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Logo of behbrainBioMed CentralBiomed Central Web Sitesearchsubmit a manuscriptregisterthis articleBehavioral and Brain Functions : BBFJournal Front Page
 
Behav Brain Funct. 2012; 8: 28.
Published online May 31, 2012. doi:  10.1186/1744-9081-8-28
PMCID: PMC3487746
Paradox of schizophrenia genetics: is a paradigm shift occurring?
Nagafumi Doi,corresponding author1 Yoko Hoshi,2 Masanari Itokawa,3 Takeo Yoshikawa,4 Tomoe Ichikawa,3 Makoto Arai,3 Chie Usui,5 and Hirokazu Tachikawa6
1Ibaraki Prefectural Medical Center of Psychiatry, 654Asahi-machi, Kasama-shi, Ibaraki, 309-1717, Japan
2Integrated Neuroscience Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan
3Project for Schizophrenia and Affective Disorders Research, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan
4Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1Hirosawa, Wako-shi, Saitama, 351-0198, Japan
5Department of Psychiatry, Juntendo University Nerima Hospital, 3-1-10 Takanodai, Nerima-ku, Tokyo, 177-8521, Japan
6Department of Psychiatry, Graduate School of Comprehensive Human Science, Tsukuba University, Tsukuba-shi, Ibaraki, Japan
corresponding authorCorresponding author.
Nagafumi Doi: n.doi/at/pref.ibaraki.lg.jp; Yoko Hoshi: hoshi-yk/at/igakuken.or.jp; Masanari Itokawa: itokawa-ms/at/igakuken.or.jp; Takeo Yoshikawa: takeo/at/brain.riken.jp; Tomoe Ichikawa: ichikawa-tm/at/igakuken.or.jp; Makoto Arai: arai-mk/at/igakuken.or.jp; Chie Usui: chiec/at/med.juntendo.ac.jp; Hirokazu Tachikawa: tachikawa/at/md.tsukuba.ac.jp
Received November 18, 2011; Accepted April 27, 2012.
Abstract
Background
Genetic research of schizophrenia (SCZ) based on the nuclear genome model (NGM) has been one of the most active areas in psychiatry for the past two decades. Although this effort is ongoing, the current situation of the molecular genetics of SCZ seems disappointing or rather perplexing. Furthermore, a prominent discrepancy between persistence of the disease at a relatively high prevalence and a low reproductive fitness of patients creates a paradox. Heterozygote advantage works to sustain the frequency of a putative susceptibility gene in the mitochondrial genome model (MGM) but not in the NGM.
Methods
We deduced a criterion that every nuclear susceptibility gene for SCZ should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. SCZ-associated variants listed in the top 45 in the SZGene Database (the version of the 23rd December, 2011) were selected, and the distribution of the genes that could meet or do not meet the criterion was surveyed.
Results
19 SCZ-associated variants that do not meet the criterion are located outside the regions where the SCZ-associated variants that could meet the criterion are located. Since a SCZ-associated variant that does not meet the criterion cannot be a susceptibility gene, but instead must be a protective gene, it should be linked to a susceptibility gene in the NGM, which is contrary to these results. On the other hand, every protective gene on any chromosome can be associated with SCZ in the MGM. Based on the MGM we propose a new hypothesis that assumes brain-specific antioxidant defenses in which trans-synaptic activations of dopamine- and N-methyl-d-aspartate-receptors are involved. Most of the ten predictions of this hypothesis seem to accord with the major epidemiological facts and the results of association studies to date.
Conclusion
The central paradox of SCZ genetics and the results of association studies to date argue against the NGM, and in its place the MGM is emerging as a viable option to account for genomic and pathophysiological research findings involving SCZ.
Keywords: Mutation-selection balance, Heterozygote advantage, Sex difference, MtDNA, Gene-gene interaction, Gene-environment interaction, Protective gene, Mitochondrial dysfunction, Oxidative stress, Genomic instability
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