Prenatal expression patterns of genes associated with neuropsychiatric disorders. 2014

Rebecca Birnbaum, and Andrew E Jaffe, and Thomas M Hyde, and Joel E Kleinman, and Daniel R Weinberger

OBJECTIVE Neurodevelopmental disorders presumably involve events that occur during brain development. The authors hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e., differentially expressed). METHODS The authors investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with six neuropsychiatric disorders in the microarray-based "BrainCloud" dorsolateral prefrontal cortex transcriptome. RESULTS Using a fetal/postnatal log2-fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10-3), intellectual disability (N=88 genes, p=5.53×10-3), and autism spectrum disorder (N=242 genes, p=3.45×10-4) were relatively enriched in prenatal transcript abundance, compared with the overall transcriptome. Genes associated with schizophrenia by genome-wide association studies were not preferentially fetally expressed (N=106 genes, p=0.46), nor were genes associated with schizophrenia by exome sequencing (N=212 genes, p=0.21), but specific genes within copy-number variant regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (N=46 genes, p=1.67×10-3). CONCLUSIONS The authors found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorder. Future transcriptome-level association studies should evaluate regions other than the dorsolateral prefrontal cortex, at other time points, and incorporate further RNA sequencing analyses.

UI MeSH Term Description Entries
D007231 Infant, Newborn An infant during the first 28 days after birth. Neonate,Newborns,Infants, Newborn,Neonates,Newborn,Newborn Infant,Newborn Infants
D008607 Intellectual Disability Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28) Disability, Intellectual,Idiocy,Mental Retardation,Retardation, Mental,Deficiency, Mental,Intellectual Development Disorder,Mental Deficiency,Mental Retardation, Psychosocial,Deficiencies, Mental,Development Disorder, Intellectual,Development Disorders, Intellectual,Disabilities, Intellectual,Disorder, Intellectual Development,Disorders, Intellectual Development,Intellectual Development Disorders,Intellectual Disabilities,Mental Deficiencies,Mental Retardations, Psychosocial,Psychosocial Mental Retardation,Psychosocial Mental Retardations,Retardation, Psychosocial Mental,Retardations, Psychosocial Mental
D011247 Pregnancy The status during which female mammals carry their developing young (EMBRYOS or FETUSES) in utero before birth, beginning from FERTILIZATION to BIRTH. Gestation,Pregnancies
D001927 Brain Diseases Pathologic conditions affecting the BRAIN, which is composed of the intracranial components of the CENTRAL NERVOUS SYSTEM. This includes (but is not limited to) the CEREBRAL CORTEX; intracranial white matter; BASAL GANGLIA; THALAMUS; HYPOTHALAMUS; BRAIN STEM; and CEREBELLUM. Intracranial Central Nervous System Disorders,Brain Disorders,CNS Disorders, Intracranial,Central Nervous System Disorders, Intracranial,Central Nervous System Intracranial Disorders,Encephalon Diseases,Encephalopathy,Intracranial CNS Disorders,Brain Disease,Brain Disorder,CNS Disorder, Intracranial,Encephalon Disease,Encephalopathies,Intracranial CNS Disorder
D002659 Child Development Disorders, Pervasive Severe distortions in the development of many basic psychological functions that are not normal for any stage in development. These distortions are manifested in sustained social impairment, speech abnormalities, and peculiar motor movements. Pervasive Child Development Disorders,Pervasive Development Disorders
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001523 Mental Disorders Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. Mental Illness,Psychiatric Diseases,Psychiatric Disorders,Psychiatric Illness,Behavior Disorders,Diagnosis, Psychiatric,Mental Disorders, Severe,Psychiatric Diagnosis,Illness, Mental,Mental Disorder,Mental Disorder, Severe,Mental Illnesses,Psychiatric Disease,Psychiatric Disorder,Psychiatric Illnesses,Severe Mental Disorder,Severe Mental Disorders
D012559 Schizophrenia A severe emotional disorder of psychotic depth characteristically marked by a retreat from reality with delusion formation, HALLUCINATIONS, emotional disharmony, and regressive behavior. Dementia Praecox,Schizophrenic Disorders,Disorder, Schizophrenic,Disorders, Schizophrenic,Schizophrenias,Schizophrenic Disorder
D013577 Syndrome A characteristic symptom complex. Symptom Cluster,Cluster, Symptom,Clusters, Symptom,Symptom Clusters,Syndromes

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