title: A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
abstract: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
authors: School of Medicine and Medical Science University College, Dublin, Ireland.
authors: Jillian P
authors: JP
authors: Casey
authors: Tiago
authors: T
authors: Magalhaes
authors: Judith M
authors: JM
authors: Conroy
authors: Regina
authors: R
authors: Regan
authors: Naisha
authors: N
authors: Shah
authors: Richard
authors: R
authors: Anney
authors: Denis C
authors: DC
authors: Shields
authors: Brett S
authors: BS
authors: Abrahams
authors: Joana
authors: J
authors: Almeida
authors: Elena
authors: E
authors: Bacchelli
authors: Anthony J
authors: AJ
authors: Bailey
authors: Gillian
authors: G
authors: Baird
authors: Agatino
authors: A
authors: Battaglia
authors: Tom
authors: T
authors: Berney
authors: Nadia
authors: N
authors: Bolshakova
authors: Patrick F
authors: PF
authors: Bolton
authors: Thomas
authors: T
authors: Bourgeron
authors: Sean
authors: S
authors: Brennan
authors: Phil
authors: P
authors: Cali
authors: Catarina
authors: C
authors: Correia
authors: Christina
authors: C
authors: Corsello
authors: Marc
authors: M
authors: Coutanche
authors: Geraldine
authors: G
authors: Dawson
authors: Maretha
authors: M
authors: de Jonge
authors: Richard
authors: R
authors: Delorme
authors: Eftichia
authors: E
authors: Duketis
authors: Frederico
authors: F
authors: Duque
authors: Annette
authors: A
authors: Estes
authors: Penny
authors: P
authors: Farrar
authors: Bridget A
authors: BA
authors: Fernandez
authors: Susan E
authors: SE
authors: Folstein
authors: Suzanne
authors: S
authors: Foley
authors: Eric
authors: E
authors: Fombonne
authors: Christine M
authors: CM
authors: Freitag
authors: John
authors: J
authors: Gilbert
authors: Christopher
authors: C
authors: Gillberg
authors: Joseph T
authors: JT
authors: Glessner
authors: Jonathan
authors: J
authors: Green
authors: Stephen J
authors: SJ
authors: Guter
authors: Hakon
authors: H
authors: Hakonarson
authors: Richard
authors: R
authors: Holt
authors: Gillian
authors: G
authors: Hughes
authors: Vanessa
authors: V
authors: Hus
authors: Roberta
authors: R
authors: Igliozzi
authors: Cecilia
authors: C
authors: Kim
authors: Sabine M
authors: SM
authors: Klauck
authors: Alexander
authors: A
authors: Kolevzon
authors: Janine A
authors: JA
authors: Lamb
authors: Marion
authors: M
authors: Leboyer
authors: Ann
authors: A
authors: Le Couteur
authors: Bennett L
authors: BL
authors: Leventhal
authors: Catherine
authors: C
authors: Lord
authors: Sabata C
authors: SC
authors: Lund
authors: Elena
authors: E
authors: Maestrini
authors: Carine
authors: C
authors: Mantoulan
authors: Christian R
authors: CR
authors: Marshall
authors: Helen
authors: H
authors: McConachie
authors: Christopher J
authors: CJ
authors: McDougle
authors: Jane
authors: J
authors: McGrath
authors: William M
authors: WM
authors: McMahon
authors: Alison
authors: A
authors: Merikangas
authors: Judith
authors: J
authors: Miller
authors: Fiorella
authors: F
authors: Minopoli
authors: Ghazala K
authors: GK
authors: Mirza
authors: Jeff
authors: J
authors: Munson
authors: Stanley F
authors: SF
authors: Nelson
authors: Gudrun
authors: G
authors: Nygren
authors: Guiomar
authors: G
authors: Oliveira
authors: Alistair T
authors: AT
authors: Pagnamenta
authors: Katerina
authors: K
authors: Papanikolaou
authors: Jeremy R
authors: JR
authors: Parr
authors: Barbara
authors: B
authors: Parrini
authors: Andrew
authors: A
authors: Pickles
authors: Dalila
authors: D
authors: Pinto
authors: Joseph
authors: J
authors: Piven
authors: David J
authors: DJ
authors: Posey
authors: Annemarie
authors: A
authors: Poustka
authors: Fritz
authors: F
authors: Poustka
authors: Jiannis
authors: J
authors: Ragoussis
authors: Bernadette
authors: B
authors: Roge
authors: Michael L
authors: ML
authors: Rutter
authors: Ana F
authors: AF
authors: Sequeira
authors: Latha
authors: L
authors: Soorya
authors: Inês
authors: I
authors: Sousa
authors: Nuala
authors: N
authors: Sykes
authors: Vera
authors: V
authors: Stoppioni
authors: Raffaella
authors: R
authors: Tancredi
authors: Maïté
authors: M
authors: Tauber
authors: Ann P
authors: AP
authors: Thompson
authors: Susanne
authors: S
authors: Thomson
authors: John
authors: J
authors: Tsiantis
authors: Herman
authors: H
authors: Van Engeland
authors: John B
authors: JB
authors: Vincent
authors: Fred
authors: F
authors: Volkmar
authors: Jacob A S
authors: JA
authors: Vorstman
authors: Simon
authors: S
authors: Wallace
authors: Kai
authors: K
authors: Wang
authors: Thomas H
authors: TH
authors: Wassink
authors: Kathy
authors: K
authors: White
authors: Kirsty
authors: K
authors: Wing
authors: Kerstin
authors: K
authors: Wittemeyer
authors: Brian L
authors: BL
authors: Yaspan
authors: Lonnie
authors: L
authors: Zwaigenbaum
authors: Catalina
authors: C
authors: Betancur
authors: Joseph D
authors: JD
authors: Buxbaum
authors: Rita M
authors: RM
authors: Cantor
authors: Edwin H
authors: EH
authors: Cook
authors: Hilary
authors: H
authors: Coon
authors: Michael L
authors: ML
authors: Cuccaro
authors: Daniel H
authors: DH
authors: Geschwind
authors: Jonathan L
authors: JL
authors: Haines
authors: Joachim
authors: J
authors: Hallmayer
authors: Anthony P
authors: AP
authors: Monaco
authors: John I
authors: JI
authors: Nurnberger
authors: Margaret A
authors: MA
authors: Pericak-Vance
authors: Gerard D
authors: GD
authors: Schellenberg
authors: Stephen W
authors: SW
authors: Scherer
authors: James S
authors: JS
authors: Sutcliffe
authors: Peter
authors: P
authors: Szatmari
authors: Veronica J
authors: VJ
authors: Vieland
authors: Ellen M
authors: EM
authors: Wijsman
authors: Andrew
authors: A
authors: Green
authors: Michael
authors: M
authors: Gill
authors: Louise
authors: L
authors: Gallagher
authors: Astrid
authors: A
authors: Vicente
authors: Sean
authors: S
authors: Ennis
mesh_terms: D000328:Adult; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D016000:Cluster Analysis; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009679:Nuclear Family; D020641:Polymorphism, Single Nucleotide