Common genetic variants, acting additively, are a major source of risk for autism
1 Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
2 Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut, USA
3 Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA
4 Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
5 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
6 Department of Psychology, University of Michigan, Ann Arbor, MI, USA
7 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
8 Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
9 Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA
10 Department of Psychiatry, McGill University, Montreal Children's Hospital, Montreal, QC, H3Z 1P2, Canada
11 Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA
12 Geisinger Health System, Danville, Pennsylvania, USA
13 Center for Autism and the Developing Brain, Weill Cornell Medical College, White Plains, New York, USA
14 Yale Center for Genome Analysis, Orange, Connecticut, USA
15 Departments of Pediatrics and Human Genetics, The University of Michigan Medical Center, Ann Arbor, Michigan, USA
16 Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
17 Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, USA
18 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
19 Department of Molecular Physiology & Biophysics, Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee, USA
20 Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
21 Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
Molecular Autism 2012, 3:9 doi:10.1186/2040-2392-3-9Published: 15 October 2012
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.
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.
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.
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.