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Individual common variants exert weak effects on the risk for autism spectrum disorders.

ABSTRACT: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

SUBMITTER: Anney R

PROVIDER: S-EPMC3471395 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Individual common variants exert weak effects on the risk for autism spectrum disorders.

Anney Richard R Klei Lambertus L Pinto Dalila D Almeida Joana J Bacchelli Elena E Baird Gillian G Bolshakova Nadia N Bölte Sven S Bolton Patrick F PF Bourgeron Thomas T Brennan Sean S Brian Jessica J Casey Jillian J Conroy Judith J Correia Catarina C Corsello Christina C Crawford Emily L EL 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 Fombonne Eric E Gilbert John J Gillberg Christopher C Glessner Joseph T JT Green Andrew A Green Jonathan J Guter Stephen J SJ Heron Elizabeth A EA Holt Richard R Howe Jennifer L JL Hughes Gillian G Hus Vanessa V Igliozzi Roberta R Jacob Suma S Kenny Graham P GP Kim Cecilia C Kolevzon Alexander A Kustanovich Vlad V Lajonchere Clara M CM Lamb Janine A JA Law-Smith Miriam M Leboyer Marion M Le Couteur Ann A Leventhal Bennett L BL Liu Xiao-Qing XQ Lombard Frances F Lord Catherine C Lotspeich Linda L Lund Sabata C SC Magalhaes Tiago R TR Mantoulan Carine C McDougle Christopher J CJ Melhem Nadine M NM Merikangas Alison A Minshew Nancy J NJ Mirza Ghazala K GK Munson Jeff J Noakes Carolyn C Nygren Gudrun G Papanikolaou Katerina K Pagnamenta Alistair T AT Parrini Barbara B Paton Tara T Pickles Andrew A Posey David J DJ Poustka Fritz F Ragoussis Jiannis J Regan Regina R Roberts Wendy W Roeder Kathryn K Roge Bernadette B Rutter Michael L ML Schlitt Sabine S Shah Naisha N Sheffield Val C VC Soorya Latha L Sousa Inês I Stoppioni Vera V Sykes Nuala N Tancredi Raffaella R Thompson Ann P AP Thomson Susanne S Tryfon Ana A Tsiantis John J Van Engeland Herman H Vincent John B JB Volkmar Fred F Vorstman J A S JA Wallace Simon S Wing Kirsty K Wittemeyer Kerstin K Wood Shawn S Zurawiecki Danielle D Zwaigenbaum Lonnie L Bailey Anthony J AJ Battaglia Agatino A Cantor Rita M RM Coon Hilary H Cuccaro Michael L ML Dawson Geraldine G Ennis Sean S Freitag Christine M CM Geschwind Daniel H DH Haines Jonathan L JL Klauck Sabine M SM McMahon William M WM Maestrini Elena E Miller Judith J Monaco Anthony P AP Nelson Stanley F SF Nurnberger John I JI Oliveira Guiomar G Oliveira Guiomar G Parr Jeremy R JR Pericak-Vance Margaret A MA Piven Joseph J Schellenberg Gerard D GD Scherer Stephen W SW Vicente Astrid M AM Wassink Thomas H TH Wijsman Ellen M EM Betancur Catalina C Buxbaum Joseph D JD Cook Edwin H EH Gallagher Louise L Gill Michael M Hallmayer Joachim J Paterson Andrew D AD Sutcliffe James S JS Szatmari Peter P Vieland Veronica J VJ Hakonarson Hakon H Devlin Bernie B

Human molecular genetics 20120726 21

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide ...[more]

PMID: 22843504

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Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males. Gene expression profiling of 116 LCL from autistic (87) and nonautistic (29) individuals were obtained using a custom-printed DNA microarray containing 39,936 elements (TIGR 40K Human array, GPL3427) and a reference design in which each sample was compared to the Stratagene Universal Human RNA standard. The 87 autistic samples were divided into phenotypic subgroups (language, mild, savant) on the basis of cluster analyses of scores from an autism diagnostic questionnaire, the Autism Diagnostic Interview-Revised instrument. Differentially expressed genes were determined for all autistic vs. control groups, as well as for each of 3 phenotypic ASD groups and controls.

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Individual common variants exert weak effects on the risk for autism spectrum disorders.

Publications

Individual common variants exert weak effects on the risk for autism spectrum disorders.

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