Three studies identify common genetic factors in autism

In three studies, including the most comprehensive study of autism genetics to date, investigators have identified common and rare genetic factors that affect the risk of autism spectrum disorders. The results point to the importance of genes that are involved in forming and maintaining the connections between brain cells.

“These findings establish that genetic factors play a strong role in autism spectrum disorder,” says Acting US National Institutes of Health Director Raynard Kington, MD, PhD. NIH part funded the research. “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 behaviours. These disorders range from severe (autism) to mild (Asperger’s syndrome). Researchers theorise that the social parts of the brain are underdeveloped in ASD.

In the United States about 1 in 150 children are affected and three quarters of those affected are boys.

“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, MD, director of NIH's National Institute of Mental Health (NIMH).

All three studies were genome-wide association studies.

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 US.

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 realise that the genetics of ASD is complex.

In the large study, researchers 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.

A second study 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 Margaret Pericak-Vance, PhD, a professor at the University of Miami Miller School of Medicine and director of the Miami Institute for Human Genomics.

Finally, in a third study, reported in Nature, researchers 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-tocell adhesion could influence susceptibility to ASD on a large scale. Researchers 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.

● References: Wang K et al. “Common Genetic Variants on 5p14.1 Associate with Autism Spectrum Disorder.” Nature, published online 3 May 2009.

● Glessner JT et al. “Autism Genome-Wide Copy Number Variation Reveals Ubiquitin and Neuronal Genes.” Nature, published online 3 May 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 3 May 2009.

Free genome toolkit to standardise measures

The US National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, has released the first version of a free online toolkit aimed at standardising measurements of research subjects’ physical characteristics and environmental exposures. The tools will give researchers more power to compare data from multiple studies, accelerating efforts to understand the complex genetic and environmental factors that cause cancer, heart disease, depression and other common diseases.

The toolkit, which is available at <https://www.phenxtoolkit.org/>, is the first product of the Consensus Measures for Phenotypes and eXposures (PhenX) initiative.



New autoinflammatory syndrome discovered

Researchers from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS have discovered a new autoinflammatory syndrome, a rare genetic condition that affects children around the time of birth. The findings appear in the 4 June 2009 issue of the New England Journal of Medicine.

The scientists have termed the new autoinflammatory syndrome DIRA (deficiency of the interleukin-1 receptor antagonist). Children with the disorder display a constellation of serious and potentially fatal symptoms that include swelling of bone tissue; bone pain and deformity; inflammation of the periosteum (a layer of connective tissue around bone); and a rash that can span from small individual pustules to extensive pustulosis that covers most of the patient’s body. Most of the children begin to have symptoms from birth to 2 weeks of age.

“The beauty of this discovery is that the symptoms of this devastating disease can now be treated,” said NIAMS director and immunodermatologist, Stephen I. Katz, MD, PhD “The abnormal inflammatory pathways seen in this disease may also help us understand other common diseases that share clinical features, such as psoriasis, as well as other autoinflammatory disorders.”

“We knew when we saw these children that we were dealing with a previously unrecognised autoinflammatory syndrome. The clinical characteristics were distinct from other diseases we had seen before,” said NIAMS researcher and lead author Raphaela Goldbach-Mansky, MD, MHS. When her colleague, Dr Ivona Aksentijevich, tested the first patient for genetic abnormalities, their suspicions were confirmed, and ultimately abnormalities were found in a number of other cases.

All the children had inherited mutations in IL1RN, a gene that encodes a protein known as interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra binds to the same cell receptors as the inflammatory protein interleukin-1, and acts as a brake on this inflammatory protein. Without IL-1Ra, the children’s bodies cannot control systemic inflammation that can be caused by interleukin- 1.

The scientists identified nine patients from six families with DIRA in the Canadian province of Newfoundland, the Netherlands, Lebanon, and Puerto Rico. Those who were alive at the time of diagnosis six in all were treated with anakinra, a drug that is normally used for rheumatoid arthritis and is a synthetic form of human IL-1Ra. Although the patients were resistant to other medications such as steroids, most responded successfully and immediately to anakinra. “Our first patient had been unresponsive to several treatments, and his health care team had almost given up. But with anakinra, he was out of the hospital in 10 days and his symptoms resolved,” Dr Goldbach-Mansky said.

● Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1 receptor antagonist. “N Engl J Med” 2009;360:2416-27.



Narcolepsy confirmed an autoimmune disorder

Ten years ago, Stanford University School of Medicine scientist Emmanuel Mignot, MD, PhD, and his colleagues made headlines when they identified the culprit behind the sleep disorder narcolepsy. Now Mignot and his collaborators have shown for the first time that a specific immune cell is involved in the disorder – confirming experts' long-held suspicion that narcolepsy is an autoimmune disease.

The work, published online 3 May in Nature Genetics, could lead to better treatments for the sleep disorder and help immunologists understand other, more common autoimmune diseases, such as multiple sclerosis and juvenile diabetes.

“We’re now getting the main pieces of what’s happening in narcolepsy,” said Mignot, a Howard Hughes Medical Institute investigator who has been studying the disease for more than two decades. “What’s most satisfying to me is that we’re bringing this story to a close and that we can use narcolepsy as a model for other diseases.”

Narcolepsy affects about one in 2,000 people and is characterised by daytime drowsiness, irregular sleep at night and cataplexy – a sudden loss of muscle tone and strength. Mignot and others showed in the late 1990s that the disease stems from a lack of hypocretin, a hormone that promotes wakefulness; they later showed that narcoleptics are missing brain cells that produce this hormone.

Mignot and others believe that the body’s immune system plays a role in killing hypocretin-making cells, primarily because of scientific literature showing a link between narcolepsy and a variant for the human leukocyte antigen, or HLA, gene. The immune system uses HLAs to differentiate between “self” cells and foreign cells (and attacks those presented as foreign), and most autoimmune diseases are associated with variants of HLA. In recent studies, more than 90% of narcolepsy patients were shown to carry one such variant.

During this study, the researchers ran whole-genome scans of 1,800 people carrying the same HLA gene variant. Of the group, 800 had narcolepsy, and the goal was to find what differentiated these people from control subjects. The team found that a specific variation of a gene belonging to T cells – specialised immune cells that play a role in all immune responses – was present in narcolepsy.

Because T cells are involved, Mignot believes the mechanism behind narcolepsy stems from the immune system. “Our discovery clearly shows narcolepsy is an autoimmune disease,” he said.

“This is a very important finding,” said Merrill Mitler, PhD, a sleep disorders expert and program director at the National Institute of Neurological Disorders and Stroke, who was not involved in the study. “It puts in place another piece of the puzzle and shows a way to link [this gene variant] to hypocretincontaining neurons via an autoimmune attack.” 

                                  
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