Published in: Personality and individual Differences 13 (1992) 1115-1134
MAJOR GENES OF GENERAL INTELLIGENCE
VOLKMAR WEISS
Summary. - Evidence in favour of the major gene theory of intelligence is stated in summary form.
Empirical distributions from studies on giftedness by Terman and Weiss and data of social mobility can be explained by the existence of a major gene that in the homozygous state is the prerequisite to have an IQ of 130 or higher. Under the assumption of about 10% misclassification of genotypes, family data are in agreement with Mendelian segregation at such a major gene locus.
Elementary cognitive tasks, highly correlated with IQ, are not distributed normally. On the absolute scale of short-term memory capacity (measured in bits), defined as the product of memory span and mental speed, the heterozygotes are intermediate between the homozygotes.
Where there are major genes, there must be an underlying biochemical code, which can be detected. To this aim enzymes, responsible for the regulation of brain energy metabolism and correlated with IQ and social status, should be the target of further research.
From the point of view of evolution, social stratification and the frequency of major genes of intelligence depend upon each other.
Content
miRNA, Trinucleotide Repeats, Glutathione Status and the Genetics of IQ
Volkmar Weiss
Until now, more than 1 000 000 SNPs have already been investigated for an association with IQ by Plomin, Deary et al. and others. No major effect has been discovered which could explain the high heritabiltiy of general cognitive ability and the pattern of Mendelian segregation of IQ in the normal range of variation. Plomin et al. found only very small and mostly non-replicable effects. Therefore, our mind should be open for a broader outlook and new hypotheses.
MicroRNAs as regulatory factors in gene expression renders them attractive candidates for harbouring genetic variants with effects on IQ. There is already ample evidence that miRNA-mediated gene regulation plays an important role in a number of neurodegenerative diseases. MiRNAs bind to complementary sequences in the three prime untranslated regions (3' UTRs) of target messenger RNA transcripts. MiRNA genes are found in intergenic regions or in anti-sense orientation to genes and contain their own miRNA gene promoter and regulatory units. As much as 40% of miRNA genes may lie in the near-gene introns of protein and non-protein coding genes or even in exons.
Our first example:
Harold, D. et al., Nature Genetics 41 (2009) 1088ff. have found out and replicated compelling evidence that rs3851179 of the PICALM gene is associated with alzheimer. The homozygotes and heterozygotes of the rare allele A of rs3851179 have a 0,86x decreased risk for alzheimer. - Since many years I am looking for such findings, because we should expect that probands of high general intelligence (high IQ) have a later onset of alzheimer and a decreased risk. Surprisingly, the allele frequencies not only of rs3851179, but even more of rs669556 and of at least 30 other SNPs in this near gene region exhibit the frequencies of a hypothetical major gene locus of general intelligence, see http://www.v-weiss.de/majgenes.html and http://knol.google.com/k/national-iq-means#
As it seems, at the moment, nobody has an explanation why the non-coding SNP rs3851179 is associated with alzheimer and why in a large chunk of DNA with copy number variation a high number of SNPs exhibits similar allele frequencies in all the populations of the HapMap project. In which way could such a phenomenon have been stabilized by natural selection? Could this region be coding for miRNA or be its binding target?
