Abstract
Identification of 108 genomic regions significantly associated with schizophrenia risk by the Psychiatric Genomics Consortium was a milestone for the field, and much work is now focused on determining the mechanism of risk associated with each locus. Within these regions, we investigated variability of DNA methylation, a low-level cellular phenotype closely linked to genotype, in two highly similar cellular populations sampled from the human hippocampus, to draw inferences about the elaboration of genotype to phenotype within these loci enriched for schizophrenia risk. DNA methylation was assessed with the Illumina HumanMethylation450 BeadArray in tissue laser-microdissected from the stratum oriens of subfield CA1 or CA2/3, regions having unique connectivity with intrinsic and extrinsic fiber systems within the hippocampus. Samples consisted of postmortem human hippocampus tissue from eight schizophrenia patients, eight bipolar disorder patients, and eight healthy control subjects. Within these genomic regions, we observed far greater difference in methylation patterns between circuit locations within subjects than in a single subregion between subjects across diagnostic groups, demonstrating the complexity of genotype to phenotype elaboration across the diverse circuitry of the human brain.
Highlights
Recent years have brought exciting advances in our understanding of the genetic underpinnings of major mental illnesses with the progress of next-generation sequencing technologies and bioinformatic methods for analysis of the complex datasets they produce
In the central nervous system, phenotypes of single neurons or glia interact at the levels of cell types, individual regions and larger networks of regions to produce the phenotype of the entire individual, from which a complex syndrome such as schizophrenia or bipolar disorder may be displayed
While patients within the SZ and bipolar disorder (BD) groups were treated with psychotropic medications [13], we argue that medication is not driving the observed changes in DNA methylation for two reasons
Summary
Recent years have brought exciting advances in our understanding of the genetic underpinnings of major mental illnesses with the progress of next-generation sequencing technologies and bioinformatic methods for analysis of the complex datasets they produce. In 2014 brought robust results from the field’s considerable investment into genome-wide association studies, with these regions in hand the quest to understand this debilitating disorder is still far from complete. These regions span more than 20 megabases of DNA (20877196 base pairs [1]), approximately two thirds the size of the entire human exome [2], and are estimated to confer only 3.4% of the variance in schizophrenia risk [3], leaving the bulk of disease liability still unexplained. In the context of the daunting complexity presented by these and other neuropsychiatric disorders whose pathology lies within the brain, it is pertinent to consider what the significance of disease-associated single nucleotide polymorphisms (SNPs) identified in peripheral tissues such as blood may be
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