PittsburghV1, Main, Exploration, bibRecord, 004305

A genomewide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Identifieur interne : 004305 ( Main/Exploration ); précédent : 004304; suivant : 004306

A genomewide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Auteurs : Pauline Chaste [États-Unis, France] ; Lambertus Klei [États-Unis] ; Stephan J. Sanders [États-Unis] ; Vanessa Hus [États-Unis] ; Michael T. Murtha [États-Unis] ; Jennifer K. Lowe [États-Unis] ; A. Jeremy Willsey [États-Unis] ; Daniel Moreno-De-Luca [États-Unis] ; Timothy W. Yu [États-Unis] ; Eric Fombonne [États-Unis] ; Daniel Geschwind [États-Unis] ; Dorothy E. Grice [États-Unis] ; David H. Ledbetter [États-Unis] ; Shrikant M. Mane [États-Unis] ; Donna M. Martin [États-Unis] ; Eric M. Morrow [États-Unis] ; Christopher A. Walsh [États-Unis] ; James S. Sutcliffe [États-Unis] ; Christa Lese Martin [États-Unis] ; Arthur L. Beaudet [États-Unis] ; Catherine Lord [États-Unis] ; Matthew W. State [États-Unis] ; Edwin H. Cook [États-Unis] ; Bernie Devlin [États-Unis]

Source :

Biological psychiatry [ 0006-3223 ] ; 2014.

RBID : PMC:4379124

Descripteurs français

KwdFr :
- Famille, Femelle, Humains, Mâle, Phénotype, Polymorphisme de nucléotide simple, Prédisposition génétique à une maladie, Trouble autistique (génétique), Trouble autistique (physiopathologie), Trouble autistique (psychologie), Trouble du spectre autistique (génétique), Trouble du spectre autistique (physiopathologie), Trouble du spectre autistique (psychologie), Variation génétique, Étude d'association pangénomique ().
MESH :
- génétique : Trouble autistique, Trouble du spectre autistique.
- physiopathologie : Trouble autistique, Trouble du spectre autistique.
- psychologie : Trouble autistique, Trouble du spectre autistique.
- Famille, Femelle, Humains, Mâle, Phénotype, Polymorphisme de nucléotide simple, Prédisposition génétique à une maladie, Variation génétique, Étude d'association pangénomique.

English descriptors

KwdEn :
- Autism Spectrum Disorder (genetics), Autism Spectrum Disorder (physiopathology), Autism Spectrum Disorder (psychology), Autistic Disorder (genetics), Autistic Disorder (physiopathology), Autistic Disorder (psychology), Family, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study (methods), Humans, Male, Phenotype, Polymorphism, Single Nucleotide.
MESH :
- genetics : Autism Spectrum Disorder, Autistic Disorder.
- methods : Genome-Wide Association Study.
- physiopathology : Autism Spectrum Disorder, Autistic Disorder.
- psychology : Autism Spectrum Disorder, Autistic Disorder.
- Family, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Phenotype, Polymorphism, Single Nucleotide.

Abstract

Background

Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of sub-phenotyping of a well-characterized ASD sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD.

Methods

Genome-wide genotypic data of 2576 families from the Simons Simplex Collection (SSC) were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study as well as estimating heritability and evaluating allele scores for each phenotypic subgroup.

Results

Association analyses revealed no genome-wide significant association signal. Sub-phenotyping did not increase power substantially. Moreover, allele scores built from the most associated SNPs, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups.

Conclusions

In genome-wide association analysis of the SSC sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of sub-phenotypes is not a productive path forward for discovering genetic risk variants in ASD.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379124

DOI: 10.1016/j.biopsych.2014.09.017
PubMed: 25534755
PubMed Central: 4379124

Affiliations:

Le document en format XML

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<wicri:regionArea>Centre hospitalier Sainte Anne, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Klei, Lambertus" sort="Klei, Lambertus" uniqKey="Klei L" first="Lambertus" last="Klei">Lambertus Klei</name>
<affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sanders, Stephan J" sort="Sanders, Stephan J" uniqKey="Sanders S" first="Stephan J." last="Sanders">Stephan J. Sanders</name>
<affiliation wicri:level="2"><nlm:aff id="A4">Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Yale University School of Medicine, New Haven, Connecticut</wicri:regionArea>
<placeName><region type="state">Connecticut</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A5">Department of Psychiatry, University of California at San Francisco, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, University of California at San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hus, Vanessa" sort="Hus, Vanessa" uniqKey="Hus V" first="Vanessa" last="Hus">Vanessa Hus</name>
<affiliation wicri:level="2"><nlm:aff id="A6">Department of Psychology, University of Michigan, Ann Arbor, MI, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychology, University of Michigan, Ann Arbor, MI</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Murtha, Michael T" sort="Murtha, Michael T" uniqKey="Murtha M" first="Michael T." last="Murtha">Michael T. Murtha</name>
<affiliation wicri:level="2"><nlm:aff id="A7">Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut</wicri:regionArea>
<placeName><region type="state">Connecticut</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lowe, Jennifer K" sort="Lowe, Jennifer K" uniqKey="Lowe J" first="Jennifer K." last="Lowe">Jennifer K. Lowe</name>
<affiliation wicri:level="2"><nlm:aff id="A8">Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Willsey, A Jeremy" sort="Willsey, A Jeremy" uniqKey="Willsey A" first="A. Jeremy" last="Willsey">A. Jeremy Willsey</name>
<affiliation wicri:level="2"><nlm:aff id="A4">Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Yale University School of Medicine, New Haven, Connecticut</wicri:regionArea>
<placeName><region type="state">Connecticut</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A5">Department of Psychiatry, University of California at San Francisco, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, University of California at San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Moreno De Luca, Daniel" sort="Moreno De Luca, Daniel" uniqKey="Moreno De Luca D" first="Daniel" last="Moreno-De-Luca">Daniel Moreno-De-Luca</name>
<affiliation wicri:level="2"><nlm:aff id="A7">Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut</wicri:regionArea>
<placeName><region type="state">Connecticut</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A9">Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut</wicri:regionArea>
<placeName><region type="state">Connecticut</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Yu, Timothy W" sort="Yu, Timothy W" uniqKey="Yu T" first="Timothy W." last="Yu">Timothy W. Yu</name>
<affiliation wicri:level="2"><nlm:aff id="A10">Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Fombonne, Eric" sort="Fombonne, Eric" uniqKey="Fombonne E" first="Eric" last="Fombonne">Eric Fombonne</name>
<affiliation wicri:level="4"><nlm:aff id="A11">Department of Psychiatry and Institute for Development and disability, Oregon Health & Science University, Portland, Oregon, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry and Institute for Development and disability, Oregon Health & Science University, Portland, Oregon</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Geschwind, Daniel" sort="Geschwind, Daniel" uniqKey="Geschwind D" first="Daniel" last="Geschwind">Daniel Geschwind</name>
<affiliation wicri:level="2"><nlm:aff id="A12">Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Grice, Dorothy E" sort="Grice, Dorothy E" uniqKey="Grice D" first="Dorothy E." last="Grice">Dorothy E. Grice</name>
<affiliation wicri:level="2"><nlm:aff id="A13">Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, Mount Sinai School of Medicine, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ledbetter, David H" sort="Ledbetter, David H" uniqKey="Ledbetter D" first="David H." last="Ledbetter">David H. Ledbetter</name>
