hundreds more of additional locations of genetic variants that influence intellectual abilities and personality. Declining costs of DNA testing will drive the rate of such discoveries up by orders of magnitude.

Share |      Randall Parker, 2004 August 16 02:21 AM  Brain Genetics


Comments
Doug said at August 16, 2004 12:26 PM:

"GRM3 SNP4 looks like it will turn out to be one of the locations in the human genome which have variations that produce different levels of intelligence. In the next 10 years expect to see the identification of dozens and perhaps even hundreds more of additional locations of genetic variants that influence intellectual abilities and personality. Declining costs of DNA testing will drive the rate of such discoveries up by orders of magnitude."

There will be hell to pay, for geneticists, psychometricians, and societies at large, if evidence mounts that the frequency distribution of SNPs with cognitive effects differs, ahem, geographically.

Randall Parker said at August 16, 2004 12:53 PM:

Doug, There will no hell to pay for the psychometricians. They will be vindicated. Their critics and attackers will be seen as a bunch of very unfair vicious ideological nutcases.

Also, hell to pay for soceities at large? Why? Whatever is true is already true.

BTW, Variations in the Prion Protein gene affect cognitive abilities and the distribution of those variations does differ geographically.

Cecilia Engstrom said at September 15, 2004 8:36 PM:

I found this article very interesting. My sister has schizophrenia. However, my brother and I are very intelligent. I was wondering about your comment regarding the healthy siblings cognitive abilities. How could I identify my impairment? Is is possible for me to have a G and my sister to have an A? Also, I am wondering what you feel the probability of my children having this disorder. It is too bad society, medical professionals, and insurance companies treat persons with this physical disorder so poorly.

Regards,
Ceci Engstrom

Randall Parker said at September 15, 2004 9:12 PM:

Ceci,

If one identical twin gets schizophrenia then the other identical twin has only a 50% chance of getting schizophrenia. The odds are even lower for non-identical siblings. Here are some numbers:

Only one out of every ten children of a schizophrenic parent will develop schizophrenia. The risk of 10% is greater than the frequency of schizophrenia in the general population, which is about 1%. Therefore, schizophrenia is more frequent in some families than others, but fortunately, most children of schizophrenic parents are completely normal. One of the enduring mysteries of this disease is that genes alone do not explain who gets ill. For example, identical twins have all their genes in common. However, if one is a schizophrenic, only half of the co-twins gets the same disease. About 40% of the co-twins of a schizophrenic live completely normal lives without disease.

Given a non-identical sibling with schizophrenia your own odds are also one in ten. I do not know what the odds would be for your offspring. Try this google search on schizophrenia inherited and see if one of the articles has some numbers.

You could also try checking out some sites that are dedicated to schizophrenia.

Amy Silberschmidt said at March 7, 2006 11:44 AM:

The odds for your offspring would be 5%, assuming your sister is the only person with schizophrenia in their gene pool. The odds for their offspring would be 2%, based on the same assumption. Intelligence (as defined by IQ) is normally distributed (i.e. on a bell curve). In the United States, 95% of the varience in IQ is due to genes (the more similar the environment of all individuals in a population, the more genetic effect will become visable. This is due to the relative equalizing of relevant environmental factors - not hard and fast laws completely resistant to change.) This facts taken together indicate that intelligence is not a monogenetic construct. There are likely several genes that contribute to IQ. Although I am not currently aware of any evidence that suggests that genes related to IQ are differentially distributed across geographic region, it may well be that particular genes that are found to have a relationship between particular componants of IQ are differentially distributed by geography. However it is important to remember that genes work together, not independantly, to produce behavior. It is also important to remember that, geographically, variation within groups is so much greater than variation between groups. The complex relationship of power, opression, class, and oppertunity have repeatedly been shown to predict performance variation between people with different geographical origins better than genes. Although the evidence supports this, equally important are the values people citing that type of evidence often hope to promote. No person or group of persons is ever justified in opressing another group of persons. No matter what.

Randall Parker said at March 7, 2006 7:14 PM:

Amy Silberschmidt erroneously claims:

The complex relationship of power, opression, class, and oppertunity have repeatedly been shown to predict performance variation between people with different geographical origins better than genes.

The standard left-liberal religious faith that you shovel is contradicted by adoption studies. Also, see here.

Reality contradicts ideology. I choose reality when that happens. I only wish intellectuals did too.

Amy Silberschmidt said at November 18, 2006 9:46 AM:

Please let me clarify both my position and the research to which Mr. Parker refers. The accusation of shoveling left-liberal religious faith, which I interpret as an accusation that I subscribe to a strict social-constructionist view of human behavior, is false. I recognize and make my living from the idea that biology is an important and likely dominant cause of the variation in individual human behavior - IQ being a trait which is more hertiable than most. But the kind of research that Mr. Parker references speaks to INDIVIDUAL difference, not differences between racial, ethnic, or geographic groups. An adoption study examining the heritablity of IQ using asian adoptees adopted by (largely white) American parents says nothing about the differences in IQ between koreans born in asia and the americans adopting them. Rather it suggests that children are more likely to resemble their bioligcal parents than their social parents. You can find research showing this same effect in twins as well as adoptive studies that match parents and chilren on race. The study design of a standard adoption study is not looking at racial differences. A much more plausible conclusion to draw from this research is that americans who adopt children have above average IQs (as a group) and koreans who give up children for adoption do not. We are not looking at all americans (who are clearly a racially/ethnically heterogeneous group anyway) nor are we looking at all koreans. In fact, we are not looking at anything resembling a random sample of these groups. We are looking at a self-selected group of people, and ergo we can only draw conclusions about the kind of people in these self-selected groups (americans who adopt korean children, koreans who give their children up for adoption). Adoption research is interesting and useful in elucidating whether or not a given trait is influenced by genes or by environment, in a given context (remember that even Einstein would likely have learned very little about physics were he born a girl in a developing country who was denied access to education; indeed this is the standard reason parents give children up for adoption - to provide their lives a better context in which to reach their potential). But adoption studies are not designed to tell us about differences between racial groups. An appeal to biological research to justify one's own racism is no more admirable in this age of genetics and neuroscience than it was when Hitler did it. Although I celebrate science and the new and exciting things we continue to learn about the way the human mind works, it is not now nor will it ever be acceptable for one group to perpetuate oppression upon another. I don't have a link, but below is a paper by the acclaimed behavioral geneticist Matt McGue of the University of MN entitled 'The Democracy of Genes' printed in the journal 'Nature' in 1997 (volume 388, issue 6641, page 417). It doesn't speak to racial difference directly, but it does speak to both the heritablility of IQ and the concept that this is not something that will persist across generations creating a class (and certainly not a geographical hot-bed) of super-elites.

The Democracy of Genes


The genetic heritability of IQ remains highly contentious. A new analysis shows that genetic influences may be weaker, and prenatal environmental influences greater, than previously appreciated.

Sir Francis Galton's contributions in 1869 alone were enough to ensure that his scientific legacy would be a lasting one. In that year, he not only helped in founding this journal, but also published the first empirical investigation of the inheritance of human achievement [1], a study that is generally credited with framing the modern nature-nurture debate. On page 468 of this issue [2], Devlin, Daniels and Roeder report a statistical analysis of more than 200 familial IQ correlations, the most recent in a long line of empirical investigations aimed at resolving issues that were raised by Galton.

Because it is associated with a wide range of social effects, including educational and occupational success, poverty and even delinquency [3], IQ has long been of interest to behavioural and social scientists. But these associations have also challenged cherished beliefs about the nature of social achievement. If social status is influenced by IQ, which is in turn substantially inherited, then social standing will, in part, be a function of one's genetic endowment. Hard work may be no guarantee of success, unless one has also received a lucky draw in the genetic lottery.

The general uneasiness over IQ reached new heights with the publication of The Bell Curve [4], by Herrnstein and Murray, in 1994. The authors described declines in the population's genetic potential for high IQ (that is, dysgenic trends), because of higher fecundity among the poorly educated relative to the well educated; and they also forecast the establishment of a caste-like cognitive elite, which would be maintained through intermarriage and the (genetic) transmission of high IQs from parents to offspring. In short, they argued that Western (and in particular US) society was becoming a two-class system, where the cognitively limited masses would be ruled by a relatively small and reproductively isolated cognitive elite.

