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Gene expression profiling differentiates autism case–controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism
Article first published online: 5 MAY 2009
DOI: 10.1002/aur.73
Copyright © 2009, International Society for Autism Research, Wiley Periodicals, Inc.
Additional Information
How to Cite
Hu, V. W., Sarachana, T., Kim, K. S., Nguyen, A., Kulkarni, S., Steinberg, M. E., Luu, T., Lai, Y. and Lee, N. H. (2009), Gene expression profiling differentiates autism case–controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism. Autism Res, 2: 78–97. doi: 10.1002/aur.73
Publication History
- Issue published online: 19 MAY 2009
- Article first published online: 5 MAY 2009
- Manuscript Accepted: 29 MAR 2009
- Manuscript Revised: 23 MAR 2009
- Manuscript Received: 8 DEC 2008
Funded by
- National Institute of Mental Health, NIH. Grant Number: R21 MH073393
- Autism Speaks. Grant Number: 2381
References
- , , , , , et al. (2008). Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics, 9, 153–161.
- , , , , & (2005). Quantitative genome scan and ordered-subsets analysis of autism endophenotypes support language QTLs. Molecular Psychiatry, 10, 747–757.
- , , & (2008). Neuroanatomy of autism. Trends in Neurosciences, 31, 137–145.
- , , , , , & (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics, 23, 185–188.
- , , , & (2005). Comparative effects of DHEA vs. testosterone, dihydrotestosterone, and estradiol on proliferation and gene expression in human LNCaP prostate cancer cells. American Journal of Physiology—Endocrinology and Metabolism, 288, E573–E584.
- , , , , , & (2000). Analysis of autism susceptibility gene loci on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q in finnish multiplex families. Molecular Psychiatry, 5, 320–322.
- , , , , , et al. (1998). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Human Molecular Genetics, 7, 571–578.
- , , , , , et al. (2007). Recurrent 10q22–q23 deletions: A genomic disorder on 10q associated with cognitive and behavioral abnormalities. American Journal of Human Genetics, 80, 938–947.
- , , , & (2006). Utilization of lymphoblastoid cell lines as a system for the molecular modeling of autism. Journal of Autism and Developmental Disorders, 36, 973–982.
- , , & (2005). Sex differences in the brain: Implications for explaining autism. Science, 310, 819–823.
- , , , , , et al. (2008). Evidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators. Molecular and Cellular Biology, 28, 3070–3075.
- (2007). The possible interplay of synaptic and clock genes in autism spectrum disorders. Cold Spring Harbor Symposia on Quantitative Biology, 72, 645–654.
- , , , , , et al. (2001). Incorporating language phenotypes strengthens evidence of linkage to autism. American Journal of Medical Genetics—Neuropsychiatric Genetics, 105, 539–547.Direct Link:
- , , , , , et al. (2001). Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. American Journal of Human Genetics, 68, 1514–1520.
- , , , & (2006). Quantitative trait locus analysis of nonverbal communication in autism spectrum disorder. Mol Psychiatry, 11, 214–220.
- , , , , , & (2007). Integration of genome and chromatin structure with gene expression profiles to predict c-MYC recognition site binding and function. PLoS Computational Biology, 3(4), e63; doi:10.1371/journal.pcbi.0030063.
- , & (2002). The genetics of variation in gene expression. Nature Genetics, 32, 522–525.
- , , , , , et al. (2003). Natural variation in human gene expression assessed in lymphoblastoid cells. Nature Genetics, 33, 422–425.
- , , & (2002). A systematic statistical linear modeling approach to oligonucleotide array experiments. Mathematical Biosciences, 176, 35–51.
- , , , , , et al. (2006). The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature, 442, 307.
- , , , , , et al. (2003). Validation of a brief quantitative measure of autistic traits: Comparison of the social responsiveness scale with the autism diagnostic interview-revised. Journal of Autism and Developmental Disorders, 33, 427–433.