The second example:
By checking routinely the bibliographical details of paper published together with A. Payton et al. on "Investigation of a functional quinine oxireductase (NQO2) polymorphism and cognitive decline" in Neurobiol. Aging 31 (2010) 351, I became aware of a publication on "Genetic variant
of glutathione peroxidase 1 in autism" Brain Dev. 32 (2010) 105
Since 1982 I did collect evidence on a relationship between glutathione peroxidase activity, general cognitive ability (IQ) and social status (for example, measured by years of education as a good surrogate). I quote in the following from an editorial published by me 1994 in the journal "Intelligence":
"In 1982 I became aware of a paper published by Sinet, Lejeune & Jerome (1979) in which a correlation of .58 between IQ and erythrocyte glutathione peroxidase activity (GSHPx, now GPX1) was reported for 50 trisomy 21 patients. None of the other enzymes studied correlated with IQ. Sinet et al. thought the correlation to be trisomy-specific, because an increase of about 50% in the superoxide dismutase activity (SOD-1) can be observed in cells from trisomy 21 patients. There is a feedback control of GSHPx concentration by the amount of superoxide, which explains the elevated activity of GSHPx in cells of trisomy 21 patients. However, Fraser and Sadovnick (1976) had found that the correlations of IQ between trisomy 21 probands with their fathers, mothers and sibs are about .50, consequently of the same size as with healthy children despite the mean IQ of trisomy 21 probands being about 70 points lower. Therefore already Lenz (1978) had concluded that individual differences in trisomy-IQ have generally the same biochemical background as in normal persons. And Brugge et al. (1992) confirmed a correlation of .73 between erythrocyte GSHPxactivity anda short-term memory score. ... By Gerli et al. (1984) GSHPx was assayed in families and the results support the existence of two Mendelian alleles.? For the full text see http://www.v-weiss.de/intellig.html
In the following years I instigated a number of colleagues from all over the world to discover the underlying genetic cause of the cited correlations, but nearly completely in vain. We investigated SNPs of GST transferases, NQO and many, many others. Therefore I came to the conclusion that the major contribution to the correlation between lipid peroxidation and IQ could or should be the effect of a gene with copy number variations and repeat polymorphisms for which data are still not available or incomplete.
In April 2010, at the present state of knowledge, GPX1 is such a gene for which at least 4 common frameshift polymorphisms are already known. The arguments in favor of a relationship between trinucleotide repeat polymorphisms of GPX1 and general cognitive ability are holding for GCLC and its GAG-repeat polymorphism, too. GCLC influences the glutathione status of an individual to a high degree. The GCLC repeat polymorphism with its known large population differences in allele frequences is located in the three prime untranslated region (3' UTR) and therefore a likely binding target of a miRNA! In view of the claimed relationship of GSH/GSSG redox status with schizophrenia and other neurodegenerative diseases, we should be eager to see whether a correlation between GCLC GAG-repeat status and general cognitive ability can be confirmed or not, see
http://www.google.de/search?hl=de&source=hp&q=GCLC+GAG-repeat&btnG=Google-Suche&meta=&aq=f&aqi=&aql=&oq=&gs_rfai
As I see, new publications and reviews on the relationship between glutathione status and brain function are not aware of some older publications. In the appendix ?Memory as a
?It would defy the most fundamental laws of thermodynamics, when individual differences in brain power would not find their counterpart in individual differences of brain energy metabolism. ? Reactions involving S-S or S-H groups of proteins may readily account for the apparently opposite effects of the same control mechanism. ? . At this point we direct attention to the correlation (.58) between IQ and glutathione peroxidase (GSHPx, now GPX) activity (SINET et. 1979) ? In modulating the GSH/GSSG ratio, GSHPx not only contributes to the regulation of glycolysis (GILBERT 1984) but consequently also the adenylate energy charge (REHNCRONA et al. 1980) and the NADP/NADPH ratio (GRIMM 1978) are prefectly correlated (r = 1.00!) with glutathione status. Thus the fundamental chemical needs of a living cell, high-energy phosphate stores (ATP) and reducing power (NADPH) depend upon the cortical concentration of glutathione, and the dynamic behavior of a complex system can be reduced to the molecular properties of a master enzyme in an energy pathway.?
The combination of autozygosity mapping and microarray RNA expression analysis has led to the discovery of new genetic polymorphisms underlying nonsyndromic mental retardation with autosomal-recessive inheritance, see http://www.medicalnewstoday.com/articles/174204.php and
http://www.cell.com/AJHG/abstract/S0002-9297(09)00522-9
We can be convinced that the application of similar methods to consanguineous families with several members in the high IQ range will lead to the discovery of gene polymorphisms underlying variability of IQ in the upper and normal range of the distribution. Sites where miRNA is coded or binding and these are especially regions with trinucleotid repeats in the 3?UTRs as GCLC should be investigated as soon as possible.
For all such neurodegenerative diseases as schizophrenia, autism, alzheimer and so on general cognitive ability (IQ) has to be seen as a major confounding variable, and nobody will obtain clearcut results in the genetics of neurodegenerative diseases as long as the genetic background of IQ in the normal range of variation remains unknown.