<affiliation wicri:level="2"><nlm:aff id="A14">Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mane, Shrikant M" sort="Mane, Shrikant M" uniqKey="Mane S" first="Shrikant M." last="Mane">Shrikant M. Mane</name>
<affiliation wicri:level="2"><nlm:aff id="A15">Yale Center for Genome Analysis, Orange, Connecticut, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Yale Center for Genome Analysis, Orange, Connecticut</wicri:regionArea>
<placeName><region type="state">Connecticut</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Martin, Donna M" sort="Martin, Donna M" uniqKey="Martin D" first="Donna M." last="Martin">Donna M. Martin</name>
<affiliation wicri:level="2"><nlm:aff id="A16">Departments of Pediatrics and Human Genetics, University of Michigan Medical Center, Ann Arbor, Michigan, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Pediatrics and Human Genetics, University of Michigan Medical Center, Ann Arbor, Michigan</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Morrow, Eric M" sort="Morrow, Eric M" uniqKey="Morrow E" first="Eric M." last="Morrow">Eric M. Morrow</name>
<affiliation wicri:level="4"><nlm:aff id="A17">Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island</wicri:regionArea>
<placeName><region type="state">Rhode Island</region>
<settlement type="city">Providence (Rhode Island)</settlement>
</placeName>
<orgName type="university">Université Brown</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="A18">Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island</wicri:regionArea>
<placeName><region type="state">Rhode Island</region>
<settlement type="city">Providence (Rhode Island)</settlement>
</placeName>
<orgName type="university">Université Brown</orgName>
</affiliation>
</author>
<author><name sortKey="Walsh, Christopher A" sort="Walsh, Christopher A" uniqKey="Walsh C" first="Christopher A." last="Walsh">Christopher A. Walsh</name>
<affiliation wicri:level="2"><nlm:aff id="A19">Howard Hughes Medical Institute and Division of Genetics, Children's Hospital Boston, and Neurology and Pediatrics, Harvard Medical School Center for Life Sciences, Boston, Massachusetts, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Howard Hughes Medical Institute and Division of Genetics, Children's Hospital Boston, and Neurology and Pediatrics, Harvard Medical School Center for Life Sciences, Boston, Massachusetts</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sutcliffe, James S" sort="Sutcliffe, James S" uniqKey="Sutcliffe J" first="James S." last="Sutcliffe">James S. Sutcliffe</name>
<affiliation wicri:level="2"><nlm:aff id="A20">Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN</wicri:regionArea>
<placeName><region type="state">Tennessee</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Martin, Christa Lese" sort="Martin, Christa Lese" uniqKey="Martin C" first="Christa Lese" last="Martin">Christa Lese Martin</name>
<affiliation wicri:level="2"><nlm:aff id="A14">Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Beaudet, Arthur L" sort="Beaudet, Arthur L" uniqKey="Beaudet A" first="Arthur L." last="Beaudet">Arthur L. Beaudet</name>
<affiliation wicri:level="2"><nlm:aff id="A21">Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lord, Catherine" sort="Lord, Catherine" uniqKey="Lord C" first="Catherine" last="Lord">Catherine Lord</name>
<affiliation wicri:level="2"><nlm:aff id="A22">Center for Autism and the Developing Brain, Weill Cornell Medical College, White Plains, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Autism and the Developing Brain, Weill Cornell Medical College, White Plains, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="State, Matthew W" sort="State, Matthew W" uniqKey="State M" first="Matthew W." last="State">Matthew W. State</name>
<affiliation wicri:level="2"><nlm:aff id="A4">Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Genetics, Yale University School of Medicine, New Haven, Connecticut</wicri:regionArea>
<placeName><region type="state">Connecticut</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A5">Department of Psychiatry, University of California at San Francisco, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, University of California at San Francisco, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cook, Edwin H" sort="Cook, Edwin H" uniqKey="Cook E" first="Edwin H." last="Cook">Edwin H. Cook</name>
<affiliation wicri:level="4"><nlm:aff id="A23">Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois</wicri:regionArea>
<placeName><region type="state">Illinois</region>