- , , , , , et al. (2003). Intestinal cytokines in children with pervasive developmental disorders. American Journal of Gastroenterolology, 98, 1777–1782.Direct Link:
- , , , , , & (2007). A quantitative trait locus analysis of social responsiveness in multiplex autism families. American Journal of Psychiatry, 164, 656–662.
- , & (2007). Using GOstats to test gene lists for GO term association. Bioinformatics, 23, 257.
- , & (2006). A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders. Hormone Research, 66, 182–188.
- , , , , , et al. (2008). Gene expression changes in children with autism. Genomics, 91, 22–29.
- , , , , , et al. (2006). Autism and environmental genomics. Neurotoxicology, 27, 671–684.
- , & (2003). Core symptoms, related disorders, and course of autism. New York, NY: Marcel Dekker, Inc. 15p.
- , , , , , & (2000). The relationship between repetitive behaviors and growth hormone response to sumatriptan challenge in adult autistic disorder. Neuropsychopharmacology, 22, 163–167.
- , , , , & (2003). Differential gene-expression patterns in genital fibroblasts of normal males and 46,XY females with androgen insensitivity syndrome: Evidence for early programming involving the androgen receptor. Genome Biology, 4(6), R37.
- , , , , & (1988). Taurine and β-alanine act on both GABA and glycine receptors in xenopus oocyte injected with mouse brain messenger RNA. Molecular Brain Research, 4, 97–105.
- , , , , & (2006). Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes. BMC Genomics, 7, 118.
- , , , , , , , , & (2009). Gene expression profiling of lymphoblasts from autistic and nonaffected sib pairs: Altered pathways in neuronal development and steroid biosynthesis. PLoS ONE, in press.
- & (2009). Novel clustering of items from the Autism Diagnostic Interview-Revised to define phenotypes within autism spectrum disorders. Autism Research, 2, 67–77 (this issue).Direct Link:
- , , , & (2007). Elevated rates of testosterone-related disorders in women with autism spectrum conditions. Hormones and Behavior, 51, 597–604.
- , , , , & (2004). Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Molecular Psychiatry, 9, 406–416.
- , , , , , et al. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34, 27–29.
- , & (2008). Sleep in children with autism spectrum disorders. Current Neurology and Neuroscience Reports, 8, 155–161.
- , , & (1992). Univariate discrete distributions. New York, NY: Wiley.
- , , & (2001). Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. Journal of Neuroimmunology, 120, 170–179.
- , , , , , et al. (2003). Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nature Genetics, 35, 171–175.
- , , , , , et al. (2004). Association of the XBP1 -116C/G polymorphism with schizophrenia in the japanese population. Psychiatry and Clinical Neurosciences, 58, 438–440.Direct Link:
- , , , , , et al. (2008). Up-regulation of ADM and SEPX1 in the lymphoblastoid cells of patients in monozygotic twins discordant for schizophrenia. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 147, 557–564.Direct Link:
- , , , , , & (2007). MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol, 8, R173.
- , , , , , et al. (2005). Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia. Molecular Psychiatry, 10, 1045–1055.
- , , , & (2005). Foetal testosterone, social relationships, and restricted interests in children. Journal of Child Psychology and Psychiatry, 46, 198–210.Direct Link:
- , & (2006). Fetal testosterone and sex differences in typical social development and in autism. J Child Neurol, 21, 825–845.
- (2006). The neuronal microRNA system. Nature Reviews. Neuroscience, 7, 911–920.
- , , , , , et al. (2008). Recurrent 16p11.2 microdeletions in autism. Human Molecular Genetics, 17, 628–638.
- , , , , , & (2007). Relationship of dietary intake to gastrointestinal symptoms in children with autistic spectrum disorders. Biological Psychiatry, 61, 492–497.
- , , , , & (2005). Mutation analysis of methyl-CpG binding protein family genes in autistic patients. Brain and Development, 27, 321–325.
- , & (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods, 25, 402.
