title: Epigenetics of autism-related impairment: copy number variation and maternal infection.
abstract: OBJECTIVE
  Epidemiological data have suggested maternal infection and fever to be associated with increased risk of autism spectrum disorder (ASD). Animal studies show that gestational infections perturb fetal brain development and result in offspring with the core features of autism and have demonstrated that behavioral effects of maternal immune activation are dependent on genetic susceptibility. The goal of this study was to explore the impact of ASD-associated copy number variants (CNVs) and prenatal maternal infection on clinical severity of ASD within a dataset of prenatal history and complete genetic and phenotypic findings.
  
  
  METHODS
  We analyzed data from the Simons Simplex Collection sample including 1971 children with a diagnosis of ASD aged 4 to 18 years who underwent array comparative genomic hybridization screening. Information on infection and febrile episodes during pregnancy was collected through parent interview. ASD severity was clinically measured through parent-reported interview and questionnaires.
  
  
  RESULTS
  We found significant interactive effects between the presence of CNVs and maternal infection during pregnancy on autistic symptomatology, such that individuals with CNVs and history of maternal infection demonstrated increased rates of social communicative impairments and repetitive/restricted behaviors. In contrast, no significant interactions were found between presence of CNVs and prenatal infections on cognitive and adaptive functioning of individuals with ASD.
  
  
  CONCLUSIONS
  Our findings support a gene-environment interaction model of autism impairment, in that individuals with ASD-associated CNVs are more susceptible to the effects of maternal infection and febrile episodes in pregnancy on behavioral outcomes and suggest that these effects are specific to ASD rather than to global neurodevelopment.
authors: *University of Washington School of Medicine, Seattle, WA; Departments of †Psychiatry, and ‡Genome Sciences, University of Washington, Seattle, WA; §Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA; ‖Howard Hughes Medical Institute, University of Washington, Seattle, WA.
authors: Varvara
authors: V
authors: Mazina
authors: Jennifer
authors: J
authors: Gerdts
authors: Sandy
authors: S
authors: Trinh
authors: Katy
authors: K
authors: Ankenman
authors: Tracey
authors: T
authors: Ward
authors: Megan Y
authors: MY
authors: Dennis
authors: Santhosh
authors: S
authors: Girirajan
authors: Evan E
authors: EE
authors: Eichler
authors: Raphael
authors: R
authors: Bernier
mesh_terms: D000067877:Autism Spectrum Disorder / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005334:Fever; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012042:Registries; D012720:Severity of Illness Index
references: Brain Behav Immun. 2012 May;26(4):607-16
references: 22310922
references: Am J Hum Genet. 2012 Jul 13;91(1):38-55
references: 22726847
references: Am J Hum Genet. 2013 Feb 7;92(2):221-37
references: 23375656
references: Transl Psychiatry. 2013;3:e240
references: 23481627
references: J Neurosci. 2013 Aug 21;33(34):13791-804
references: 23966700
references: Brain Behav Immun. 2013 Oct;33:153-63
references: 23880236
references: Brain Behav Immun. 2015 Feb;44:100-5
references: 25218900
references: J Autism Dev Disord. 2000 Jun;30(3):205-23
references: 11055457
references: J Autism Dev Disord. 2003 Aug;33(4):427-33
references: 12959421
references: J Autism Dev Disord. 1994 Oct;24(5):659-85
references: 7814313
references: PLoS Genet. 2006 Feb;2(2):e20
references: 16482228
references: Science. 2007 Apr 20;316(5823):445-9
references: 17363630
references: J Autism Dev Disord. 2007 May;37(5):855-66
references: 17048092
references: J Neurosci. 2007 Oct 3;27(40):10695-702
references: 17913903
references: Nat Rev Genet. 2008 May;9(5):341-55
references: 18414403
references: Br J Psychiatry. 2009 Jul;195(1):7-14
references: 19567888
references: Neuron. 2010 Oct 21;68(2):192-5
references: 20955926
references: J Autism Dev Disord. 2010 Dec;40(12):1521-30
references: 20405194
references: Neuron. 2011 Jun 9;70(5):863-85
references: 21658581
references: Nature. 2011 Jun 16;474(7351):380-4
references: 21614001
references: Brain Behav Immun. 2012 Mar;26(3):383-92
references: 21906670
references: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81
references: 22802640
references: J Autism Dev Disord. 2013 Jan;43(1):25-33
references: 22562209
references: PLoS One. 2012;7(12):e48835
references: 23239965
references: Pediatrics. 2012 Dec;130(6):e1447-54
references: 23147969