I thank my eldest daughter, Dr. Cornelia Weiss-Haljiti, for helpful discussions, Easter 2010.
Volkmar Weiss
In 2009 the combination of autozygosity mapping and microarray RNA expression analysis has led to the discovery of new genetic polymorphisms underlying nonsyndromal intellectual disability (ARNSID) with autosomal recessive inheritance. We can be convinced that the application of similar methods to consanguineous families with several members in the high IQ range will lead to the discovery of copy number variations and other gene polymorphisms underlying the variability of IQ in the upper and normal range of the IQ distribution. Time and methods are ripe for such an approach.
ARNSMR polymorphisms can be understood as a bridge to IQ variation in the normal range. However, for example, until now nothing is known on the correlation of IQ with common polymorphisms of the human cereblon gene (CRBN). Higgins et al. did nothing publish about the mean IQ of heterozygotes of the mutation in the CRBN gene, whose homozygotes have an IQ between 50 and 70.
To date (February 2010), about 20 ARNSMR loci have been mapped and four genes identified. The ARSNMR causing genes belong to different protein families, including serine proteases, adenosine 5'-triphosphate-dependent Lon proteases and calcium-regulated transcriptional repressors. All of the mutations in the ARNSMR-causing genes are protein truncating, indicating a severe loss-of-function effect. Analogous polymorphisms can be assumed to be underlying IQ in the normal range of distribution between IQ 70 and 140.
Volkmar Weiss
March 26, 2009
If we take seriously the results of more than a century of research on a possible genetic background of general intelligence (IQ), then a different distribution of allele frequencies in different populations and social strata should be expected (see "Major genes of general intelligence":www.v-weiss.de/majgenes.html and the final chapter of "Gene frequencies underlying national IQ means":www.v-weiss.de/calibration.html).
The present state of knowledge allows a first attempt to search for a major gene locus of IQ by data mining. From the total of 76690 nonsynonymously coding SNPs in the HapMap database, I have used the database SNPlogic to filter out 204 SNPs fitting within the expected ranges of allele frequencies in samples of European (CEU), Chinese (CHB), Japanese (JPT) and Sub-Saharan Yoruba (YRI) populations. Because among Europeans the frequency of the minor allele underlying high IQ in the homozygous state should not exceed 0.30, homozygosity by pure chance (0.30 x 0.30) can be expected in less than 0.10 of cases. Assuming (without IQ testing) that Craig Venter is a proband of high IQ, I used the published “Craig Venter genome”:http://jimwatsonsequence.cshl.edu/cgi-perl/gbrowse/cvsequence/ by looking for homozygosity of the rare allele and reduced in this way the list of candidate SNPs from 204 to 22.
Theoretically, by adding a second high-IQ proband with decoded genome data of similar quality to that of Craig Venter’s, this list could be further reduced by a factor of 0.10 to about 2, including the sought-after major gene locus. However, the next step, to exclude from these 22 at least the SNPs where James Watson is homozygous for the opposite (common) allele, led to no result at all. For 10 candidate SNPs there are no data in the James Watson genome database. All other SNPs are given as heterozygous with differing probabilities. In other words: The published James Watson genome database is completely unreliable.
However, with the help of Steven Pinker I came a step further. The Personal Genome Project and 23andMe are using the 500 K Affymetrix chip for genotyping. From analysing the Pinker data it follows that a high IQ gene cannot be on this chip. By data mining (and without any funding) I am replicating in this way the completely negative results of Plomin et al., who found no replicable correlation between any SNP on the 500 K Affymetrix chip and IQ. Contrary to Plomin, who is of the opinion that there exists no single gene with any substantial contribution to IQ, I drew the conclusion from his research that he always searched with insufficient methods at the wrong places.