- , , & (2001). Quantifying the phenotype in autism spectrum disorders. American Journal of Medical Genetics, 105, 36–38.Direct Link:
- , , , , , & (2007). Transcriptional profiling of alzheimer blood mononuclear cells by microarray. Neurobiology of Aging, 28, 1795–1809.
- (2004). Sleep disorders, epilepsy, and autism. Mental Retardation and Developmental Disabilities Research Reviews, 10, 122–125.Direct Link:
- , , , , , et al. (2007). Haploinsufficiency of c-met in CD44−/− mice identifies a collaboration of CD44 and c-met in vivo. Molecular and Cellular Biology, 27, 8797–8806.
- , , , , , et al. (2005). Genome-wide and ordered-subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates. BMC Medical Genetics, 6, 1.
- , , , , , et al. (2008). Abnormal melatonin synthesis in autism spectrum disorders. Molecular Psychiatry, 13, 90–98.
- , , , , , et al. (2005). Gene expression analysis of peripheral blood leukocytes from discordant sib-pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches. American Journal of Medical Genetics—Neuropsychiatric Genetics, 136B, 12–25.Direct Link:
- , , , , , & (2004). Genetic analysis of genome-wide variation in human gene expression. Nature, 12, 430.
- , , , , , et al. (2008). DEC1 modulates the circadian phase of clock gene expression. Molecular and Cellular Biology, 28, 4080–4092.
- , , , , , & (2007). Association of Per1 and Npas2 with autistic disorder: Support for the clock genes/social timing hypothesis. Molecular Psychiatry, 12, 581–592.
- , , , , , & (1995). Brief report: Circadian melatonin, thyroid-stimulating hormone, prolactin, and cortisol levels in serum of young adults with autism. Journal of Autism and Developmental Disorders, 25, 641–654.
- , , , , , et al. (2007a). Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Human Molecular Genetics, 16, 1682–1698.
- , , , , , et al. (2007b). Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Human Molecular Genetics, 16, 1682–1698.
- , , , , , & (2003). Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11–q13. Journal of the American Academy of the Child and Adolescent Psychiatry, 42, 856–863.
- , , , & (2004). Neuropathological findings in autism. Brain, 127, 2572–2583.
- , , & (2005). Immunity, neuroglia and neuroinflammation in autism. International Review of Psychiatry, 17, 485–495.
- , & (2006). Searching for ways out of the autism maze: Genetic, epigenetic and environmental clues. Trends in Neurosciences, 29, 349–358.
- , , , , , et al. (1999). Genome-wide scan for autism susceptibility genes. Paris autism research international sibpair study. Human Molecular Genetics, 8, 505–512.
- , , , , , et al. (2008). Regulation of jumonji-domain-containing histone demthylases by hypoxia-inducible factor (HIF)-1alpha. The Biochemical Journal, 416, 387.
- , & (2004). Toward a developmental neurobiology of autism. Mental Retardation and Developmental Disabilities Research Reviews, 10, 303–317.Direct Link:
- , , , , & (2001). Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology, 57, 1618–1628.
- (2002). Microarray data normalization and transformation. Nature Genetics, 32, 496–501.
- (2005). Small RNAs in human brain development and disorders. Biochemistry (Mosc), 70, 1404–1407.
- , , , , , et al. (2003). TM4: A free, open-source system for microarray data management and analysis. BioTechniques, 34, 374–378.
- , , , , , & (2000). Combined analysis of data on chromosome 7q from three autism genome scans. American Journal of Medical Genetics—Neuropsychiatric Genetics, 96, 480.
- , , , , , et al. (2004). Functional analysis of the basic helix-loop-helix transcription factor DEC1 in circadian regulation: Interaction with BMAL1. European Journal of Biochemistry, 271, 4409–4419.Direct Link:
- , , , , , et al. (2006). Evidence for multiple loci from a genome scan of autism kindreds. Molecular Psychiatry, 11, 1049–1060.
- , , , , , et al. (2008). Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: Implications for an animal model of autism. Neuropharmacology 54, 901–911.
- , , , , , et al. (2007). Strong association of de novo copy number mutations with autism. Science, 316, 445–449.
