Autism Genes Discovered; Help Shape Connections Among Brain Cells
-Findings Suggest Biological Reasons for Altered Early Neural Development-
PHILADELPHIA, April 28 /PRNewswire-USNewswire/ — A research team has connected more of the intricate pieces of the autism puzzle, with two studies that identify genes with important contributions to the disorder. One study pinpoints a gene region that may account for as many as 15 percent of autism cases, while another study identifies missing or duplicated stretches of DNA along two crucial gene pathways. Significantly, both studies detected genes implicated in the development of brain circuitry in early childhood.
“Because other autism researchers have made intriguing suggestions that autism arises from abnormal connections among brain cells during early development, it is very compelling to find evidence that mutations in genes involved in brain interconnections increase a child’s risk of autism,” said study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia. He is on the faculty of the University of Pennsylvania School of Medicine, as is his main collaborator, neuroscientist Gerard D. Schellenberg, Ph.D.
“This comprehensive research opens the door to more focused investigations into the causes of autism disorders,” said Philip R. Johnson, M.D., chief scientific officer at The Children’s Hospital of Philadelphia. “It moves the field of autism research significantly ahead, similar to the way oncology research progressed a few decades ago with the discovery of specific genes that give rise to cancers. Our extensive pediatric genomics program has pinpointed particular genes and biological pathways, and this discovery provides a starting point for translating biological knowledge into future autism treatments.” The hospital’s Center for Applied Genomics, launched in 2006, is the world’s largest facility dedicated to the genetic analysis of childhood diseases.
Collaborating with researchers from more than a dozen institutions, including members of the Autism Genome Project (AGP), Hakonarson led both studies, which appear today in the online publication Nature.
Autism is the best known of the autism spectrum disorders (ASDs), a group of childhood neurodevelopmental disorders that cause impairments in verbal communication, social interaction and behavior. Currently estimated to affect as many as one in 150 U.S. children, ASDs are known from family studies to be strongly influenced by genetics. Previous studies have implicated several chromosome regions harboring rare variants in raising the risk of ASDs, but until now, research has not been consistent in identifying and replicating common genetic variants.
One of the two studies by Hakonarson’s team is the first to identify common genetic variants associated with autism. By using highly automated genotyping tools that scan the entire genome of thousands of individuals, the researchers found that children with ASDs were more likely than healthy controls to have gene variants on a particular region of chromosome 5. That region is located between two genes, cadherin 9 (CDH9) and cadherin 10 (CDH10), which carry codes to produce neuronal cell-adhesion molecules.
Neuronal cell-adhesion molecules are important because they affect how nerve cells communicate with each other, thought to be an underlying problem in ASDs. “These molecules are expressed on the cell surfaces of neurons, and they are involved with shaping both the physical structure of the developing brain and the functional connections among different brain regions,” Hakonarson said. “Although a particular gene variant may contribute a small risk for an ASD in a particular individual, we estimate that the variants we discovered may contribute to as many as 15 percent of ASD cases in a population — typically referred to as the population — attributed risk of the variant.”
Hakonarson’s team first performed genome-wide association studies on DNA from over 3,100 subjects from 780 families of children affected with ASDs, then performed further studies in a cohort of 1,200 affected subjects and 6,500 unaffected controls. They then replicated their results in two additional independent cohorts. In total, they analyzed DNA from 12,834 subjects.
“Autism Speaks is pleased to have facilitated this critical research, having provided both funding and access to thousands of DNA samples through Autism Speaks’ Autism Genome Research Exchange (AGRE),” said Geraldine Dawson, Ph.D., Chief Science Officer for Autism Speaks. “Access to biomaterials and clinical data from thousands of families through the AGRE substantially expedites the research our community seeks and needs. Our goal is to accelerate genetic research that can ultimately lead to improved detection and medical treatments.” Dawson also is a co-author of both studies in her role as a faculty member of the University of Washington.
Hakonarson’s second study in Nature, also using genome-wide association tools, identified copy number variations — deletions or duplications of DNA — that increase a child’s risk of having an ASD. Interestingly, these variants were enriched in genes that belong to two biological pathways, one including the same neuronal cell-adhesion molecule gene family that harbored the common variant reported in Hakonarson’s first study. The other gene cluster impacted by copy number variations belongs to the ubiquitin degradation pathway. Ubiquitins are a class of enzymes that eliminate connections among nerve cells, and are involved with processing and degrading neuronal cell-adhesion molecules –thus linking the two gene pathways together.
“The copy number variations we discovered are active on two gene networks that play critical roles in the development of neuronal connectivity within the central nervous system,” said Hakonarson. “Finding genes that are biologically relevant to these neuronal systems increases our understanding of how autism originates.”
The gene discoveries, added Hakonarson, converge with evidence from functional magnetic resonance imaging that children with ASDs may have reduced connectivity among neural cells, and with anatomy studies that have found abnormal development of the brain’s frontal lobes in patients with autism.
“Many of the genes we identified concentrate their effects in brain regions that develop abnormally in autistic children,” said Hakonarson. “Our current findings, when coupled with anatomical and imaging studies, may suggest that ASDs are a problem of neuronal disconnection.”
His group’s ongoing research, continued Hakonarson, focuses on investigating the exact mechanisms by which these genetic variations cause autistic disorders. “For instance, we expect to manipulate similar cell-adhesion genes in mice to see if the animals show altered social behaviors that may correspond to human behaviors.” In addition, other genes remain to be discovered.
