Dataset Information

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.

SUBMITTER: Casey JP

PROVIDER: S-EPMC3303079 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Casey Jillian P JP Magalhaes Tiago T Conroy Judith M JM Regan Regina R Shah Naisha N Anney Richard R Shields Denis C DC Abrahams Brett S BS Almeida Joana J Bacchelli Elena E Bailey Anthony J AJ Baird Gillian G Battaglia Agatino A Berney Tom T Bolshakova Nadia N Bolton Patrick F PF Bourgeron Thomas T Brennan Sean S Cali Phil P Correia Catarina C Corsello Christina C Coutanche Marc M Dawson Geraldine G de Jonge Maretha M Delorme Richard R Duketis Eftichia E Duque Frederico F Estes Annette A Farrar Penny P Fernandez Bridget A BA Folstein Susan E SE Foley Suzanne S Fombonne Eric E Freitag Christine M CM Gilbert John J Gillberg Christopher C Glessner Joseph T JT Green Jonathan J Guter Stephen J SJ Hakonarson Hakon H Holt Richard R Hughes Gillian G Hus Vanessa V Igliozzi Roberta R Kim Cecilia C Klauck Sabine M SM Kolevzon Alexander A Lamb Janine A JA Leboyer Marion M Le Couteur Ann A Leventhal Bennett L BL Lord Catherine C Lund Sabata C SC Maestrini Elena E Mantoulan Carine C Marshall Christian R CR McConachie Helen H McDougle Christopher J CJ McGrath Jane J McMahon William M WM Merikangas Alison A Miller Judith J Minopoli Fiorella F Mirza Ghazala K GK Munson Jeff J Nelson Stanley F SF Nygren Gudrun G Oliveira Guiomar G Oliveira Guiomar G Pagnamenta Alistair T AT Papanikolaou Katerina K Parr Jeremy R JR Parrini Barbara B Pickles Andrew A Pinto Dalila D Piven Joseph J Posey David J DJ Poustka Annemarie A Poustka Fritz F Ragoussis Jiannis J Roge Bernadette B Rutter Michael L ML Sequeira Ana F AF Soorya Latha L Sousa Inês I Sykes Nuala N Stoppioni Vera V Tancredi Raffaella R Tauber Maïté M Thompson Ann P AP Thomson Susanne S Tsiantis John J Van Engeland Herman H Vincent John B JB Volkmar Fred F Vorstman Jacob A S JA Wallace Simon S Wang Kai K Wassink Thomas H TH White Kathy K Wing Kirsty K Wittemeyer Kerstin K Yaspan Brian L BL Zwaigenbaum Lonnie L Betancur Catalina C Buxbaum Joseph D JD Cantor Rita M RM Cook Edwin H EH Coon Hilary H Cuccaro Michael L ML Geschwind Daniel H DH Haines Jonathan L JL Hallmayer Joachim J Monaco Anthony P AP Nurnberger John I JI Pericak-Vance Margaret A MA Schellenberg Gerard D GD Scherer Stephen W SW Sutcliffe James S JS Szatmari Peter P Vieland Veronica J VJ Wijsman Ellen M EM Green Andrew A Gill Michael M Gallagher Louise L Vicente Astrid A Ennis Sean S

Human genetics 20111014 4

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 ...[more]

PMID: 21996756

Similar Datasets

Project description:BACKGROUND: HOXB1 plays a major role in brainstem morphogenesis and could partly determine the cranial circumference in conjunction with HOXA1. In our sample, HOXA1 alleles significantly influence head growth rates both in autistic patients and in population controls. An initial report, suggesting that HOXB1 could confer autism vulnerability in interaction with HOXA1, was not confirmed by five small association studies. METHODS: Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios. RESULTS: We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS)], rs12939811 [c.309A>T (Q103H)], and rs7207109 [c.450G>A (A150A)] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V)] and c.872_873delinsAA (S291N). SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13) or a family-based design [transmission/disequilibrium test (TDT)chi2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N) were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest and shows no interaction with HOXA1 alleles. The INS-T309 allele is also associated with more severe stereotypic behaviours, according to ADI-R scores (N = 60 patients, P < 0.01). CONCLUSIONS: HOXB1 mutations do not represent a common cause of autism, nor do HOXB1 common variants play important roles in autism vulnerability. HOXB1 provides minor, albeit detectable contributions to head circumference in autistic patients, with HOXA1 displaying more prominent effects. HOXB1 variants may modulate the clinical phenotype, especially in the area of stereotypic behaviours.

Dataset Information

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Publications

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets