ABSTRACT
Monoamine Oxidase A (MAOA) is a critical enzyme in the catabolism of monoaminergic neurotransmitters. MAOA transcriptional activity is thought to be regulated by a well characterized 30 base pair (bp) variable nucleotide repeat (VNTR) that lies approximately â¼1000 bp upstream of the transcriptional start site (TSS). However, clinical associations between this VNTR genotype and behavioral states have been inconsistent. Herein, we describe a second, 10 bp VNTR that lies â¼1500 bp upstream of the TSS. We provide in vitro and in silico evidence that this new VNTR region may be more influential in regulating MAOA transcription than the more proximal VNTR and that methylation of this CpG-rich VNTR is genotype dependent in females. Finally, we demonstrate that genotype at this new VNTR interacts significantly with history of child abuse to predict antisocial personality disorder (ASPD) in women and accounts for variance in addition to that explained by the prior VNTR.
Subject(s)
Antisocial Personality Disorder/genetics , Gene Expression Regulation , Monoamine Oxidase/genetics , Adult , Alleles , Female , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Promoter Regions, GeneticABSTRACT
There is a growing body of data indicating that Gene x Child Maltreatment interactions at monoamine oxidase A (MAOA) play a role in vulnerability to symptoms of antisocial personality disorder (ASPD) but not major depression (MD). Using a sample of 538 participants from the Iowa Adoption Studies, we introduce a conceptual model that highlights two distinct pathways from child maltreatment to symptoms of MD, suggesting that maltreatment has different effects depending on genotype and highlighting the importance of including the indirect pathway through ASPD. As predicted by the model, high activity alleles predispose to symptoms of MD in the context of child maltreatment whereas low activity alleles predispose to symptoms of ASPD. We conclude that the Gene x Environment interplay at this locus (MAOA) contributes to both symptoms of ASPD and MD and that careful specification of child maltreatment may be essential if genetic association research is to produce replicable results.
Subject(s)
Antisocial Personality Disorder/genetics , Antisocial Personality Disorder/psychology , Child Abuse/psychology , Child Abuse/statistics & numerical data , Depressive Disorder, Major/genetics , Depressive Disorder, Major/psychology , Monoamine Oxidase/genetics , Child, Preschool , Female , Genotype , Humans , Infant , Male , Middle AgedABSTRACT
The serotonin reuptake transporter (5HTT) is thought to be the principal regulator of serotonergic activity and epigenetic effects at this locus are thought to be important moderators of vulnerability to neuropsychiatric illness. In attempt to understand the basis of this regulation, several gene polymorphisms that affect 5HTT mRNA levels have been described. But to date, no clear mechanism linking these polymorphisms to vulnerability to epigenetic effects have been described. In this communication, we describe a CpG island in the 5' region of the 5HTT gene that contains an alternative exon 1 and possible promoter for 5HTT. We then confirm the existence of this transcript and ascertain the methylation status of this CpG island in 49 lymphoblast cell lines and analyze the relationship between methylation and 5HTT mRNA levels. We demonstrate that methylation at this CpG island is associated with decreased levels of 5HTT mRNA, but that this effect is evident only when 5HTTLPR genotype is taken into account. We suggest that these findings have significant implications for the understanding of the role of this locus in behavioral illness.
Subject(s)
RNA, Messenger/genetics , RNA, Messenger/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Base Sequence , Cell Line , CpG Islands , DNA Methylation , DNA, Complementary/genetics , Epigenesis, Genetic , Exons , Genetics, Behavioral , Genotype , Humans , Molecular Sequence Data , Promoter Regions, GeneticABSTRACT
Some serological and genetic studies have suggested that alterations in folate metabolism are associated with increased vulnerability to schizophrenia. In particular, these findings are most striking for the role of a putatively functional variant (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene. To test the hypothesis that the T allele and the TT genotype are risk factors for psychosis, we genotyped the C677T polymorphism in 206 participants with schizophrenia or schizoaffective disorder and 359 participants from a population control sample. Neither the T allele nor the TT genotype was associated with increased risk for schizophrenia. These results do not support a role for the C677T MTHFR variant in schizophrenia.
