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Faculty partnering with Utah Autism Research have a number of publications related to studying Autism Spectrum Disorder. Below we list some of our faculty members' recent publications.

Publications List

Synaptic, transcriptional and chromatin genes disrupted in autism.

De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P,Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK; DDD Study; Homozygosity Mapping Collaborative for Autism;UK10K Consortium, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD.

Nature. 2014 Nov 13;515(7526):209-15. doi: 10.1038/nature13772. Epub 2014 Oct 29. PMID: 25363760 [PubMed - indexed for MEDLINE] PMCID: PMC4402723

Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Maternal prenatal weight gain and autism spectrum disorders.

Bilder DABakian AV, Viskochil J, Clark EA, Botts EL, Smith KR, Pimentel R, McMahon WM, Coon H.

Pediatrics. 2013 Nov;132(5):e1276-83. doi: 10.1542/peds.2013-1188. Epub 2013 Oct 28. PMID:24167172 [PubMed - indexed for MEDLINE] PMCID: PMC3813395

Abstract: The rising population of individuals identified with an autism spectrum disorder (ASD) calls for further investigation of its underlying etiology. A disturbance in the fetal steroid hormone environment may be a mechanism in which environmental and genetic risk factors interact. The mother, fetus, and placenta collectively create the fetal steroid environment. Pre-pregnancy BMI and pregnancy weight gain have served as markers for fetal steroid hormone exposure in other disease states. This study's objective is to determine whether pre-pregnancy BMI and pregnancy weight gain are associated with increased ASD risk across study designs and cohorts while controlling for important confounding variables. METHODS: A population-based Utah ASD cohort (n = 128) was ascertained in a 3-county surveillance area and gender- and age-matched to 10,920 control subjects. A second, research-based ASD cohort of Utah children (n = 288) and their unaffected siblings (n = 493) were ascertained through participation in an ASD genetics study. Prenatal variables were obtained from birth certificate records. RESULTS: ASD risk was significantly associated with pregnancy weight gain (adjusted odds ratio = 1.10, 95% confidence interval: 1.03 to 1.17; adjusted odds ratio = 1.17, 95% confidence interval: 1.01 to 1.35 for each 5 pounds of weight gained), but not pre-pregnancy BMI, in population and research-based cohorts, respectively. When analyses were restricted to ASD cases with normal IQ, these associations remained significant. CONCLUSIONS: ASD risk associated with a modest yet consistent increase in pregnancy weight gain suggests that pregnancy weight gain may serve as an important marker for autism's underlying gestational etiology. This justifies an investigation into phenomena that link pregnancy weight gain and ASD independent of pre-pregnancy BMI.

Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes.

Chapman NH, Nato AQ Jr, Bernier R, Ankenman K, Sohi H, Munson J, Patowary A, Archer M, Blue EM, Webb SJ, Coon H, Raskind WH, Brkanac Z, Wijsman EM.

Human Genetics. 2015 Oct;134(10):1055-68. doi: 10.1007/s00439-015-1585-y. Epub 2015 Jul 24. PMID: 26204995 [PubMed - indexed for MEDLINE] PMCID:PMC4578871 [Available on 2016-10-01]

Abstract: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders, characterized by impairment in communication and social interactions, and by repetitive behaviors. ASDs are highly heritable, and estimates of the number of risk loci range from hundreds to >1000. We considered 7 extended families (size 12-47 individuals), each with ≥3 individuals affected by ASD. All individuals were genotyped with dense SNP panels. A small subset of each family was typed with whole exome sequence (WES). We used a 3-step approach for variant identification. First, we used family-specific parametric linkage analysis of the SNP data to identify regions of interest. Second, we filtered variants in these regions based on frequency and function, obtaining exactly 200 candidates. Third, we compared two approaches to narrowing this list further. We used information from the SNP data to impute exome variant dosages into those without WES. We regressed affected status on variant allele dosage, using pedigree-based kinship matrices to account for relationships. The p value for the test of the null hypothesis that variant allele dosage is unrelated to phenotype was used to indicate strength of evidence supporting the variant. A cutoff of p = 0.05 gave 28 variants. As an alternative third filter, we required Mendelian inheritance in those with WES, resulting in 70 variants. The imputation- and association-based approach was effective. We identified four strong candidate genes for ASD (SEZ6L, HISPPD1, FEZF1, SAMD11), all of which have been previously implicated in other studies, or have a strong biological argument for their relevance.

Spatial relative risk patterns of autism spectrum disorders in Utah.

Bakian AVBilder DACoon H, McMahon WM.

Autism Dev Disord. 2015 Apr;45(4):988-1000. doi: 10.1007/s10803-014-2253-0. PMID: 25241009 [PubMed - indexed for MEDLINE]  PMCID: PMC4379991

Abstract: Heightened areas of spatial relative risk for autism spectrum disorders (ASD), or ASD hotspots, in Utah were identified using adaptive kernel density functions. Children ages four, six, and eight with ASD from multiple birth cohorts were identified by the Utah Registry of Autism and Developmental Disabilities. Each ASD case was gender-matched to 20 birth cohort controls. Demographic and socioeconomic characteristics of children born inside versus outside ASD hotspots were compared. ASD hotspots were found in the surveillance area for all but one birth cohort and age group sample; maximum relative risk in these hotspots ranged from 1.8 to 3.0. Associations were found between higher socioeconomic status and birth residence in an ASD hotspot in five out of six birth cohort and age group samples.

The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses.

Buxbaum JD, Bolshakova N, Brownfeld JM, Anney RJ, Bender P, Bernier R, Cook EH, Coon H, Cuccaro M, Freitag CM, Hallmayer J,Geschwind D, Klauck SM, Nurnberger JI, Oliveira G, Pinto D, Poustka F, Scherer SW, Shih A, Sutcliffe JS, Szatmari P, Vicente AM,Vieland V, Gallagher L.

Molecular Autism. 2014 May 20;5:34. doi: 10.1186/2040-2392-5-34. eCollection 2014. PMID: 25392729 [PubMed] PMCID: PMC4228819

Abstract: There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. METHODS: In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. RESULTS: Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children's or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI). CONCLUSIONS: TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.

A unified test of linkage analysis and rare-variant association for analysis of pedigree sequence data.

Hu H, Roach JC, Coon H, Guthery SL, Voelkerding KV, Margraf RL, Durtschi JD, Tavtigian SV, Shankaracharya, Wu W, Scheet P, Wang S,Xing J, Glusman G, Hubley R, Li H, Garg V, Moore B, Hood L, Galas DJ, Srivastava D, Reese MG, Jorde LB, Yandell M, Huff CD.

Nature Biotechnology. 2014 Jul;32(7):663-9. doi: 10.1038/nbt.2895. Epub 2014 May 18. PMID: 24837662 [PubMed - indexed for MEDLINE] PMCID:PMC4157619

Abstract: High-throughput sequencing of related individuals has become an important tool for studying human disease. However, owing to technical complexity and lack of available tools, most pedigree-based sequencing studies rely on an ad hoc combination of suboptimal analyses. Here we present pedigree-VAAST (pVAAST), a disease-gene identification tool designed for high-throughput sequence data in pedigrees. pVAAST uses a sequence-based model to perform variant and gene-based linkage analysis. Linkage information is then combined with functional prediction and rare variant case-control association information in a unified statistical framework. pVAAST outperformed linkage and rare-variant association tests in simulations and identified disease-causing genes from whole-genome sequence data in three human pedigrees with dominant, recessive and de novo inheritance patterns. The approach is robust to incomplete penetrance and locus heterogeneity and is applicable to a wide variety of genetic traits. pVAAST maintains high power across studies of monogenic, high-penetrance phenotypes in a single pedigree to highly polygenic, common phenotypes involving hundreds of pedigrees.

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R,Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA,De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E,Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S,Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, Scherer SW.

American Journal of Human Genetics. 2014 May 1;94(5):677-94. doi: 10.1016/j.ajhg.2014.03.018. Epub 2014 Apr 24. PMID: 24768552 [PubMed - indexed for MEDLINE] PMCID: PMC4067558. 

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Abstract: Rare copy-number variation (CNV) is a critical indicator and risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families. In these families we identified additional gene deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)). In addition, subjects who were affected had exonic pathogenic CNVs in conjunction with loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs frequently showed variable expressivity. They had rare de novo and inherited events at 36 loci, suggesting ASD-associated genes (CHD2, HDAC4, and GDI1) were involved. These were previously associated with other neurodevelopmental disorders, in addition to other genes including SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have CNVs that had a high penetrant rate (p = 0.017). They were also overrepresented among test subjects with weak X syndrome protein targets (p = 0.02). Genes that were affected by de novo CNVs and/or single-nucleotide variants that had lost function combined on networks related to synapse function, chromatin regulation, and the signaling and development of neurons.