Devlin and colleagues' findings will lead to a reconsideration of these most dire conclusions from The Bell Curve. The likelihood of dysgenic trends occurring, as well as the ability of parents genetically to reproduce desired traits in their children, both depend on the strength of parent-offspring transmission, which in turn depends on the narrow-sense, rather than the broad-sense (total) heritability. Quantitative geneticists distinguish additive gene effects, which are independent of genetic background and thus shared by parents and their offspring, from non-additive gene effects, which are dependent on genetic background and thus not shared by parents and offspring. Narrow-sense heritability is the proportion of a trait's variance that is attributable to additive gene effects; broad-sense heritability is the proportion attributable to both additive and non-additive gene effects.

Herrnstein and Murray [4] based their arguments on an IQ heritability of 60%; Devlin et al. report a broad-sense heritability estimate of 48% and a narrow-sense heritability of only 34%. Although a narrow-sense heritability of this magnitude does not preclude dysgenic trends (albeit at a slower rate than Herrnstein and Murray projected), it is certainly too low to support the establishment of a high-IQ caste. Over the long term, unless both the narrow-sense heritability and the rate of intermarriage is very high, genes for quantitative traits such as IQ are essentially democratic; by the third or fourth generation, descendants of gifted individuals are not much more likely to be gifted than are descendants of ordinary people.

Although their paper is entitled "The heritability of IQ", Devlin and colleagues' most important finding probably concerns the nurture rather than nature of IQ. Behavioural geneticists had previously pointed out an inconsistency in the familial IQ correlations. From data on twins that have been reared together, the heritability of IQ is estimated to be about 50%; but from twins reared apart, it is estimated at about 70% [5]. Because IQ correlations for twins reared together are based primarily on adolescents or children, whereas correlations for twins reared apart are based primarily on middle-aged adults, the discrepancy had been thought to reflect age-related increases in the heritability of IQ. This hypothesis is supported by research on octogenarian twins published earlier this year [6], as well as by studies of other familial pairings [7].

Devlin et al. offer, and provide statistical support for, an alternative account of this anomaly. Specifically, they hypothesize that failure to consider the shared prenatal environment of twins results in an overestimation of IQ heritability in studies of twins reared apart, but would not bias heritability estimates in studies of twins reared together, where shared prenatal effects are cancelled out in the comparison of monozygotic and dizygotic twin similarity. When shared prenatal environments were included in the statistical model that Devlin et al. fitted to the IQ correlations, they accounted for 20% of IQ similarity among twins but only 5% among non-twin siblings. The former estimate is particularly remarkable given that twins, and especially monozygotic twins, can experience radically different intrauterine environments even though they share the womb at the same time [8].

Devlin and colleagues' report supports the view that the main environmental influences on IQ occur early in life. If indeed they do, improved cognitive functioning might be an unexpected benefit of public health initiatives aimed at improving maternal nutrition and reducing prenatal exposure to toxins. Nonetheless, it is important to recognize that the evidence of Devlin et al., like that supporting the influence of early intellectual stimulation on synapse formation and subsequent human intellectual performance, is indirect and as yet unreplicated.

Caution is certainly warranted. In large-scale studies where pre- or perinatal influences on IQ have been assessed directly, little evidence for any strong effect has been found [9]. Perhaps this early work lacked precise assessments of prenatal exposures, or perhaps the effect of any single prenatal factor is relatively minor and thus difficult to detect. Even though it does not establish the effect of any specific prenatal factor, Devlin and colleagues' statistical analysis implies that a relatively sizable portion of IQ variability can be attributed to the aggregate effect of the prenatal environment, and so provides a rationale for reconsidering these earlier studies.

That the IQ debate now centres on whether IQ is 50% or 70% heritable is a remarkable indication of how the nature-nurture debate has shifted over the past two decades. The anti-hereditarian position that there are no genetic influences on IQ has crumbled for want of any empirical data that would support such a radical view. Equally remarkable is the increasingly dominant view that the major environmental influences on IQ occur within the first few years of life, or in the womb, and directly affect the development of the brain. Research on the nature and nurture of IQ is converging on the view that human intellectual ability has a strong, but malleable, biological basis-a convergence that Galton would, no doubt, have found quite congenial.

