title: Global increases in both common and rare copy number load associated with autism.
abstract: Children with autism have an elevated frequency of large, rare copy number variants (CNVs). However, the global load of deletions or duplications, per se, and their size, location and relationship to clinical manifestations of autism have not been documented. We examined CNV data from 516 individuals with autism or typical development from the population-based Childhood Autism Risks from Genetics and Environment (CHARGE) study. We interrogated 120 regions flanked by segmental duplications (genomic hotspots) for events >50 kbp and the entire genomic backbone for variants >300 kbp using a custom targeted DNA microarray. This analysis was complemented by a separate study of five highly dynamic hotspots associated with autism or developmental delay syndromes, using a finely tiled array platform (>1 kbp) in 142 children matched for gender and ethnicity. In both studies, a significant increase in the number of base pairs of duplication, but not deletion, was associated with autism. Significantly elevated levels of CNV load remained after the removal of rare and likely pathogenic events. Further, the entire CNV load detected with the finely tiled array was contributed by common variants. The impact of this variation was assessed by examining the correlation of clinical outcomes with CNV load. The level of personal and social skills, measured by Vineland Adaptive Behavior Scales, negatively correlated (Spearman's r = -0.13, P = 0.034) with the duplication CNV load for the affected children; the strongest association was found for communication (P = 0.048) and socialization (P = 0.022) scores. We propose that CNV load, predominantly increased genomic base pairs of duplication, predisposes to autism.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. sxg47@psu.edu
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Johnson
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.forename: Jorune
authors.initials: J
authors.lastname: Balciuniene
authors.forename: Neerja
authors.initials: N
authors.lastname: Katiyar
authors.forename: Keolu
authors.initials: K
authors.lastname: Fox
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.forename: Abhinaya
authors.initials: A
authors.lastname: Srikanth
authors.forename: Kian Hui
authors.initials: KH
authors.lastname: Yeoh
authors.forename: Su Jen
authors.initials: SJ
authors.lastname: Khoo
authors.forename: Therese B
authors.initials: TB
authors.lastname: Nauth
authors.forename: Robin
authors.initials: R
authors.lastname: Hansen
authors.forename: Marylyn
authors.initials: M
authors.lastname: Ritchie
authors.forename: Irva
authors.initials: I
authors.lastname: Hertz-Picciotto
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.forename: Scott B
authors.initials: SB
authors.lastname: Selleck
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D056916:Segmental Duplications, Genomic; D017384:Sequence Deletion
references.citation: PLoS Genet. 2011 Nov;7(11):e1002334
references.pmid: 22102821
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1193-8
references.pmid: 22223662
references.citation: Int J Epidemiol. 2009 Oct;38(5):1239-41; author reply 1243-4
references.pmid: 19737792
references.citation: Environ Health Perspect. 2006 Jul;114(7):1119-25
references.pmid: 16835068
references.citation: Nat Genet. 2011 Aug 14;43(9):838-46
references.pmid: 21841781
references.citation: Am J Med Genet. 2001 Jan 8;105(1):36-8
references.pmid: 11424991
references.citation: Nature. 2012 Apr 04;485(7397):242-5
references.pmid: 22495311
references.citation: Nat Rev Genet. 2010 Jun;11(6):446-50
references.pmid: 20479774
references.citation: Am J Med Genet C Semin Med Genet. 2012 May 15;160C(2):118-29
references.pmid: 22499536
references.citation: Mol Psychiatry. 2011 Jan;16(1):17-25
references.pmid: 19786961
references.citation: PLoS Genet. 2012;8(5):e1002692
references.pmid: 22615578
references.citation: J Mol Diagn. 2008 Jan;10(1):43-9
references.pmid: 18165273
references.citation: J Neurodev Disord. 2010 Mar;2(1):26-38
references.pmid: 21731881
references.citation: Neuron. 2011 Jun 9;70(5):863-85
