Some researchers in the field of psychiatric genetics have become somewhat pessimistic about the ability to detect robust genotype-phenotype correlations using the diagnostic criteria defined by DSM-IV. If we analyze tens of thousands of samples, the ensuing results may be statistically robust, but still the effect of common variant(s) of each gene will be modest. Recently, Tan et al. (2008) reported that the AKT1 gene SNP rs1130233 and its encompassing haplotypes are significantly associated with IQ/processing speed, activities that may reflect frontal cortex function. They also showed that performance in their psychological test battery is influenced not only by AKT1 genetic variants but also the well-known COMT gene non-synonymous polymorphism (SNP rs4680, Val158Met). By undertaking fMRI analysis, they intertwined the IQ/processing speed-frontal cortex-AKT1 signal-DA system, i.e., the. integration of multidimensional disciplines. In citing references (Meyer-Lindenberg and Weinberger, 2006; Weinberger et al., 2001), they state that “there is a growing body of data showing that genes weakly associated with complex constellations of behavioral symptoms are much more strongly associated with in vivo brain measures.” Indeed, they have succeeded in explaining a possible role for AKT1 in brain execution capability, but have not provided convincing evidence for genetic associations between AKT1 and schizophrenia.
Their current results are elegantly derived from “a complex set of experiments addressing association of multiple variants in a gene with many phenotypic measures.” However, from a genetic perspective, we may still ask the following questions, irrelevant of the current study:
1. What is the genetic component (or heritability) of each psychological and imaging trait? Can variations in some of the psychological/cognitive/intellectual performances be fully captured by a single gene in an experimental set that examines, at the most, a hundred samples? We have learned the hard way from genetic association studies done in the 1990s, which examined a small number of samples, that we simply cannot trust those results. With regard to this point, the heritability calculations of so-called “endophenotypes” as reported by Greenwood et al. (2007) can give helpful information [also see Watanabe et al., 2007, supplementary Table S2]. There is the possibility that the genetic architecture of neurocognitive functions and imaging measures may not be simpler than the current disease category (entity).
2. Given the rapid advances in genotyping technology, we may be able to generate genome-wide genetic test results for every neuropsychiatric trait in the near future.
3. Because of the functional significance of AKT1 and the divergence in the signaling cascade downstream of AKT1, it would be wise to confine analysis to this gene. However, it is frustrating that we still do not know the functionally important SNP(s) of AKT1 in spite of numerous association studies.
4. Nackley et al. (2006) have convincingly demonstrated that the haplotype of the COMT gene constructed by synonymous SNPs has much more functional impact than the Val158Met polymorphism. Therefore, we would like to see the association studies examining this haplotype in future neuropsychiatric studies.
From a biochemical perspective, the following issues would be interesting and future targets for clarification:
1. The authors suggest that the coding synonymous variation of AKT1 affects protein expression, leading to the alteration of frontostriatal function and gray matter volume. The activity of AKT1 is regulated by its phosphorylation status. Therefore, readers would want to know whether the reduction of AKT1 expression levels actually affect the AKT signaling pathway. Behavioral analysis and an MRI study of Akt1 heterozygote knockout mice may provide relevant information.
2. Impairment of the AKT signal is known to result in tau hyperphosphorylation through activation of GSK3 as seen in Alzheimer disease brains. According to this idea, a reduction of AKT levels caused by SNP(s) should elicit hyperphosphorylation of tau and ultimately form neurofibrillary tangles (NFTs). In contrast, there are some reports suggesting the absence of NFTs and neuroinjury in elderly patients with schizophrenia (Arnold et al., 1998; Purohit et al., 1998). It is also reported that GSK3 is reduced in schizophrenia (Beasley et al., 2001). It would be interesting to know whether the genetic variation(s) of AKT1 that induce decreased protein expression affect tau accumulation.
3. Lithium inhibits the arrestin-Akt signal (Beaulieu et al., 2008). If so, it would be interesting to know whether lithium treatment can restore some of the effects of reduced AKT1 expression levels caused by the SNP(s) of interest.
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