<settlement type="city">Chicago</settlement>
</placeName>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
</affiliation>
</author>
<author><name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name>
<affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Biological psychiatry</title>
<idno type="ISSN">0006-3223</idno>
<idno type="eISSN">1873-2402</idno>
<imprint><date when="2014">2014</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Autism Spectrum Disorder (genetics)</term>
<term>Autism Spectrum Disorder (physiopathology)</term>
<term>Autism Spectrum Disorder (psychology)</term>
<term>Autistic Disorder (genetics)</term>
<term>Autistic Disorder (physiopathology)</term>
<term>Autistic Disorder (psychology)</term>
<term>Family</term>
<term>Female</term>
<term>Genetic Predisposition to Disease</term>
<term>Genetic Variation</term>
<term>Genome-Wide Association Study (methods)</term>
<term>Humans</term>
<term>Male</term>
<term>Phenotype</term>
<term>Polymorphism, Single Nucleotide</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Famille</term>
<term>Femelle</term>
<term>Humains</term>
<term>Mâle</term>
<term>Phénotype</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Prédisposition génétique à une maladie</term>
<term>Trouble autistique (génétique)</term>
<term>Trouble autistique (physiopathologie)</term>
<term>Trouble autistique (psychologie)</term>
<term>Trouble du spectre autistique (génétique)</term>
<term>Trouble du spectre autistique (physiopathologie)</term>
<term>Trouble du spectre autistique (psychologie)</term>
<term>Variation génétique</term>
<term>Étude d'association pangénomique ()</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Autism Spectrum Disorder</term>
<term>Autistic Disorder</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Trouble autistique</term>
<term>Trouble du spectre autistique</term>
</keywords>
<keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Genome-Wide Association Study</term>
</keywords>
<keywords scheme="MESH" qualifier="physiopathologie" xml:lang="fr"><term>Trouble autistique</term>
<term>Trouble du spectre autistique</term>
</keywords>
<keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Autism Spectrum Disorder</term>
<term>Autistic Disorder</term>
</keywords>
<keywords scheme="MESH" qualifier="psychologie" xml:lang="fr"><term>Trouble autistique</term>
<term>Trouble du spectre autistique</term>
</keywords>
<keywords scheme="MESH" qualifier="psychology" xml:lang="en"><term>Autism Spectrum Disorder</term>
<term>Autistic Disorder</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Family</term>
<term>Female</term>
<term>Genetic Predisposition to Disease</term>
<term>Genetic Variation</term>
<term>Humans</term>
<term>Male</term>
<term>Phenotype</term>
<term>Polymorphism, Single Nucleotide</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Famille</term>
<term>Femelle</term>
<term>Humains</term>
<term>Mâle</term>
<term>Phénotype</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Prédisposition génétique à une maladie</term>
<term>Variation génétique</term>
<term>Étude d'association pangénomique</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background</title>
<p id="P1">Phenotypic heterogeneity in autism has long been conjectured to be a
major hindrance to the discovery of genetic risk factors, leading to
numerous attempts to stratify children based on phenotype to increase power
of discovery studies. This approach, however, is based on the hypothesis
that phenotypic heterogeneity closely maps to genetic variation, which has
not been tested. Our study examines the impact of sub-phenotyping of a
well-characterized ASD sample on genetic homogeneity and the ability to
discover common genetic variants conferring liability to ASD.</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P2">Genome-wide genotypic data of 2576 families from the Simons Simplex
Collection (SSC) were analyzed in the overall sample and phenotypic
subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We
conducted a family-based association study as well as estimating
heritability and evaluating allele scores for each phenotypic subgroup.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">Association analyses revealed no genome-wide significant association
signal. Sub-phenotyping did not increase power substantially. Moreover,
allele scores built from the most associated SNPs, based on the odds ratio