“Although we cannot immediately apply this research to clinical treatments, these findings increase our understanding of how autism spectrum disorders arise, and may in time foster the development of strategies for prevention and early treatment,” said developmental pediatrician Susan E. Levy, M.D., a co-author of both studies who is the medical director of the Regional Autism Center and a member of the Center for Autism Research (CAR), both at Children’s Hospital.
Support for both studies was provided by The Children’s Hospital of Philadelphia, the National Institutes of Health, Autism Speaks, and many other sources, including the Margaret Q. Landenberger Foundation, the Cotswold Foundation, the Beatrice and Stanley A. Seaver Foundation, the Department of Veterans Affairs, and the Utah Autism Foundation. Scientists from 14 other centers in addition to Children’s Hospital and the University of Pennsylvania contributed to the discovery or replication of the findings.
Wang et al, “Common genetic variants on 5p14.1 associate with autism spectrum disorders,” Nature, published online April 28, 2009.
(http://dx.doi.org/10.1038/nature07999)
Glessner et al, “Autism genome-wide copy number variation reveals ubiquitin and neuronal genes,” Nature, published online April 28, 2009. (http://dx.doi.org/10.1038/nature07953)
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I just wanted to share with you some of the research I have uncovered over the 35-plus years I have been looking at the impact of fertility drugs on the human embryo. Genetics, of course, play a role in most, if not all, congenital anomalies, whether ASD or some form of birth defect. It’s what makes one of us more vulnerable to an environmental insult while another slips by unscathed.
On May 20, 2010, researchers from the Harvard School of Public Health presented their findings from a study exploring the possible relationship between the use of fertility drugs and autism spectrum disorder (ASD). The scientists reported to attendees at the International Meeting for Autism Research in Philadelphia that women who used fertility drugs to get pregnant had almost double the risk of having a child with ASD verses nonusers. The drugs studied included Clomid (clomiphene citrate) and Pergonal (gonadotropin).
Some have expressed skepticism about the study. However, although its value cannot be fully assessed until it appears in a peer-reviewed journal, there are several factors that argue in favor of its merits. In an effort to rule out other causes, Dr. Lyall and her colleagues made an “adjustment for pregnancy complications, maternal age, and other possible risk factors,” before making a determination that use of fertility drugs represented a 91% increased risk. This was at a highly significant statistical level – namely, the odds that their data did not occur by chance were 993 out of 1,000 (P=0.007). They also determined that a history of infertility – exclusive of fertility drugs – was not significantly associated with ASD, and that the “odds ratio for autism spectrum disorder increased with the number of reports of use of ovulation inducing drugs” (P=0.008).
This recent study is part of a growing body of research that strengthens the argument that Clomid and other fertility drugs are a cause of ASD via their ability to deny cholesterol to a developing embryo shortly after conception. About 58% of ASD children have low total cholesterol (<160 mg/dL) and about 19% have extremely low total cholesterol (<100 mg/dL). The average level for children is about 165 mg/dL. It has also been observed that a high percentage of children (71-86%) born with Smith-Lemli-Opitz syndrome (SLOS), in addition to a wide array of birth defects are also born with ASD. Infants with SLOS are born with a defective enzyme that impairs the body’s ability to convert a precursor (7-dehydrocholesterol) to cholesterol. Cholesterol is essential for growth of the myelin membranes that cover the brain and abnormalities in the myelin sheath are believed to be a contributing cause of ASD. Many experts thus believe that low cholesterol during early embryonic development is one of the causes of ASD.
Clomid has a long half-life and is present during the embryonic period (first 8 weeks) even when taken before conception. Studies have shown it to be biologically active for up to 54 days after ingestion and that it can accumulate over successive cycles of treatment. As mentioned, in the Harvard study they found that the longer the use of fertility drugs, the higher the risk of developing ASD. A critically important fact – and one not known by most physicians prescribing the drug – is that Clomid is a cholesterol inhibitor and impairs its production by acting upon enzymes in the body similar to Lipitor and other statin drugs. Its chemical structure is also similar to the cholesterol-reducing drug, Triparanol, which was briefly available during the 1960s. Animal studies have shown that Clomid and Triparanol both act on the same enzyme and affect developing organs in a similar way, with Triparanol being slightly more potent.
Pergonal (also known as human menopausal gonadotropin or hMG) likewise reduces cholesterol, but by way of a different mechanism. Namely, it suppresses cholesterol levels in early pregnancy via its ability to elevate estrogen production. Studies have established that following hyperstimulation of the ovaries by Pergonal, the resulting elevated estrogen during the luteal (post-ovulation) phase of the cycle suppresses the level of total cholesterol. In fact, there is an inverse correlation between concentrations of estrogen and the level of total cholesterol – the higher the level of estrogen, the lower the concentration of total cholesterol.
The GOOD NEWS is that many ASD children with low cholesterol, treated with cholesterol supplementation, have shown dramatic improvement. Scientists at Johns Hopkins University Medical Center, led by Dr. Richard Kelley, have shown such treatment resulting in improved mobility, verbalization, growth, behavior, sociability and alertness. Better yet, once we have a full understanding about one of the causes of ASD, some day in the future we might be in a position to eliminate that cause. As I postulated over two years ago, maintaining an optimum level of cholesterol throughout pregnancy could likely eliminate many cases of birth defects and autism spectrum disorder. http://www.terencemix.com.
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