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Fine mapping of autism susceptibility loci on chromosome 1q23-q24 and chromosome 13q13-q14

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TypeOfResource
Text
TitleInfo
Title
Fine mapping of autism susceptibility loci on chromosome 1q23-q24 and chromosome 13q13-q14
Identifier
ETD_1877
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051819
Identifier (type = doi)
doi:10.7282/T3BK1CJ5
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Genre (authority = marcgt)
theses
Genre (authority = ExL-Esploro)
ETD doctoral
Subject (authority = RUETD)
Topic
Microbiology and Molecular Genetics
Subject (authority = ETD-LCSH)
Topic
Autism spectrum disorders
Subject (authority = ETD-LCSH)
Topic
Autism--Genetics aspects
Subject (authority = ETD-LCSH)
Topic
Autism--Etiology
Abstract
Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders where genetic heterogeneity has complicated the identification of genes involved in the pathogenesis in these disorders. To address this issue, we fine mapped a 30cM linkage interval on chromosome 1q23-q24 through high density microsatellite genotyping of 46 phenotypically homogeneous families described by Bartlett et al (2005) who re-analyzed the Autism Genetic Resource Exchange (AGRE) genome scan by the Posterior Probability of Linkage (PPL). We identified genotyping errors in the original AGRE genome scan that led to an inflation of the linkage signal (PPL of 0.55) due to a false assumption of identity-by-descent (IBD). Our Multipoint PPL analysis narrowed the 30cM linkage interval to 5cM (PPL of 0.27). Subsequently, the Posterior Probability of Linkage Disequilibrium (PPLD) analysis of the AGRE 550K SNP data generated by the Autism Genome Project Consortium (AGP) and 116 tag SNPs genotyped and analyzed in our lab for the pre-B-cell leukemia transcription factor 1 (PBX1), provided the highest PPLD score for rs2800785 (0.13 and 0.12 respectively) which indicates possible association for rs2800785 (located in intron 2 of PBX1) with the trait locus. In addition, PDTPHASE single and multilocus analysis for the 116 tagSNPs showed association for rs7529254 which remained statistically significant (nominal P-value=0.0006) after correction for multiple testing with the simple M method by Gao, (╬▒corrected=0.05/58)=0.0009. Four-marker PDTPHASE haplotype analysis showed transmission disequilibrium for rs1780334, rs7529254, rs2792253 and rs2800785. Global Chi-squared tests for all haplotypes produced a nominal P-value of 0.0077.
The second locus investigated was identified by multipoint PPL genome scan analysis of the 10K SNP data generated by the AGP. Ninety nine phenotypically homogeneous families were used to identify a 1.5 Mb linkage peak on chromosome 13q13-q14 with a maximum multipoint PPL score of 0.38. PPLD analysis of 142 genotyped tagSNPs from a 620.5kb peak interval which included TSC22D1, NUFIP1 and KIAA1704 showed weak evidence of LD.
No other studies have proposed PBX1 as a candidate gene for ASD. However, our positive association results with the two-point PPLD and single and multimarker PDTPHASE analysis suggests PBX1 as a likely susceptibility gene for ASD that warrants further investigation.
PhysicalDescription
Form (authority = gmd)
electronic resource
Extent
xiii, 204 p. : ill.
InternetMediaType
application/pdf
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text/xml
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references (p. 108-121)
Note (type = statement of responsibility)
by Maria del Pilar Garavito
Name (type = personal)
NamePart (type = family)
Pilar Garavito
NamePart (type = given)
Maria del
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author
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Maria del Pilar Garavito
Name (type = personal)
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Matise
NamePart (type = given)
Tara
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chair
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Advisory Committee
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Tara C Matise
Name (type = personal)
NamePart (type = family)
Brzustowicz
NamePart (type = given)
Linda
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internal member
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Advisory Committee
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Linda M Brzustowicz
Name (type = personal)
NamePart (type = family)
Millonig
NamePart (type = given)
James
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internal member
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Advisory Committee
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James H Millonig
Name (type = personal)
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DiCicco-Bloom
NamePart (type = given)
Emanuel
Role
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internal member
Affiliation
Advisory Committee
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Emanuel DiCicco-Bloom
Name (type = personal)
NamePart (type = family)
Buyske
NamePart (type = given)
Steve
Role
RoleTerm (authority = RULIB)
outside member
Affiliation
Advisory Committee
DisplayForm
Steve Buyske
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
OriginInfo
DateCreated (qualifier = exact)
2009
DateOther (qualifier = exact); (type = degree)
2009-10
Place
PlaceTerm (type = code)
xx
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
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The author owns the copyright to this work
Copyright
Status
Copyright protected
Notice
Note
Availability
Status
Open
Reason
Permission or license
Note
RightsHolder (ID = PRH-1); (type = personal)
Name
FamilyName
Garavito
GivenName
Maria
Role
Copyright holder
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DateTime
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Name
Maria Garavito
Affiliation
Rutgers University. Graduate School - New Brunswick
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License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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