Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.
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 γ-aminobutyric acid (GABA), dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders.
Genomic Functional Analysis Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Chen
Neurobehavioral Clinical Research Section, Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Sudre
Neurobehavioral Clinical Research Section, Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Sharp
Genomics Core and Cancer Genomics Unit, Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Donovan
Genomics Core and Cancer Genomics Unit, Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Chandrasekharappa
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Hansen
Genomic Functional Analysis Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Elnitski
Neurobehavioral Clinical Research Section, Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Shaw
D001289:Attention Deficit Disorder with Hyperactivity / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000033:anatomy & histology / Q000503:physiopathology; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000502:physiology; D002648:Child; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000503:physiopathology; D019175:DNA Methylation; D004200:Diseases in Twins / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics; D010641:Phenotype; D014430:Twins, Monozygotic / Q000235:genetics / Q000523:psychology