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  The IQ-gene: Glutathione S-transferase Omega 1?

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Author Topic:   The IQ-gene: Glutathione S-transferase Omega 1?
Volkmar Weiss
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posted 11-07-2003 08:48 PM     Click Here to See the Profile for Volkmar Weiss   Click Here to Email Volkmar Weiss     Edit/Delete Message Reply w/Quote
In 1979 Sinet, Lejeune and Jerome reported a correlation of .58 between IQ and erythrocyte glutathione peroxidase activity (GSHPx). None of the other enzymes studied correlated with IQ. However, also glutathione S-transferases (GST) possess GSH peroxidase properties. Since 1982 Weiss (Weiss 1984) is accumulating evidence that the glutathione status (Chiueh and Rauhala 1999, Janaky et al. 1999, Dringen 2000, De Maria et al. 2003) of an individual is related to its general cognitive ability and hence its IQ, also leading to correlations of cognitive decline and biochemical parameters during normal aging and diseases as Alzheimer and Parkinson. After publication of the editorial “The advent of a molecular genetics of general intelligence“, reviewing all correlations between glutathione status and IQ (read Weiss 1995 for the necessary theoretical background of this short communication here and further references, see http://www.volkmar-weiss.de/intellig.html ), in 1996 all known polymorphisms of glutathione S-transferases and glutathione peroxidases were tested (and newly discovered polymorphisms again in 2000, but not GSTO1) for any relationship with IQ by five independent research groups (personal communications by H. Moises, Kiel; H.-H. Borchert, Berlin; F. Oesch, Mainz; and others) and no association was found. (These negative findings were not published.) October 21, 2003, Li et al. at Duke University Medical Center (see http://dukemednews.org/news/article.php?id=7122 ) published the exciting finding, that a single gene (glutathione S-transferase omega-1 or GSTO1) influences the age at which individuals show symptoms of Alzheimer and Parkinson.
Already on November 1st, 1995, Weiss had written the following “Open Letter to Research Workers in the Field of the Molecular Genetics of Alzheimer’s Disease”: “Dear colleagues: Now the most important familial loci of Alzheimer’s disease are known. However, a complete understanding of the consequences of the disease will be impossible without considering the IQ of an individual before the onset of the cognitive decline. For example, a person with an original IQ of 130 will have an IQ of 100 some time after the onset of the disease and will be diagnosed far later than a person with an original IQ of 90 reduced to an IQ of 60 by Alzheimer, even when the time passed after the onset of the disease is similar in both cases. What we need, is a better understanding of the genetics of the normal IQ, too. … If the GST Theta 1 locus will be confirmed, ….”
In 1995 GSTT1 was the wrong hypothesis, but GSTO1 has been confirmed now (Li et al. 2003, see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14570706&dopt=Abstract ). Gene chips were used to test probes for about 22,000 human gene loci. After filtering and analysis at several levels a highly significant allelic association was found for age-at-onset effects in Alzheimer and Parkinson for GSTO1 and GSTO2, but not in any of the other 21, 998 genes investigated. The single nucleotide polymorphism (SNP) Ala140Asp in GSTO1 has probably in socially representative samples an Ala140 allele frequency of about .80 in populations of Eurasian descent and hence of about .20 of the Asp140 allele. The less common Asp140 allele proved to be associated with later age-at-onset for both Alzheimer and Parkinson. “Age-at-onset for Alzheimer patients was defined as the age at which the caregiver, family, and/or individual first noted cognitive problems sufficient to interfere with independent daily activities” (Li et al. 2003).
From the empirical data follows a clear-cut hypothesis: The individuals with the genotype Asp140/Asp140 should have high IQ, genotype Ala140/Ala140 a low IQ. (Other polymorphisms of GSTO1 and GSTO2 could and should be investigated later.) The allele frequencies for this polymorphism are within the range, derived from pedigree data (Weiss 1992, see http://www.volkmar-weiss.de/table.html and http://www.volkmar-weiss.de/majgenes.html ). High IQ is highly correlated with high social status. If any research group uses data on the social status (occupation, education) of their subjects, the hypothesis can be checked in a rough way (without IQ testing) with moderate efforts. The association between this polymorphism and IQ should be a strong one, for social reasons at least for male individuals.
The allele frequency of GSTO1 Asp140 has been reported 0.12 among Japanese (Reference SNP Cluster Report rs4925, see http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?searchType=adhoc_search&type=rs&rs=4925 ), 0.34 among European Australians from around Canberra , 0.08 among Bantu Africans from around Durban and 0.17 among Chinese from Hongkong (the latter three frequencies from Whitbread et al. 2003, see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12618591&dopt=Abstract ). There are no data, whether these samples were representative from the point of view of social status. There is no doubt that the activity of the Asp140 allele of the rate-limiting enzyme GSTO1 responds different from the Ala140 allele, depending on the biochemical substrate provided (Tanaka-Kagawa 2003, see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12565892&dopt=Abstract ).
What is needed, is the direct and undeniable proof that GSTO1 Ala140Asp is the major gene locus of general intelligence or the rejection of this hypothesis. For a first check in an industrialized country only genotyping of a handful of high IQ individuals (or with high social status) is necessary. When they have not the Asp140-allele, the hypothesis is proven wrong.

