@article{2baed1c64d6d476d962ed44efba0e8dd,
title = "Common genetic variants, acting additively, are a major source of risk for autism",
abstract = "Background: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods. By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.",
keywords = "Multiplex, Narrow-sense heritability, Quantitative genetics, Simplex",
author = "Lambertus Klei and Sanders, {Stephan J.} and Murtha, {Michael T.} and Vanessa Hus and Lowe, {Jennifer K.} and Willsey, {A. Jeremy} and Daniel Moreno-De-Luca and Yu, {Timothy W.} and Eric Fombonne and Daniel Geschwind and Grice, {Dorothy E.} and Ledbetter, {David H.} and Catherine Lord and Mane, {Shrikant M.} and Martin, {Christa Lese} and Martin, {Donna M.} and Morrow, {Eric M.} and Walsh, {Christopher A.} and Melhem, {Nadine M.} and Pauline Chaste and Sutcliffe, {James S.} and State, {Matthew W.} and Cook, {Edwin H.} and Kathryn Roeder and Bernie Devlin",
note = "Funding Information: Research supported by grants from the Simons Foundation and MH057881. SSC: We are grateful to all of the families participating in the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC). This work was supported by a grant from the Simons Foundation. We wish to thank the SSC principal investigators A.L. Beaudet, R. Bernier, J. Constantino, E.H. Cook, Jr., E. Fombonne, D. Geschwind, D.E. Grice, A. Klin, D.H. Ledbetter, C. Lord, C.L. Martin, D.M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M.W. State, W. Stone, J.S. Sutcliffe, C.A. Walsh, and E. Wijsman; the coordinators and staff at the SSC sites; the SFARI staff, in particular M. Benedetti; Prometheus Research; the Yale Center of Genomic Analysis staff, in particular M. Mahajan, S. Umlauf, I. Tikhonova and A. Lopez; T. Brooks-Boone, N. Wright-Davis and M. Wojciechowski for their help in administering the project at Yale; I. Hart for support; and G.D. Fischbach, A. Packer, J. Spiro, M. Benedetti and M. Carlson for their helpful suggestions throughout. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org. AGP: We used data from the Autism Genome Project (AGP) Consortium - Whole Genome Association and Copy Number Variation Study of over 1,500 Parent-Offspring Trios - Stage I (dbGaP Study Accession: phs000267.v1.p1). Funding for AGP was provided from National Institutes of Health (HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261); The Canadian Institutes for Health Research (CIHR); Assistance Publique - H{\^o}pitaux de Paris, France; Autism Speaks UK; Canada Foundation for Innovation/Ontario Innovation Trust; Grant: Po 255/17-4. Deutsche Forschungsgemeinschaft, Germany; EC Sixth FP AUTISM MOLGEN; Funda{\c c}{\~a}o Calouste Gulbenkian, Portugal; Fondation de France; Fondation FondaMental, France; Fondation Orange, France; Fondation pour la Recherche M{\'e}dicale, France; Funda{\c c}{\~a}o para a Ci{\^e}ncia e Tecnologia, Portugal; The Hospital for Sick Children Foundation and University of Toronto, Canada; INSERM, France; Institut Pasteur, France; Convention 181 of 19.10.2001. Italian Ministry of Health; John P Hussman Foundation, USA; McLaughlin Centre, Canada; Rubicon 825.06.031. Netherlands Organization for Scientific Research; TMF/DA/5801. Royal Netherlands Academy of Arts and Sciences; Ontario Ministry of Research and Innovation, Canada; Seaver Foundation, USA; Swedish Science Council; The Centre for Applied Genomics, Canada; Utah Autism Foundation, USA; Core award 075491/Z/04. Wellcome Trust, UK. Genotype and phenotype data were obtained from dbGap, as provided by AGP Study Investigators. HealthABC: These controls were obtained from Database for Genotypes and Phenotypes (dbGap) at http://www.ncbi.nlm.nih.gov/gap. Funding support for the “CIDR Visceral Adiposity Study” (Study accession number: phs000169.v1.p1) was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. The CIDR Visceral Adiposity Study includes a genome-wide association study funded as part of the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Heath ABC Study Investigators. NGRC: We also used the NINDS dbGaP database from the CIDR: NGRC Parkinson{\textquoteright}s Disease Study (dbGap accession number phs000196.v2.p1). The genetic arm of the study has been funded by NIH since 1998 (R01 NS36960, Haydeh Payami, PI). In 2004, the consortium was formalized as a Michael J Fox Foundation Funded Global Genetic Consortium, and an epidemiologic arm was implemented. Genotype and phenotype data were obtained from dbGap, as provided by NGRC Parkinson{\textquoteright}s Disease Study Investigators. For both the HealthABC and NGRC studies, genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C and HHSN268201100011I.",
year = "2012",
doi = "10.1186/2040-2392-3-9",
language = "English (US)",
volume = "3",
journal = "Molecular Autism",
issn = "2040-2392",
publisher = "BioMed Central",
number = "1",
}