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A genome-wide scan for common alleles affecting risk for autism.

ABSTRACT: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

SUBMITTER: Anney R

PROVIDER: S-EPMC2947401 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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A genome-wide scan for common alleles affecting risk for autism.

Anney Richard R Klei Lambertus L Pinto Dalila D Regan Regina R Conroy Judith J Magalhaes Tiago R TR Correia Catarina C Abrahams Brett S BS Sykes Nuala N Pagnamenta Alistair T AT Almeida Joana J Bacchelli Elena E Bailey Anthony J AJ Baird Gillian G Battaglia Agatino A Berney Tom T Bolshakova Nadia N Bölte Sven S Bolton Patrick F PF Bourgeron Thomas T Brennan Sean S Brian Jessica J Carson Andrew R AR Casallo Guillermo G Casey Jillian J Chu Su H SH Cochrane Lynne L Corsello Christina C Crawford Emily L EL Crossett Andrew A Dawson Geraldine G de Jonge Maretha M Delorme Richard R Drmic Irene I Duketis Eftichia E Duque Frederico F Estes Annette A Farrar Penny P Fernandez Bridget A BA Folstein Susan E SE Fombonne Eric E Freitag Christine M CM Gilbert John J Gillberg Christopher C Glessner Joseph T JT Goldberg Jeremy J Green Jonathan J Green Jonathan J Guter Stephen J SJ Hakonarson Hakon H Heron Elizabeth A EA Hill Matthew M Holt Richard R Howe Jennifer L JL Hughes Gillian G Hus Vanessa V Igliozzi Roberta R Kim Cecilia C Klauck Sabine M SM Kolevzon Alexander A Korvatska Olena O Kustanovich Vlad V Lajonchere Clara M CM Lamb Janine A JA Laskawiec Magdalena M Leboyer Marion M Le Couteur Ann A Leventhal Bennett L BL Lionel Anath C AC Liu Xiao-Qing XQ Lord Catherine C Lotspeich Linda L Lund Sabata C SC Maestrini Elena E Mahoney William W Mantoulan Carine C Marshall Christian R CR McConachie Helen H McDougle Christopher J CJ McGrath Jane J McMahon William M WM Melhem Nadine M NM Merikangas Alison A Migita Ohsuke O Minshew Nancy J NJ Mirza Ghazala K GK Munson Jeff J Nelson Stanley F SF Noakes Carolyn C Noor Abdul A Nygren Gudrun G Oliveira Guiomar G Oliveira Guiomar G Papanikolaou Katerina K Parr Jeremy R JR Parrini Barbara B Paton Tara T Pickles Andrew A Piven Joseph J Posey David J DJ Poustka Annemarie A Poustka Fritz F Prasad Aparna A Ragoussis Jiannis J Renshaw Katy K Rickaby Jessica J Roberts Wendy W Roeder Kathryn K Roge Bernadette B Rutter Michael L ML Bierut Laura J LJ Rice John P JP Salt Jeff J Sansom Katherine K Sato Daisuke D Segurado Ricardo R Senman Lili L Shah Naisha N Sheffield Val C VC Soorya Latha L Sousa Inês I Stoppioni Vera V Strawbridge Christina C Tancredi Raffaella R Tansey Katherine K Thiruvahindrapduram Bhooma B Thompson Ann P AP Thomson Susanne S Tryfon Ana A Tsiantis John J Van Engeland Herman H Vincent John B JB Volkmar Fred F Wallace Simon S Wang Kai K Wang Zhouzhi Z Wassink Thomas H TH Wing Kirsty K Wittemeyer Kerstin K Wood Shawn S Yaspan Brian L BL Zurawiecki Danielle D 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 Gallagher Louise L Geschwind Daniel H DH Gill Michael M Haines Jonathan L JL Miller Judith J Monaco Anthony P AP Nurnberger John I JI Paterson Andrew D AD Pericak-Vance Margaret A MA Schellenberg Gerard D GD Scherer Stephen W SW Sutcliffe James S JS Szatmari Peter P Vicente Astrid M AM Vieland Veronica J VJ Wijsman Ellen M EM Devlin Bernie B Ennis Sean S Hallmayer Joachim J

Human molecular genetics 20100727 20

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs ...[more]

PMID: 20663923

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Project description:BackgroundNo single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS).ObjectiveTo test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer.Design, setting, and participantsSNPs implicated in any phenotype other than prostate cancer (p≤10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24,534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.Outcome measurements and statistical analysisOdds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated.Results and limitationsA total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p=1.6×10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p=3.22×10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86-0.94; p=2.5×10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p=4.67×10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL.ConclusionsWe did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology.Patient summaryWe evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified.

Project description:BackgroundBovine leukemia virus (BLV) infection is omnipresent in dairy herds causing direct economic losses due to trade restrictions and lymphosarcoma-related deaths. Milk production drops and increase in the culling rate are also relevant and usually neglected. The BLV provirus persists throughout a lifetime and an inter-individual variation is observed in the level of infection (LI) in vivo. High LI is strongly correlated with disease progression and BLV transmission among herd mates. In a context of high prevalence, classical control strategies are economically prohibitive. Alternatively, host genomics studies aiming to dissect loci associated with LI are potentially useful tools for genetic selection programs tending to abrogate the viral spreading. The LI was measured through the proviral load (PVL) set-point and white blood cells (WBC) counts. The goals of this work were to gain insight into the contribution of SNPs (bovine 50KSNP panel) on LI variability and to identify genomics regions underlying this trait.ResultsWe quantified anti-p24 response and total leukocytes count in peripheral blood from 1800 cows and used these to select 800 individuals with extreme phenotypes in WBCs and PVL. Two case-control genomic association studies using linear mixed models (LMMs) considering population stratification were performed. The proportion of the variance captured by all QC-passed SNPs represented 0.63 (SE ± 0.14) of the phenotypic variance for PVL and 0.56 (SE ± 0.15) for WBCs. Overall, significant associations (Bonferroni's corrected -log10p > 5.94) were shared for both phenotypes by 24 SNPs within the Bovine MHC. Founder haplotypes were used to measure the linkage disequilibrium (LD) extent (r2 = 0.22 ± 0.27 at inter-SNP distance of 25-50 kb). The SNPs and LD blocks indicated genes potentially associated with LI in infected cows: i.e. relevant immune response related genes (DQA1, DRB3, BOLA-A, LTA, LTB, TNF, IER3, GRP111, CRISP1), several genes involved in cell cytoskeletal reorganization (CD2AP, PKHD1, FLOT1, TUBB5) and modelling of the extracellular matrix (TRAM2, TNXB). Host transcription factors (TFs) were also highlighted (TFAP2D; ABT1, GCM1, PRRC2A).ConclusionsData obtained represent a step forward to understand the biology of BLV-bovine interaction, and provide genetic information potentially applicable to selective breeding programs.

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A genome-wide scan for common alleles affecting risk for autism.

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A genome-wide scan for common alleles affecting risk for autism.

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