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Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.

ABSTRACT: The study of monozygotic twins discordant for attention deficit hyperactivity disorder can elucidate mechanisms that contribute to the disorder, which affects ~7% of children. First, using in vivo neuroanatomic imaging on 14 pairs of monozygotic twins (mean age 9.7, s.d. 1.9 years), we found that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole-blood DNA from the same twins, we found a significant enrichment of epigenetic differences in genes expressed in these 'discordant' brain structures. Specifically, there is differential methylation of probes lying in the shore and shelf and enhancer regions of striatal and cerebellar genes. Notably, gene sets pertaining to the cerebral cortex (which did not differ in volume between affected and unaffected twins) were not enriched by differentially methylated probes. Genotypic differences between the twin pairs-such as copy number and rare, single-nucleotide variants-did not contribute to phenotypic discordance. Pathway analyses of the genes implicated by the most differentially methylated probes implicated ?-aminobutyric acid (GABA), dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders.

SUBMITTER: Chen YC

PROVIDER: S-EPMC5914518 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.

Chen Y-C YC Sudre G G Sharp W W Donovan F F Chandrasekharappa S C SC Hansen N N Elnitski L L Shaw P P

Molecular psychiatry 20170321 3

The study of monozygotic twins discordant for attention deficit hyperactivity disorder can elucidate mechanisms that contribute to the disorder, which affects ~7% of children. First, using in vivo neuroanatomic imaging on 14 pairs of monozygotic twins (mean age 9.7, s.d. 1.9 years), we found that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole-blood DNA from the same twins, we ...[more]

PMID: 28322272

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Project description:Although monozygotic (MZ) twins share the majority of their genetic makeup, they can be phenotypically discordant on several traits and diseases. DNA methylation is an epigenetic mechanism that can be influenced by genetic, environmental and stochastic events and may have an important impact on individual variability. In this study we explored epigenetic differences in peripheral blood samples in three MZ twin studies on major depressive disorder (MDD). Epigenetic data for twin pairs were collected as part of a previous study using 8.1-K-CpG microarrays tagging DNA modification in white blood cells from MZ twins discordant for MDD. Data originated from three geographical regions: UK, Australia and the Netherlands. Ninety-seven MZ pairs (194 individuals) discordant for MDD were included. Different methods to address non independently-and-identically distributed (non-i.i.d.) data were evaluated. Machine-learning methods with feature selection centered on support vector machine and random forest were used to build a classifier to predict cases and controls based on epivariations. The most informative variants were mapped to genes and carried forward for network analysis. A mixture approach using principal component analysis (PCA) and Bayes methods allowed to combine the three studies and to leverage the increased predictive power provided by the larger sample. A machine-learning algorithm with feature reduction classified affected from non-affected twins above chance levels in an independent training-testing design. Network analysis revealed gene networks centered on the PPAR-γ (NR1C3) and C-MYC gene hubs interacting through the AP-1 (c-Jun) transcription factor. PPAR-γ (NR1C3) is a drug target for pioglitazone, which has been shown to reduce depression symptoms in patients with MDD. Using a data-driven approach we were able to overcome challenges of non-i.i.d. data when combining epigenetic studies from MZ twins discordant for MDD. Individually, the studies yielded negative results but when combined classification of the disease state from blood epigenome alone was possible. Network analysis revealed genes and gene networks that support the inflammation hypothesis of MDD.

Dataset Information

Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.

Publications

Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.

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