"These findings establish that genetic factors play a strong role in autism spectrum disorder," says Acting NIH Director Raynard Kington, M.D., Ph.D. "Detailed analysis of the genes and how they affect brain development is likely to yield better strategies for diagnosing and treating children with autism."
Autism spectrum disorders (ASD) comprise a group of disorders with core symptoms that include social interaction problems, poor verbal and nonverbal communication and repetitive behaviors. These disorders range from severe (autism) to mild (Asperger's syndrome), and in total affect some 1 in 150 American children, about three-quarters of whom are boys. Researchers theorize that the social parts of the brain are underdeveloped in ASD.
"Previous studies have suggested that autism is a developmental disorder resulting from abnormal connections in the brain. These three studies suggest some of the genetic factors which might lead to abnormal connectivity," says Thomas Insel, M.D., director of NIH's National Institute of Mental Health (NIMH).
The studies were funded in part by the NIMH, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute on Deafness and Other Communication Disorders (NIDCD) and the National Center for Research Resources (NCRR), all components of NIH.
All three studies were genome-wide association studies, which are undertaken to find clues about the causes of complex disorders. Typically, these studies involve scanning the genome – the entire set of DNA – for small differences between people who have a disorder and people who do not.
The largest study, reported in Nature, involved more than 10,000 subjects, including individuals with ASD, their family members and other volunteers from across the U.S. The study was led by Hakon Hakonarson, M.D., Ph.D., a professor at the University of Pennsylvania School of Medicine and director of the Center for Applied Genomics at The Children's Hospital of Philadelphia. Among other principal investigators on the study were Gerard D. Schellenberg, Ph.D., also a professor at the University of Pennsylvania School of Medicine; and Daniel Geschwind, M.D., Ph.D., a professor at the University of California, Los Angeles and director of UCLA's Center for Autism Research and Treatment; and Margaret Pericak-Vance, Ph.D., a professor at the University of Miami Miller School of Medicine and director of the Miami Institute for Human Genomics, who also led an independent study that generated similar results.
Major funding for Dr. Hakonarson's work came from The Children's Hospital of Philadelphia. Dr. Pericak-Vance's work was supported in part by the Hussman Foundation. The DNA samples came from a repository called the Autism Genetic Resource Exchange (AGRE), and from subjects recruited at clinics in Philadelphia, Miami, Los Angeles and other sites. AGRE is run by Autism Speaks, with partial support from NIMH.
Previous studies of twins with ASD, other children with ASD and their relatives provided evidence of a strong genetic contribution. Yet until now, only a few genetic risk factors had been identified, and most of those turned out to be rare, with unclear significance for ASD in the general population. Researchers came to realize that the genetics of ASD is complex.
"There are going to be many genes involved in causing autism," says Dr. Hakonarson. "In most cases, it's likely that each gene contributes a small amount of risk, and interacts with other genes and environmental factors to trigger the onset of disease."
In their large study, Dr. Hakonarson and his colleagues found several genetic variants that were commonly associated with ASD, all of them pointing to a spot between two genes on chromosome 5, called CDH9 and CDH10. Both genes encode cadherins – cell surface proteins that enable cells to adhere to each other. The researchers also found that a group of about 30 genes that encode cell adhesion proteins (including cadherins and neurexins) were more strongly associated with ASD than all other genes in their data set. In the developing brain, cell adhesion proteins enable neurons to migrate to the correct places and to connect with other neurons.
In a second study, Dr. Pericak-Vance completed an independent search for small genetic variants associated with ASD, in collaboration with Jonathan Haines, Ph.D., of Vanderbilt University Medical Center in Nashville. Published in the Annals of Human Genetics, the study provides a striking confirmation that ASD is associated with variation near CDH9 and CDH10.
"We are starting to see genetic pathways in ASD that make sense," says Dr. Pericak-Vance.
Finally, in a third study, reported in Nature, Drs. Hakonarson and Schellenberg led a search for genes that were duplicated or deleted in individuals with ASD. In the rare cases where those variations occurred, many tended to affect genes involved in cell adhesion. Others tended to affect genes involved in the ubiquitin-proteasome system, a cellular waste disposal system that probably affects the turnover of adhesion proteins at the cell surface.
Previous, smaller genetic studies reported a connection between male-only autism and CNTNAP2, a type of neurexin. Together, the three new studies suggest that genetic differences in cell-to-cell adhesion could influence susceptibility to ASD on a large scale. Dr. Hakonarson and his colleagues are planning an even more extensive genome-wide association study to gain a more complete picture of the genes and gene interactions involved in ASD.
The mission of NIMH (www.nimh.nih.gov) is to reduce the burden of mental and behavioral disorders through research on mind, brain and behavior. NINDS (www.ninds.nih.gov) is the nation's primary supporter of biomedical research on the brain and nervous system. NICHD (www.nichd.nih.gov) sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NIDCD (www.nidcd.nih.gov) supports and conducts research and research training on the normal and disordered processes of hearing, balance, smell, taste, voice, speech and language and provides health information, based upon scientific discovery, to the public. NCRR (www.ncrr.nih.gov) provides laboratory scientists and clinical researchers with the resources and training they need to understand, detect, treat and prevent a wide range of diseases. NCRR supports all aspects of translational and clinical research, connecting researchers, patients and communities across the nation.
The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
For more information about autism, visit http://www.ninds.nih.gov/disorders/autism/detail_autism.htm or http://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-pervasive-developmental-disorders/index.shtml.References:
Glessner JT et al. "Autism Genome-Wide Copy Number Variation Reveals Ubiquitin and Neuronal Genes." Nature, published online May 3, 2009.
Ma D et al. "A Genome-Wide Association Study of Autism Reveals a Common Novel Risk Locus at 5p14.1." Annals of Human Genetics, published online May 3, 2009.
Further reports about: > 5p14 > AGRE > ASD > Autism > CDH10 > CDH9 > DNA > Genetic clues > Genomics > Health > Human Genetics > Human vaccine > Medical Wellness > NCRR > NICHD > NIDCD > NIH > NIMH > NINDS > Nature Immunology > Neurological Disorder > Pericak-Vance > Ressource > cell surface > genetic factors > genetic variant > medical research > risk factor
New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)
Reusable carbon nanotubes could be the water filter of the future, says RIT study
30.03.2017 | Rochester Institute of Technology
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
26.04.2017 | Materials Sciences
26.04.2017 | Agricultural and Forestry Science
26.04.2017 | Physics and Astronomy