Association study of suicidal behavior and affective disorders with a genetic polymorphism in ABCG1, a positional candidate on chromosome 21q22.3

The gene that codes for the ABC transporter ABCG1 is located in a chromosomal susceptibility region (21q22.3) for affective disorders. Genetic variations in ABCG1 have been associated with affective disorders in Japanese males. In this study, we investigated the distribution of a G2457A polymorphism in patients with affective disorders, suicide attempters with various psychiatric diagnoses and healthy subjects, We initially found a trend towards a modest association with affective disorders in males (p = 0.046 for allele frequencies and p = 0.046 for AA versus GG). We conducted a replication study with independent patients and controls, There was no association with affective disorders, either in the replication or in the combined group, Furthermore, we found no association with suicidal behavior, These findings do not support the hypothesis that ABCG1 is a susceptibility gene for affective disorders or suicidal behavior. Copyright (C) 2000 S. Karger AG, Basel

No association of a set of candidate genes on haloperidol side effects

We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 ( 3c one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p\u200a=\u200a0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effect

Mild expression differences of MECP2 influencing aggressive social behavior

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (∼50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2mRNA expression differs in peripheral blood mononuclear cells by ∼50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior