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NDAR provides a single access to de-identified autism research data. For permission to download data, you will need an NDAR account with approved access to NDAR or a connected repository (AGRE, IAN, or the ATP). For NDAR access, you need to be a research investigator sponsored by an NIH recognized institution with federal wide assurance. See Request Access for more information.

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Collection Summary Collection Charts
Collection Title Collection Investigators Collection Description
The Role of Germline Mutation and Parental Age in Autism Spectrum Disorders
Jonathan Sebat 
In the new phase of our project, we will apply a whole genome sequencing-based approach to determine the role of ROHs in ASD. We will investigate the nature intrinsic hypermutability and the extrinsic forces, such as paternal age, that influence rates of germline mutation. We will accomplish these goals through the following specific aims: Specific Aim 1 will characterize germline de novo mutations (DNMs) by whole genome sequencing in families. These studies will identify and validate ~8,000 de novo point mutations and structural variants in a sample of 120 trios (60 ASD and 60 controls) and determine the parent of origin of DNMs. Specific Aim 2 will investigate the role of ROHs in ASD. We will identify ROHs based on the regional density of DNMs in the genome, and determine the effects of DNA sequence features on rates of mutation. We will determine the association of ROHs with ASD in the discovery sample and in exome and CNV datasets from an independent sample of 2700 cases and 2700 controls. Specific Aim 3 will characterize the effects of extrinsic factors, including parental age and environment, on genome-wide rates of mutation. We will quantify the effect of paternal age on pathogenic and neutral alleles in sperm and investigate whether some DNMs confer a germline selective advantage. The findings of this study will provide fundamental insights into the genetic basis of autism risk and the genetic mechanism of the observed parental age effects in ASD. We will identify genes that confer significant risk for autism, and we will determine how intrinsic properties of the genome interact with extrinsic forces to determining risk for disease in offspring.
NDAR
Closed
Shared
$3,685,804.00
1,140
1500
287
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NIH - Extramural None

sequencing_files_readme_col_2019.pdf Background Readme for sequencing files Qualified Researchers

R01MH076431-07 The Role of Germline Mutation and Parental Age in Autism Spectrum Disorders 09/01/2012 08/31/2016 1500 287 UNIVERSITY OF CALIFORNIA SAN DIEGO $3,685,804.00

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Experiments

To create a new Omics, eye tracking, fMRI, or EEG experiment, press the "+ New Experiment" button. Once an experiment is created, then raw files for these types of experiments should be provided, associating the experiment – through Experiment_ID – with the metadata defined in the experiments interface.

IDNameCreated DateStatusType
563Whole Genome Sequencing at HLI12/29/2016ApprovedOmics
466Whole Genome Sequencing05/18/2016ApprovedOmics
76Whole Genome Sequencing in Autism Families01/03/2013ApprovedOmics

Collection Owners and those with Collection Administrator permission, may edit a collection. The following is currently available for Edit on this page:

Shared Data

Data structures with the number of subjects submitted and shared are provided.

Genomics Sample Genomics 1140
Genomics Subject Genomics 1140

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Publications

Publications relevant to NDAR data are listed below. Most displayed publications have been associated with the grant within Pubmed. Use the "+ New Publication" button to add new publications. Publications relevant/not relevant to data expected are categorized. Relevant publications are then linked to the underlying data by selecting the Create Study link. Study provides the ability to define cohorts, assign subjects, define outcome measures and lists the study type, data analysis and results. Analyzed data and results are expected in this way.

PubMed IDStudyTitleJournalAuthorsDateStatus
27018473Study (410)Frequency and Complexity of De Novo Structural Mutation in Autism.American journal of human geneticsBrandler WM, Antaki D, Gujral M, Noor A, Rosanio G, Chapman TR, Barrera DJ, Lin GN, Malhotra D, Watts AC, Wong LC, Estabillo JA, Gadomski TE, Hong O, Fajardo KV, Bhandari A, Owen R, Baughn M, Yuan J, Solomon T, Moyzis AG, Maile MS, Sanders SJ, Reiner GE, Vaux KK, et al.April 2016Relevant
26391891Create StudyThe Influence of Microdeletions and Microduplications of 16p11.2 on Global Transcription Profiles.Journal of child neurologyKusenda M, Vacic V, Malhotra D, Rodgers L, Pavon K, Meth J, Kumar RA, Christian SL, Peeters H, Cho SS, Addington A, Rapoport JL, Sebat JDecember 2015Not Determined
25587659Create StudyFrom de novo mutations to personalized therapeutic interventions in autism.Annual review of medicineBrandler, William M; Sebat, Jonathan2015Not Relevant
24722188Create StudyProtein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.Nature communicationsCorominas R, Yang X, Lin GN, Kang S, Shen Y, Ghamsari L, Broly M, Rodriguez M, Tam S, Trigg SA, Fan C, Yi S, Tasan M, Lemmens I, Kuang X, Zhao N, Malhotra D, Michaelson JJ, Vacic V, Calderwood MA, Roth FP, Tavernier J, Horvath S, Salehi-Ashtiani K, Korkin D, et al.2014Not Relevant
23260136Study (322)Whole-genome sequencing in autism identifies hot spots for de novo germline mutation.CellMichaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D, Jin X, Jian M, Liu G, Greer D, Bhandari A, Wu W, Corominas R, Peoples A, Koren A, Gore A, Kang S, Lin GN, Estabillo J, Gadomski T, Singh B, Zhang K, Akshoomoff N, Corsello C, McCarroll S, Iakoucheva LM, et al.December 21, 2012Relevant
23176822Create StudyDifferential relationship of DNA replication timing to different forms of human mutation and variation.American journal of human geneticsKoren A, Polak P, Nemesh J, Michaelson JJ, Sebat J, Sunyaev SR, McCarroll SADecember 7, 2012Not Determined
22751202Create StudyforestSV: structural variant discovery through statistical learning.Nature methodsMichaelson JJ, Sebat JAugust 2012Not Relevant
22424231Create StudyCNVs: harbingers of a rare variant revolution in psychiatric genetics.CellMalhotra D, Sebat JMarch 16, 2012Not Relevant
22196331Create StudyHigh frequencies of de novo CNVs in bipolar disorder and schizophrenia.NeuronMalhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, Cichon S, Corvin A, Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nöthen MM, Potash JB, Rietschel M, Schulze TG, et al.December 22, 2011Not Relevant
21448237Create StudyReduced transcript expression of genes affected by inherited and de novo CNVs in autism.European journal of human genetics : EJHGNord AS, Roeb W, Dickel DE, Walsh T, Kusenda M, O'Connor KL, Malhotra D, McCarthy SE, Stray SM, Taylor SM, Sebat J, , King B, King MC, McClellan JMJune 2011Not Determined
21346763Create StudyDuplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.NatureVacic V, McCarthy S, Malhotra D, Murray F, Chou HH, Peoples A, Makarov V, Yoon S, Bhandari A, Corominas R, Iakoucheva LM, Krastoshevsky O, Krause V, Larach-Walters V, Welsh DK, Craig D, Kelsoe JR, Gershon ES, Leal SM, Dell Aquila M, Morris DW, Gill M, Corvin A, Insel PA, McClellan J, et al.March 24, 2011Not Relevant
19883952Create StudyRare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders.Trends in genetics : TIGSebat J, Levy DL, McCarthy SEDecember 2009Not Relevant
19855392Create StudyMicroduplications of 16p11.2 are associated with schizophrenia.Nature geneticsMcCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, et al.November 2009Not Relevant
19657104Create StudySensitive and accurate detection of copy number variants using read depth of coverage.Genome researchYoon S, Xuan Z, Makarov V, Ye K, Sebat JSeptember 2009Not Determined
19287137Create StudyThe role of rare structural variants in the genetics of autism spectrum disorders.Cytogenetic and genome researchKusenda M, Sebat J2008Not Relevant
18179893Create StudyLinkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene.American journal of human geneticsAlarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DHJanuary 2008Not Relevant
17363630Create StudyStrong association of de novo copy number mutations with autism.Science (New York, N.Y.)Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, et al.April 20, 2007Not Determined
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PubMed IDStudyTitleJournalAuthorsDate
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Data Expected
Data ExpectedTargeted EnrollmentInitial SubmissionSubjects SharedStatus
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Collection Owners and those with Collection Administrator permission, may edit a collection. The following is currently available for Edit on this page:

Associated Studies

Studies that have been defined using data from a Collection are important criteria to determine the value of data shared. The number of subjects column displays the counts from this Collection that are included in a Study, out of the total number of subjects in that study. The Data Use column represents whether or not the study is a primary analysis of the data or a secondary analysis. State indicates whether the study is private or shared with the research community.

Study Name Description Number of Subjects
Collection / Total
Data Use State
Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. De novo mutation plays an important role in autism spectrum disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes and may also include nucleotide-substitution hot spots. We investigated global patterns of germline mutation by whole-genome sequencing of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely throughout the genome (by 100-fold) and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Dense clusters of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing data sets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans. 41 / 41 Primary Analysis Shared
Paternally inherited noncoding structural variants contribute to autism The genetic architecture of autism spectrum disorder (ASD) is known to consist of contributions from gene-disrupting de novo mutations and common variants of modest effect. We hypothesize that the unexplained heritability of ASD also includes rare inherited variants with intermediate effects. We investigated the genome-wide distribution and functional impact of structural variants (SVs) through whole genome analysis (>30X coverage) of 3,169 subjects from 829 families affected by ASD. Genes that are intolerant to inactivating variants in the exome aggregation consortium (ExAC) were depleted for SVs in parents, specifically within fetal-brain promoters, UTRs and exons. Rare paternally-inherited SVs that disrupt promoters or UTRs were over-transmitted to cases (P = 0.0013) and not to their typically-developing siblings. Protein-coding SVs were also associated with ASD (P = 0.0025). Recurrent functional noncoding deletions implicate the gene LEO1 in ASD. Our results establish that rare inherited SVs predispose children to ASD, with differing contributions from each parent. 1098 / 3170 Primary Analysis Shared
Frequency and Complexity of De Novo Structural Mutation in Autism Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement. 235 / 235 Primary Analysis Shared
* Data not on individual level
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