Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk
has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation,
the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million
single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In
one of four primary association analyses, the association signal for marker rs4141463, located within
MACROD2, crossed the genome-wide association significance threshold of P < 5 3 1028. When a smaller
replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent
with the winner?s curse, its effect size in the replication sample was much smaller; and, for the combined
samples, the association signal barely fell below the P < 5 3 1028 threshold. Exploratory analyses of phenotypic
subtypes yielded no significant associations after correction for multiple testing. They did, however,
yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
This research was primarily supported by Autism Speaks
(USA), the Health Research Board (HRB, Ireland), The
Medical Research Council (MRC; UK); Genome Canada/
Ontario Genomics Institute and the Hilibrand Foundation
(USA). Additional support for individual groups was provided
by the US National Institutes of Health [HD055751,
HD055782, HD055784, HD35465, MH52708, MH55284,MH057881, MH061009, MH06359, MH066673, MH077930,
MH080647, MH081754, MH66766, NS026630, NS042165,
NS049261]; the Canadian Institutes for Health Research
(CIHR), Assistance Publique - Ho?pitaux de Paris (France),
Autistica, Canada Foundation for Innovation/Ontario Innovation
Trust, Deutsche Forschungsgemeinschaft (grant: Po
255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundac
?a?o Calouste Gulbenkian (Portugal), Fondation de France,
Fondation FondaMental (France), Fondation Orange
(France), Fondation pour la Recherche Me'dicale (France),
Fundac?a?o para a Cie?ncia e Tecnologia (Portugal),
GlaxoSmithKline-CIHR Pathfinder Chair (Canada), the Hospital
for Sick Children Foundation and University of
Toronto (Canada), INSERM (France), Institut Pasteur
(France), the Italian Ministry of Health [convention 181 of
19.10.2001], the John P. Hussman Foundation (USA),
McLaughlin Centre (Canada), Netherlands Organization for
Scientific Research [Rubicon 825.06.031], Ontario Ministry
of Research and Innovation (Canada), Royal Netherlands
Academy of Arts and Sciences [TMF/DA/5801], the Seaver
Foundation (USA), the Swedish Science Council, The
Centre for Applied Genomics (Canada), the Utah Autism
Foundation (USA) and the Wellcome Trust core award
[075491/Z/04 UK]. We wish to acknowledge SAGE as part
of this study. Funding support for the Study of Addiction:
Genetics and Environment (SAGE) was provided through
the NIH Genes, Environment and Health Initiative [GEI]
(U01 HG004422). SAGE is one of the genome-wide association
studies funded as part of the Gene Environment Association
Studies (GENEVA) under GEI. Assistance with
phenotype harmonization and genotype cleaning, as well as
with general study coordination, was provided by the
GENEVA Coordinating Center (U01 HG004446). Assistance
with data cleaning was provided by the National Center for
Biotechnology Information. Support for collection of datasets
and samples was provided by the Collaborative Study on the
Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative
Genetic Study of Nicotine Dependence (COGEND;
P01 CA089392), and the Family Study of Cocaine Dependence
(FSCD; R01 DA013423). Funding support for genotyping,
which was performed at the Johns Hopkins University
Center for Inherited Disease Research, was provided by the
NIH GEI (U01 HG004438), the National Institute on
Alcohol Abuse and Alcoholism, the National Institute on
Drug Abuse, and the NIH contract `High throughput genotyping
for studying the genetic contributions to human disease?
(HHSN268200782096C). Funding to pay the Open Access
Charge was provided by Autism Speaks
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