Subject(s)
Carrier Proteins/genetics , Gene Expression Regulation/physiology , Nuclear Proteins/genetics , RNA, Messenger/metabolism , Racemases and Epimerases/genetics , Schizophrenia/genetics , Suicide , Analysis of Variance , Bipolar Disorder/genetics , Bipolar Disorder/metabolism , Carrier Proteins/metabolism , Humans , Nuclear Proteins/metabolism , Racemases and Epimerases/metabolism , Schizophrenia/metabolism , Schizophrenic PsychologyABSTRACT
Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of approximately 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 x 10(-294)). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.
Subject(s)
DNA Methylation , Gene Expression Profiling , Twins, Dizygotic/genetics , Twins, Monozygotic/genetics , Adolescent , Animals , Animals, Outbred Strains , Case-Control Studies , Child , Chromosome Mapping , CpG Islands , DNA Methylation/physiology , Epithelial Cells/metabolism , Female , Humans , Leukocytes/metabolism , Male , Mice , Mice, Inbred Strains , Mouth Mucosa/metabolism , Oligonucleotide Array Sequence Analysis , Promoter Regions, GeneticABSTRACT
Dopamine-and-cAMP-regulated neuronal phosphoprotein (32 kDa) (DARPP-32), encoded by PPP1R1B, is expressed in brain regions receiving dopaminergic projections, including the prefrontal cortex (PFC), and is implicated in the pathophysiology of schizophrenia. The broad functional capacity of DARPP-32 has potential relevance to both psychotic and negative symptoms of schizophrenia. We wished to determine if DARPP-32 gene expression and variation at selected SNPs correlated significantly with patient phenotypes. We performed RT-PCR to quantify DARPP-32 mRNA from brain samples (Brodmann Area 46) donated by the Stanley Medical Research Institute (SMRI, Array Collection): 35 from unaffected controls (UC), 35 from patients with schizophrenia (SCZ), and 35 with bipolar disorder (BP). Relative mRNA expression was calculated in relation to the housekeeping gene Cyclophilin. SNP genotyping was conducted by PCR on DNA obtained from Brodmann Area 46. We found a significant difference in gene expression levels between SCZ patients who died by suicide (SCZ-S) (n=6) vs. other causes of death (SCZ-NS) (P<0.004), as well as between SCZ-S and UC (P<0.04). We genotyped the intron SNP rs907094 and found that the SCZ-S group was more similar to UC than to the SCZ-NS population. DARPP-32 expression differences between SCZ-S, SCZ-NS, and UC populations are consistent with previous literature suggesting that serotonin system components are also altered in suicide. Work in a larger sample is needed to confirm these findings.