- , , , , , & (2001). Symptom domains in autism and related conditions: Evidence for familiality. American Journal of Medical Genetics—Neuropsychiatric Genetics, 105, 593.
- , , , , , et al. (2000). Subgroups of children with autism by cluster analysis: A longitudinal examination. Journal of the American Academy of Child and Adolescent Psychiatry, 39, 346–352.
- , , , , & (2007). High density SNP association study of a major autism linkage region on chromosome 17. Human Molecular Genetics, 16, 704–715.
- , , & (2006). Evaluating the comparability of gene expression in blood and brain. American Journal of Medical Genetics—Neuropsychiatric Genetics, 141B, 261–268.Direct Link:
- , , , , , et al. (2007a). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39, 319–328.
- , , , , , et al. (2007b). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39, 319–328.
- , , , , , et al. (2003). A principal components analysis of the autism diagnostic interview-revised. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 864–872.
- , , , , , & (2006). Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. Journal of Medical Genetics, 43, e21.
- , , & (2008). Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism. Autism Research, 1, 307.Direct Link:
- , , , , & (2002). Genomic responses of the brain to ischemic stroke, intracerebral haemorrhage, kainate seizures, hypoglycemia, and hypoxia. European Journal of Neuroscience, 15, 1937–1952.Direct Link:
- , , , , & (2003). Blood genomic expression profile for neuronal injury. Journal of Cerebral Blood Flow and Metabolism, 23, 310–319.
- , , & (1998). A dimensional classification of autism spectrum disorder by social communication domains. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 271–277.
- , , & (2001). Significance analysis of microarrays applied to the ionizing radiation response. Proceedings of the National Academy of Sciences of the United States of America, 98, 5116–5121.
- , , , , & (2008). Androgen regulation of the androgen receptor coregulators. BMC Cancer, 8, 219.
- , & (2001). Mutations in the gene encoding methyl-CpG-binding protein 2 cause rett syndrome. Brain and Development, 23, S147–S151.
- , , , & (2007). Structure/function analysis of xenopus cryptochromes 1 and 2 reveals differential nuclear localization mechanisms and functional domains important for interaction with and repression of CLOCK-BMAL1. Molecular and Cellular Biology, 27, 2120–2129.
- , , , , ., et al. (1999). Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Human Genetics, 104, 1–9.
- , , , , & (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology, 57, 67–81.Direct Link:
- , , , , , & (2007). Association of deletion 9p,46,XY gonadal dysgenesis and autistic spectrum disorder. Molecular Human Reproduction, 13, 685.
- , , & (2006). Cultured lymphocytes from autistic children and non-autistic siblings up-regulate heat shock protein RNA in response to thimerosal challenge. Neurotoxicology, 27, 685–692.
- , , , , , et al. (2008). Posterior probability of linkage analysis of autism dataset identifies linkage to chromosome 16. Psychiatric Genetics, 18, 85–91.
- , , , , , et al. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine, 358, 667–675.
- , , & (2002). Social timing, clock genes and autism: A new hypothesis. Journal of Intellectual Disability Research, 46, 352–358.Direct Link:
- , & (2002). The social deficits of the oxytocin knockout mouse. Neuropeptides, 36, 221–229.
- , , & (1993). Dual activation of GABA(A) and glycine receptors by β-alanine: Inverse modulation by progesterone and 5α-pregnan-3α-ol-20-one. European Journal of Pharmacology—Molecular Pharmacology Section, 246, 239–246.
- , , , , , et al. (2008). Fragile X-related proteins regulate mammalian circadian behavioral rhythms. American Journal of Human Genetics, 83, 43–52.
- , , , , , et al. (2005). Genome-wide characterization of gene expression variations and DNA copy number changes in prostate cancer cell lines. Prostate, 63, 187–197.Direct Link:
- , , , , , et al. (2005). Cerebrospinal fluid and serum markers of inflammation in autism. Pediatric Neurology, 33, 195–201.

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