Genetic tests of biologic systems in affective disorders

Hattori, Eiji; Liu, Chun Yu; Zhu, Hongming; Gershon, Elliot S.

doi:10.1038/sj.mp.4001695

Cited by 30 publications

(22 citation statements)

References 225 publications

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“…Third, the induced depressive behavior in either sex shows an apparently identical underlying phenomenon: its induction is independent of novel protein synthesis, whereas the antidepressant effects depend on novel protein synthesis. Nevertheless, these observations are consistent with the view that a unified basis for the development of the mood disorders must exist (Hattori et al, 2005), because they occur in both men and women.…”

Section: Sun and Alkonsupporting

confidence: 78%

Differential Gender-Related Vulnerability to Depression Induction and Converging Antidepressant Responses in Rats

Sun¹,

Alkon²

2005

J Pharmacol Exp Ther

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Vulnerability of females to depression among humans has not previously been reflected in animal models. Here, we show, by using a novel animal model of depression, that young female Wistar rats are clearly more vulnerable to depression induction than the males. This differential female vulnerability follows estrous cycle stages, is associated with cognitive impairment, and can be markedly transformed with sex hormones. Male hormone reduces vulnerability in females, whereas female hormone increases vulnerability in males. The induced depressive behavior in both sexes, however, is sensitive to imipramine and to the antagonism of the glucocorticoid receptors within a hormonal pathway previously implicated in human depression. Anisomycin, a protein synthesis inhibitor, eliminates the antidepressive effects of both antidepressants and male hormone but does not affect depression induction and estradiol-induced higher vulnerability. Moreover, direct cerebroventricular administration of brain-derived neurotrophic factor (BDNF), whose mRNA levels in the hippocampus and frontal cortex reach its lowest levels when estrogen levels are highest, is sufficient to rescue the antidepressive effects in the presence of the protein synthesis inhibitor. A selective enhancement of BDNF expression and/or BDNF signal cascades in the neural circuits controlling mood may represent an effective strategy for the development of novel antidepressants for both sexes, whereas blocking the gender-related higher vulnerability to potentially depressogenic events may lead to the development of specific antidepressants for the females.

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Section: Sun and Alkonsupporting

confidence: 78%

Differential Gender-Related Vulnerability to Depression Induction and Converging Antidepressant Responses in Rats

Sun¹,

Alkon²

2005

J Pharmacol Exp Ther

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“…As a third definition of CNS genes, we applied independent expert knowledge by using a manually defined list of candidate genes for affective disorder, 28 235 of them fulfilling our inclusion criteria. These CNS candidate genes displayed a significant association with hotspots with similar effect size (OR: 1.21, P ¼ 0.03).…”

Section: Resultsmentioning

confidence: 99%

Enrichment of HapMap recombination hotspot predictions around human nervous system genes: evidence for positive selection ?

Freudenberg

Ptáček

2007

Eur J Hum Genet

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Channels and developmental genes belong to the molecular key players in the human central nervous system (CNS). Mutations in these genes often cause monogenic neurological disease and interspecies comparisons had shown reduced divergence. On the other hand, accelerated evolution of genes with roles in neurotransmission and development had indicated widespread positive selection in hominids. In the present study, we hypothesized that recombination hotspots could be enriched at genes with particularly important role in the CNS, because at those loci beneficial mutations may occur on a highly constrained background and consequently increased recombination could promote their fixation. To test this hypothesis, we retrieved CNS genes based on keyword search, expression data and expert knowledge. Consistent with our hypothesis, we find an enrichment of hotspot predictions around genes that are retrieved by all three strategies. Moreover, when comparing human genes based on their Gene Ontology annotations, we find hotspot predictions preferentially located around channels and neurodevelopmental genes. Taken together with the distinct sequence evolution that was reported by comparative genomic studies, this finding indicates continued positive selection at many CNS gene loci. In support of this interpretation, we also find an enrichment of recombination hotspot predictions around conserved noncoding regions that were reported to display a signature of accelerated evolution in the human lineage. Widespread positive selection acting on CNS gene loci could relate to the high prevalence of human nervous system disorders with genetically complex inheritance, potentially under an ancestral susceptibility allele model.

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“…An independent list of 252 genes had been compiled by the Gershon laboratory, which contains genes that are hypothesized to be involved in affective disorders. 57 One hundred and fifty-three genes from the Gershon laboratory list were not in our list (Supplementary Table S3) and these are listed in Supplementary Table S4. Of these, 74 genes had at least one variant represented on the GeneChip within 100 kb.…”

Section: Association Of Variants In or Near Candidate Genesmentioning

confidence: 99%

Genotype patterns that contribute to increased risk for or protection from developing heroin addiction

Nielsen

Yuferov

et al. 2008

Mol Psychiatry

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A genome-wide association study was conducted using microarray technology to identify genes that may be associated with the vulnerability to develop heroin addiction, using DNA from 104 individual former severe heroin addicts (meeting Federal criteria for methadone maintenance) and 101 individual control subjects, all Caucasian. Using separate analyses for autosomal and X chromosomal variants, we found that the strongest associations of allele frequency with heroin addiction were with the autosomal variants rs965972, located in the Unigene cluster Hs.147755 (experiment-wise q = 0.053), and rs1986513 (q = 0.187). The three variants exhibiting the strongest association with heroin addiction by genotype frequency were rs1714984, located in an intron of the gene for the transcription factor myocardin (P = 0.000022), rs965972 (P = 0.000080) and rs1867898 (P = 0.000284). One genotype pattern (AG-TT-GG) was found to be significantly associated with developing heroin addiction (odds ratio (OR) = 6.25) and explained 27% of the population attributable risk for heroin addiction in this cohort. Another genotype pattern (GG-CT-GG) of these variants was found to be significantly associated with protection from developing heroin addiction (OR = 0.13), and lacking this genotype pattern explained 83% of the population attributable risk for developing heroin addiction. Evidence was found for involvement of five genes in heroin addiction, the genes coding for the l opioid receptor, the metabotropic receptors mGluR6 and mGluR8, nuclear receptor NR4A2 and cryptochrome 1 (photolyase-like). This approach has identified several new genes potentially associated with heroin addiction and has confirmed the role of OPRM1 in this disease.

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Genetic tests of biologic systems in affective disorders

Cited by 30 publications

References 225 publications

Differential Gender-Related Vulnerability to Depression Induction and Converging Antidepressant Responses in Rats

Differential Gender-Related Vulnerability to Depression Induction and Converging Antidepressant Responses in Rats

Enrichment of HapMap recombination hotspot predictions around human nervous system genes: evidence for positive selection ?

Genotype patterns that contribute to increased risk for or protection from developing heroin addiction

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