references.pmid: 21658581
references.citation: Am J Med Genet A. 2010 Aug;152A(8):2112-4
references.pmid: 20635338
references.citation: J Autism Dev Disord. 2000 Jun;30(3):205-23
references.pmid: 11055457
references.citation: Am J Med Genet A. 2003 Jun 1;119A(2):111-20
references.pmid: 12749048
references.citation: Ann Epidemiol. 2012 Mar;22(3):143-50
references.pmid: 22277122
references.citation: N Engl J Med. 2010 Jan 21;362(3):239-52
references.pmid: 20089974
references.citation: Mol Psychiatry. 2010 Jun;15(6):637-46
references.pmid: 19546859
references.citation: Nat Rev Genet. 2012 Jul 10;13(8):537-51
references.pmid: 22777127
references.citation: Am J Hum Genet. 2001 Aug;69(2):463-6
references.pmid: 11452364
references.citation: Dev Psychol. 2009 Jan;45(1):77-89
references.pmid: 19209992
references.citation: Science. 2002 Aug 9;297(5583):1003-7
references.pmid: 12169732
references.citation: Am J Hum Genet. 2007 Nov;81(5):1057-69
references.pmid: 17924346
references.citation: J Pediatr Psychol. 1985 Jun;10(2):215-25
references.pmid: 4020603
references.citation: Cell. 2012 Mar 16;148(6):1223-41
references.pmid: 22424231
references.citation: Int J Methods Psychiatr Res. 2004;13(2):93-121
references.pmid: 15297906
references.citation: Hum Mol Genet. 2010 Oct 15;19(R2):R176-87
references.pmid: 20807775
references.citation: Arch Gen Psychiatry. 2011 Nov;68(11):1095-102
references.pmid: 21727249
references.citation: J Autism Dev Disord. 2007 Apr;37(4):748-59
references.pmid: 17146708
references.citation: Genomics. 2002 Aug;80(2):129-34
references.pmid: 12160723
references.citation: J Med Genet. 1994 May;31(5):423-4
references.pmid: 8064827
references.citation: Nature. 2009 Oct 8;461(7265):802-8
references.pmid: 19812673
references.citation: Am J Hum Genet. 2009 Feb;84(2):148-61
references.pmid: 19166990
references.citation: J Autism Dev Disord. 1989 Jun;19(2):185-212
references.pmid: 2745388
references.citation: Am J Med Genet. 2000 Summer;97(2):136-46
references.pmid: 11180221
references.citation: Annu Rev Genet. 2011;45:203-26
references.pmid: 21854229
references.citation: Nat Genet. 2011 Jun;43(6):585-9
references.pmid: 21572417
references.citation: Nat Genet. 2006 Sep;38(9):1038-42
references.pmid: 16906162
references.citation: BMC Med Genet. 2004 Apr 16;5:10
references.pmid: 15090072
references.citation: Hum Mutat. 2010 Jul;31(7):840-50
references.pmid: 20506139
references.citation: N Engl J Med. 2008 Feb 14;358(7):667-75
references.pmid: 18184952
references.citation: Am J Hum Genet. 2007 Feb;80(2):232-40
references.pmid: 17236129
references.citation: Nature. 2009 May 28;459(7246):528-33
references.pmid: 19404256
references.citation: Hum Mol Genet. 2010 Oct 15;19(20):4072-82
references.pmid: 20663923
references.citation: Am J Hum Genet. 1997 Apr;60(4):928-34
references.pmid: 9106540
references.citation: Am J Hum Genet. 2013 Feb 7;92(2):221-37
references.pmid: 23375656
references.citation: Am J Hum Genet. 2007 May;80(5):938-47
references.pmid: 17436248
references.citation: Neuron. 2012 Apr 26;74(2):285-99
references.pmid: 22542183
references.citation: Nat Genet. 2009 Nov;41(11):1223-7
references.pmid: 19855392
references.citation: Child Neuropsychol. 2006 Aug;12(4-5):269-77
references.pmid: 16911972
references.citation: Am J Psychiatry. 2003 Apr;160(4):621-2
references.pmid: 12668346
references.citation: Nature. 2012 Apr 04;485(7397):237-41
references.pmid: 22495306
references.citation: J Am Acad Child Adolesc Psychiatry. 2012 May;51(5):477-486.e1
references.pmid: 22525954
references.citation: Am J Hum Genet. 2010 Nov 12;87(5):618-30
references.pmid: 21055719
references.citation: Science. 2007 Apr 20;316(5823):445-9
references.pmid: 17363630
references.citation: Epidemiology. 2011 Jul;22(4):476-85
references.pmid: 21610500
references.citation: Psychol Med. 1995 Jan;25(1):63-77
references.pmid: 7792363
references.citation: Am J Hum Genet. 2003 Feb;72(2):408-18
references.pmid: 12457340
references.citation: Circulation. 2012 Jan 24;125(3):474-81
references.pmid: 22179534
references.citation: Nature. 2006 Nov 23;444(7118):444-54
references.pmid: 17122850
references.citation: Trends Genet. 2009 Jul;25(7):298-307
references.pmid: 19560228