References
Chiueh, C.C. and P. Rauhala: The redox pathway of S-nitrosoglutathione, glutathione and nitric oxide in cell to neuron communication. Free Radical Research 31 (1999) 641-650 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10630687&dopt=Abstract
De Maria, F., Pedersen, J. Z, Caccuri, A, M., Antonini, G., Turella, P., Stella, L., Bello, M. L., Federici, G. and G. Ricci: The specific interaction of dinitrosyl-diglutathionyl-iron complex, a natural NO carrier, with the glutathione transferase superfamily. Suggestion for an evolutionary pressure in the direction of the storage of nitric oxide. Journal of Biological Chemistry 278 (2003) 42283-42293 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12498981&dopt=Abstract
Dringen, R.: Metabolism and functions of glutathione in brain. Progress in Neurobiology 62 (2000) 649-671 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10880854&dopt=Abstract
Janáky, R., Ogita, K., Pasqualotto, B. A., Bains, J. S., Oja, S. S., Yoneda, Y., and C. A. Shaw: Glutathione and signal transduction in the mammalian CNS. Journal of Neurochemistry 73 (1999) 889-902 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10461878&dopt=Abstract
Li, Y-J., Oliveira, S. A., Xu, P., Martin, E. R., Stenger, J. E., Scherzer, C. R., Hauser, M. A., Scott, W. K., Small, G. W., Nance, M. A., Watts, R. L., Hubble, J. P., Koller, W. C., Pahwa, R., Stern, B., Hiner, B. C., Anodic, J., Goetz, C. G., Mastaglia, F., Middleton, L. T., Roses, A. D., Saunders, A. M., Schmechel, D. E., Gullans, S. R., Haines, J. L, Gilbert, J. R., Vance, J. M. and M. A. Pericak-Vance: Glutathione S-transferase Omega 1 modifies age-at-onset of Alzheimer Disease and Parkinson Disease. Human Molecular Genetics, Advance Access published online ahead of print October 21, 2003 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14570706&dopt=Abstract
Sinet, P.-M., Lejeune, J. and H. Jerome: Trisomy 21 (Down`s syndrome), glutathione peroxidase, hexose monophosphate shunt and I.Q.. Life Sciences 24 (1979) 29-33
Tanaka-Kagawa, T., Jinno, H., Hasegawa, T., Makino, Y., Seko, Y., Hanioka, N. and M. Ando: Functional characterization of two variant human GSTO 1-1s (Ala140Asp and Thr217Asn). Biochemical and Biophysical Research Communications 301 (2003) 516-520 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12565892&dopt=Abstract
Weiss, V.: Psychometric intelligence correlates with interindividual different rates of lipid peroxidation. Biomedica Biochimica Acta 43 (1984) 755-763
Weiss, V.: Major genes of general intelligence. Personality and individual differences 13 (1992) 1115-1134 http://www.volkmar-weiss.de/majgenes.html
Weiss, V.: The advent of a molecular genetics of general intelligence. Intelligence 20 (1995) 115-124 http://www.volkmar-weiss.de/intellig.html
Whitbread, A. K., Tetlow, N., Eyre, H. J., Sutherland, G. R. and P. G. Board: Characterization of the human Omega class glutathione transferase genes and associated polymorphisms. Pharmacogenetics 13 (2003) 131-144 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12618591&dopt=Abstract

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