At present, after the exclusion of all the SNPs which are on the 500 K Affymetrix chip, there remain the following 11 or 12 SNPs as candidates for a major gene locus of IQ (listed below with the Venter genotype and HapMap population frequencies of this allele):
rs238234 CAMTA2 Venter CC CEU 0.17 CHB 0.50 JPT 0.53 YRI 0.03
rs428785 ADAMTS1 Venter CC CEU 0.22 CHB 0.57 JPT 0.59 YRI 0.03
rs1919128 C2orf16 Venter GG CEU 0.24 CHB 0.56 JPT 0.62 YRI 0.04
rs2584625 probably identical with rs2727288 FTSJ3 Venter GG and/or TT CEU 0.38 CHB 0.40 JPT 0.46 YRI 0.00
rs3095726 ZNF573 Venter TT CEU 0.18 CHB 0.58 JPT 0.72 YRI 0.00
rs6961834 tcag7956 Venter TT CEU 0.37 CHB 0.48 JPT 0.44 YRI 0.06
rs4883918 DIS3 Venter CC CEU 0.19 CHB 0.51 JPT 0.51 YRI 0.03
rs12507582 DDX60L Venter TT CEU 0.31 CHB 0.63 JPT 0.70 YRI 0.03
rs12764004 BMS1 Venter AA CEU 0.20 CHB 0.48 JPT 0.34 YRI 0.03
rs13151700 DDX60L Venter GG CEU 0.32 CHB 0.60 JPT 0.70 YRI 0.05
rs17078347 PCDH24 Venter AA CEU 0.21 CHB 0.39 JPT 0.38 YRI 0.00
For some of these 10 genes very little is known. For others, for example CAMTA2 (now on the Illumina 1M chip), the present state of knowledge suggests they may be involved in information processing. The protein encoded by this gene is a member of the calmodulin-binding transcription activator (CAMTA) protein family and may function as a transcription factor that responds to calcium signalling by directly binding to calmodulin.
One should be aware that the Asian samples drawn from Beijing and Tokyo are not socially representative in any way. The Chinese HapMap (CHB) sample comes from a Beijing university resident academic population. Because little or nothing is known on the social representativeness of such population samples in general, thresholds for filtering out candidate SNPs could only be set using assumptions that could be wrong. Other sources of possible error are the incompleteness and unreliability of current databases.
After surviving two attacks of non-Hodgkin lymphoma, I had to retire and no longer have access to laboratory facilities of my own. Therefore, I am calling on colleagues all over the world to reduce this list of 10 candidate high-IQ genes to one or none. If the sought-after gene should actually be among these 10, we should all be surprised. I myself would rather expect a deletion and copy number variation (CNV) should or could underlie major IQ differences and not a single nucleotide polymorphism. However, at present, databases do still not contain population frequencies of CNV.
It should be demonstrated that by applying the powerful logic of genetics and available knowledge it is already possible to put forward reasonable hypotheses on IQ genes simply by data mining. Within a few years we will have open access to more and better databases. Therefore, we should be confident that a true breakthrough in IQ genetics is imminent, even without any funding and despite all political opposition and repression of this type of research. After their retirement, old men have nothing to fear anymore.
Without the help of Ivan Smirnov (SNPlogic), Steven Pinker and Andrew Walsh this data mining would not have been possible.
For the genetics of general intelligence, the copy number variation of genes causes methodological challenges of a new and unexpected magnitude. What is needed to overcome these challenges is array-based homozygosity mapping and high-resolution microarray-based comparative genomic hybridization (array CGH) within consangineous families, see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16311745&query_hl=11 comprising a number of probands with an IQ above 124.
The investigation of pooled DNA samples by Plomin et al. has led to nothing at all. His opinion that high IQ is caused by a very large number of genes each accounting for a very small percentage of variance is nothing else than the declaration of complete bankruptcy of his approach. It is practically equivalent with the politically motivated point of view that there are no genes at all underlying general intelligence. I see no decisive difference.
Of course, array-based homozygosity mapping of candidate genes regions and high-resolution microarray-based comparative genomic hybridization (array CGH) within consangineous families, in order to detect such regions, needs fare more money and effort than investigating pooled DNA.
Percentage of higly gifted and high IQ subjects among the relatives of highly gifted
This is an exceptional book ... . It leaves the protected intellectual field of 'pure science' and extends psychology into the battle field of politics, sociodemographic and economic statistics and statements by promoting ideas which are partly contrary to the present Zeitgeist. ... It is recommended for everybody who engages in intelligence research and wants to convey the idea of the relevance of this concept to all areas of social and political life, and it should be recommended to students of psychology. It would be useful to have an English translation.
Charles Spearman: "General intelligence," objectively determined and measured.