in the full sample, predicted case status in subsets of the sample equally
well and heritability estimates were very similar for all subgroups.</p>
</sec>
<sec id="S4"><title>Conclusions</title>
<p id="P4">In genome-wide association analysis of the SSC sample, reducing
phenotypic heterogeneity had at most a modest impact on genetic homogeneity.
Our results are based on a relatively small sample, one with greater
homogeneity than the entire population; if they apply more broadly, they
imply that analysis of sub-phenotypes is not a productive path forward for
discovering genetic risk variants in ASD.</p>
</sec>
</div>
</front>
</TEI>
<affiliations><list><country><li>France</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Connecticut</li>
<li>Illinois</li>
<li>Massachusetts</li>
<li>Michigan</li>
<li>Oregon</li>
<li>Pennsylvanie</li>
<li>Rhode Island</li>
<li>Tennessee</li>
<li>Texas</li>
<li>État de New York</li>
<li>Île-de-France</li>
</region>
<settlement><li>Chicago</li>
<li>Créteil</li>
<li>Paris</li>
<li>Portland</li>
<li>Providence (Rhode Island)</li>
</settlement>
<orgName><li>Université Brown</li>
<li>Université de l'Illinois à Chicago</li>
<li>Université des sciences et de la médecine de l'Oregon</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Chaste, Pauline" sort="Chaste, Pauline" uniqKey="Chaste P" first="Pauline" last="Chaste">Pauline Chaste</name>
</region>
<name sortKey="Beaudet, Arthur L" sort="Beaudet, Arthur L" uniqKey="Beaudet A" first="Arthur L." last="Beaudet">Arthur L. Beaudet</name>
<name sortKey="Cook, Edwin H" sort="Cook, Edwin H" uniqKey="Cook E" first="Edwin H." last="Cook">Edwin H. Cook</name>
<name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name>
<name sortKey="Fombonne, Eric" sort="Fombonne, Eric" uniqKey="Fombonne E" first="Eric" last="Fombonne">Eric Fombonne</name>
<name sortKey="Geschwind, Daniel" sort="Geschwind, Daniel" uniqKey="Geschwind D" first="Daniel" last="Geschwind">Daniel Geschwind</name>
<name sortKey="Grice, Dorothy E" sort="Grice, Dorothy E" uniqKey="Grice D" first="Dorothy E." last="Grice">Dorothy E. Grice</name>
<name sortKey="Hus, Vanessa" sort="Hus, Vanessa" uniqKey="Hus V" first="Vanessa" last="Hus">Vanessa Hus</name>
<name sortKey="Klei, Lambertus" sort="Klei, Lambertus" uniqKey="Klei L" first="Lambertus" last="Klei">Lambertus Klei</name>
<name sortKey="Ledbetter, David H" sort="Ledbetter, David H" uniqKey="Ledbetter D" first="David H." last="Ledbetter">David H. Ledbetter</name>
<name sortKey="Lord, Catherine" sort="Lord, Catherine" uniqKey="Lord C" first="Catherine" last="Lord">Catherine Lord</name>
<name sortKey="Lowe, Jennifer K" sort="Lowe, Jennifer K" uniqKey="Lowe J" first="Jennifer K." last="Lowe">Jennifer K. Lowe</name>
<name sortKey="Mane, Shrikant M" sort="Mane, Shrikant M" uniqKey="Mane S" first="Shrikant M." last="Mane">Shrikant M. Mane</name>
<name sortKey="Martin, Christa Lese" sort="Martin, Christa Lese" uniqKey="Martin C" first="Christa Lese" last="Martin">Christa Lese Martin</name>
<name sortKey="Martin, Donna M" sort="Martin, Donna M" uniqKey="Martin D" first="Donna M." last="Martin">Donna M. Martin</name>
<name sortKey="Moreno De Luca, Daniel" sort="Moreno De Luca, Daniel" uniqKey="Moreno De Luca D" first="Daniel" last="Moreno-De-Luca">Daniel Moreno-De-Luca</name>
<name sortKey="Moreno De Luca, Daniel" sort="Moreno De Luca, Daniel" uniqKey="Moreno De Luca D" first="Daniel" last="Moreno-De-Luca">Daniel Moreno-De-Luca</name>
<name sortKey="Morrow, Eric M" sort="Morrow, Eric M" uniqKey="Morrow E" first="Eric M." last="Morrow">Eric M. Morrow</name>
<name sortKey="Morrow, Eric M" sort="Morrow, Eric M" uniqKey="Morrow E" first="Eric M." last="Morrow">Eric M. Morrow</name>
<name sortKey="Murtha, Michael T" sort="Murtha, Michael T" uniqKey="Murtha M" first="Michael T." last="Murtha">Michael T. Murtha</name>
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   |wiki=    Wicri/Amérique
   |area=    PittsburghV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     PMC:4379124
   |texte=   A genomewide association study of autism using the Simons Simplex
Collection: Does reducing phenotypic heterogeneity in autism increase genetic
homogeneity?
}}

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A genomewide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

A genomewide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

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