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Gabriele S.,Biomedical University of Rome | Lombardi F.,Biomedical University of Rome | Lombardi F.,Laboratory of Psychiatric Genetics | Sacco R.,Biomedical University of Rome | And 8 more authors.
Journal of Psychiatric Research

Glyoxalase I (GLO1) is a homodimeric Zn2+-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with "unaffected sibling" status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P<0.05 and P<0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N=38 and 13, respectively) of typically developing C332 allele carriers (P<0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P=0.001), with a strong negative correlation between glyoxalase activity and AGE levels (τ=-0.588, P<0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (τ=-0.209, P=0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P<0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects. © 2014 Elsevier Ltd. All rights reserved. Source

Hammer C.,University of Heidelberg | Cichon S.,University of Bonn | Cichon S.,Institute of Neuroscience and Medicine INM 1 | Muhleisen T.W.,University of Bonn | And 18 more authors.
Translational Psychiatry

Serotonin type 3 receptors (5-HT 3) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the HTR3A and HTR3B genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P = 0.009, 95% confidence intervals = 0.802-0.968) for the non-synonymous functional SNP HTR3B p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR = 0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of HTR3A and HTR3B mRNA in the human brain. HTR3A and HTR3B were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired 5-HT 3 receptor function in BPAD. © 2012 Macmillan Publishers Limited All rights reserved. Source

Szczepankiewicz A.,Laboratory of Psychiatric Genetics | Szczepankiewicz A.,Poznan University of Medical Sciences | Leszczynska-Rodziewicz A.,Laboratory of Psychiatric Genetics | Pawlak J.,Laboratory of Psychiatric Genetics | And 5 more authors.
Psychiatric Genetics

OBJECTIVE: Genes involved in the regulation of the hypothalamus-pituitary- adrenal axis are responsible for altered susceptibility to mood disorders. The aim of this study was to analyze the possible association of CRHR1 and AVPR1b gene variants with bipolar disorder and major depressive disorder (MDD). METHODS: In the study, we included 486 patients with bipolar disorder and 215 patients with MDD. Consensus diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, using the Structured Clinical Interview for DSM Disorders. The control group consisted of 712 healthy participants. Genotyping of CRHR1 and AVPR1b polymorphisms was performed using TaqMan single nucleotide polymorphism genotyping assays. Linkage disequilibrium analysis was carried out on Haploview. Gene-gene interactions were analyzed using the multifactor dimensionality reduction method. RESULTS: By single marker analysis we have found an association of rs28536160 of AVPR1b and rs4076452 and rs16940655 of CRHR1 with mood disorders (P=0.036, 0.0013, and 0.003, respectively). We observed strong linkage disequilibrium between seven CRHR1 polymorphisms grouped in two haplotype blocks; however, none of them showed an association with MDD or bipolar disorder. Similarly, no association was found for three of four strongly linked AVPR1b polymorphisms. Gene-gene interaction analysis revealed a significant epistatic interaction between AVPR1b and CRHR1 genes in susceptibility to MDD (P=0.017). CONCLUSION: Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

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