Abstract
Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.
Highlights
We previously reported a single, large family where a balanced translocation between chromosomes 1 and 11 [t(1;11)] shows genome-wide significant linkage for SZ, rMDD and BD.[1,2] On chromosome 1, the translocation disrupts the protein coding geneDisrupted in schizophrenia 1 (DISC1) and the antisense non-coding gene Disrupted in Schizophrenia 2 (DISC2)
There are multiple mechanisms by which the translocation might confer risk for psychiatric illness; our goal was to investigate whether it was associated with altered DNA methylation, which has been previously implicated in psychiatric illness
Four significant differentially methylated positions (DMPs) mapped to the DISC1 gene, which is interrupted by the translocation and has been implicated in neurodevelopment, cognitive function and susceptibility to psychiatric illness.[24,25,26,27]
Summary
We previously reported a single, large family where a balanced translocation between chromosomes 1 and 11 [t(1;11)] shows genome-wide significant linkage for SZ, rMDD and BD.[1,2] On chromosome 1, the translocation disrupts the protein coding gene. Disrupted in schizophrenia 1 (DISC1) and the antisense non-coding gene Disrupted in Schizophrenia 2 (DISC2). On chromosome 11, the translocation disrupts the non-coding gene DISC1 Fusion Partner 1 (DISC1FP1).[3,4] DISC1 is expressed in the brain throughout development and adulthood, where it plays a role in multiple processes including neurogenesis and neuronal migration, integration, maturation and signalling.[5] Lymphoblastoid cell lines from carriers of the translocation show a ~50% reduction in DISC1 protein expression, implicating haploinsufficiency as a potential pathogenic mechanism.[3]. Altered methylation is present in individuals with SZ and BD, both in MZ twins who are discordant for illness[10] and in case/control comparisons of each of these illnesses.[11,12,13] In light of this evidence, we hypothesised that investigating DNA methylation in the t(1;11) pedigree may further our understanding of the aetiology of illness in this family
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