REFERENCES
1. Galton, F. Hereditary Genius: An Inquiry into its Laws and Consequences (Macmillan, London, 1869). [Context Link]

2. Devlin, B., Daniels, M. & Roeder, K. Nature 388, 468-471 (1997). [Context Link]

3. Neisser, U. et al. Am. Psychol. 51, 77-101 (1996). [Context Link]

4. Herrnstein, R. J. & Murray, C. The Bell Curve: Intelligence and Class Structure in American Life (Free Press, New York, 1994). [Context Link]

5. Plomin, R. & Loehlin, J. C. Behav. Genet. 19, 331-342 (1989). [Context Link]

6. McClearn, G. E. et al. Science 276, 1560-1563 (1997). Bibliographic Links [Context Link]

7. McGue, M., Bouchard, T. J. Jr, Iacono, W. G. & Lykken, D. T. in Nature, Nurture and Psychology (eds Plomin, R. & McClearn, G. E.) 59-76 (Am. Psychol. Assoc., Washington DC, 1993). [Context Link]

8. Price, B. Am. J. Hum. Genet. 2, 293-352 (1950). [Context Link]

9. Broman, S. H., Nichols, P. L. & Kennedy, W. A. Preschool IQ: Prenatal and Early Developmental Correlates (Erlbaum, Hillsdale, NJ, 1975). [Context Link]

Randall Parker said at November 18, 2006 12:19 PM:

Amy,

I do not understand where this claim of yours comes from:

An adoption study examining the heritablity of IQ using asian adoptees adopted by (largely white) American parents says nothing about the differences in IQ between koreans born in asia and the americans adopting them. Rather it suggests that children are more likely to resemble their bioligcal parents than their social parents.

....

A much more plausible conclusion to draw from this research is that americans who adopt children have above average IQs (as a group) and koreans who give up children for adoption do not.

Those Korean kids at age 28 are doing better on income than the average in America at the same age. See Alex Tabarrok's comments on this. So contrary to your guess the Korean biological parents are probably above the white IQ average. That's not surprising. Koreans have higher IQs.

As for heritability of IQ: There's not a single heritability rate. With higher IQ people in more affluent settings with less disease, hunger, and environmental toxins the heritability rate will be higher because they'll do a better job of controlling and optimizing environment. Also, heritability rises with age. So claims about low heritability based on studies of kids underestimate the effects of genes.

Left-liberal religious faith: The idea that some magical force held out his hand and stopped selective pressures from acting on genes that code for the brain differently on different populations as humans spread out across the Earth. It would take nothing less than the power of God to produce that outcome.

See A Map of Recent Positive Selection in the Human Genome, my post about Greg Cochran's theory on how selective pressures made Ashkenazi Jews so smart, and also Greg Cochran and John Hawks (and his follow-up) on news out of Bruce Lahn's lab at U Chicago for evidence of Neanderthal genes in humans.

Here's the abstract from the PNAS paper from Patrick Evans et. al. in the Lahn lab:

At the center of the debate on the emergence of modern humans and their spread throughout the globe is the question of whether archaic Homo lineages contributed to the modern human gene pool, and more importantly, whether such contributions impacted the evolutionary adaptation of our species. A major obstacle to answering this question is that low levels of admixture with archaic lineages are not expected to leave extensive traces in the modern human gene pool because of genetic drift. Loci that have undergone strong positive selection, however, offer a unique opportunity to identify low-level admixture with archaic lineages, provided that the introgressed archaic allele has risen to high frequency under positive selection. The gene microcephalin (MCPH1) regulates brain size during development and has experienced positive selection in the lineage leading to Homo sapiens. Within modern humans, a group of closely related haplotypes at this locus, known as haplogroup D, rose from a single copy 37,000 years ago and swept to exceptionally high frequency (70% worldwide today) because of positive selection. Here, we examine the origin of haplogroup D. By using the interhaplogroup divergence test, we show that haplogroup D likely originated from a lineage separated from modern humans 1.1 million years ago and introgressed into humans by 37,000 years ago. This finding supports the possibility of admixture between modern humans and archaic Homo populations (Neanderthals being one possibility). Furthermore, it buttresses the important notion that, through such adminture, our species has benefited evolutionarily by gaining new advantageous alleles. The interhaplogroup divergence test developed here may be broadly applicable to the detection of introgression at other loci in the human genome or in genomes of other species.

The full paper is free access btw.

How could all races have stayed at the same IQ level if genes came in from another species and started sweeping? Not all those genes swept the entire world. Lahn's already shown that with other genes that are expressed in the brain.

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