MicroRNA, trinucleotide repeats, and the genetics of general cognitive ability (IQ)

A full understanding of the genetics of schizophrenia, autism, dyslexia, attention deficit hyperactivity disorder (ADHD), alzheimer and a large number of neurodegenerative diseases seems to be impossible without reckoning with IQ as a major confounding variable. Nobody will obtain clearcut results in the genetics of neurodegenerative diseases as long as the genetic background of general intelligence remains unknown. Despite this in many samples IQ variation is not controlled by collecting data on years of education and social status of probands which provide good surrogates of IQ estimates, at least in industrialized countries.

Until now, more than 1 million of 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 heritability of general cognitive ability and the known 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. 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. 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.” 

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 repeat polymorphisms, too.  Glutamate-cysteine ligase (GCL) is the rate limiting enzyme in glutathione synthesis. GCLC repeat polymorphisms are located in the 3' UTR and 5’UTR regions and therefore a likely binding target of 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 and its trinucleotide repeats and IQ can be confirmed or not. For the GLCL GAG-repeat status ethnic differences of allele frequencies are known.

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 Macroscopic Ordered State by Entrainment and Resonance in Energy Pathways”, pp. 201-221, of the monograph “Psychogenetik der Intelligenz”. Dortmund. Verlag Modernes Lernen 1986, I wrote on p. 210ff:

“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 Medical News Today and Cell.  

Conclusion

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 are coded or binding and those are especially regions with trinucleotid repeats in the UTRs as in the case of GCLC should be investigated as soon as possible. Until now, all known cases of a causal relationship between copy number variation of trinucleotid repeats and disease have been neurodegenerative diseases and are associated with different degrees of  mental retardation . Therefore the idea, that also the hitherto unknown genetic variation underlying the normal range of IQ could have similar causes (see Tam et al,  Anthony et al, and Barbato et al) , seems not be far fetched.