title: A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?
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 subphenotyping of a well-characterized autism spectrum disorder (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 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. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, 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 Simons Simplex Collection 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 subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; FondaMental Foundation, Créteil; Centre Hospitalier Sainte Anne, Paris, France. Electronic address: p.chaste@ch-sainte-anne.fr.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chaste
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Klei
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, University of California at San Francisco, San Francisco, California.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Department of Psychology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hus
authors.affiliation: Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Murtha
authors.affiliation: 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.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lowe
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, University of California at San Francisco, San Francisco, California.
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Willsey
authors.affiliation: Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moreno-De-Luca
authors.affiliation: Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Yu
authors.affiliation: Department of Psychiatry and Institute for Development and Disability, Oregon Health & Science University, Portland, Oregon.
authors.forename: Eric
authors.initials: E
authors.lastname: Fombonne
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Geschwind
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York.
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Grice
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania.
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
authors.affiliation: Yale Center for Genome Analysis, Orange, Connecticut.
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.affiliation: Departments of Pediatrics and Human Genetics, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, and Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Morrow
authors.affiliation: 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.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.affiliation: Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee.
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania.
authors.forename: Christa
authors.initials: C
authors.lastname: Lese Martin
authors.affiliation: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.affiliation: Center for Autism and the Developing Brain, Weill Cornell Medical College, White Plains, New York.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lord
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, University of California at San Francisco, San Francisco, California.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.affiliation: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
keywords: Autism; GWAS; Genetics; Heterogeneity; Phenotype; Power