John Hopkins Study: Gene-Environment Interactions Influence Psychiatric Disorders

“Psychiatric diseases have genetic roots, but genes alone do not explain the entire disease ... When we study genes in conjunction with environmental challenges, we can better understand how diseases develop.” 

-  Mikhail V. Pletnikov, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, Study: Gene-environment interactions influence psychiatric disorders, John Hopkins University Gazette

In a John Hopkins University study pregnant laboratory mice bred with a specific genetic variation known as mhDISC1 were given a drug to stimulate their immune systems at the end of the first trimester of  their pregnancies while other mice with the same genetic variation did not receive the drug. The genetic variation involved is believed to be associated with mental illnesses in humans. The mice receiving the drug produced behavioral abnormalities, elevated anxiety, depressionlike responses, an altered pattern of sociability and a weakened response to stress. These responses were not present in the mice who did not receive the drug which suggested that the conditions resulted from the gene-environment interaction not the genetic variation alone. The study reports  also indicate that the same genetic variation can give rise to different illnesses depending on interactions with environmental factors and can impact on the size of different brain parts incuding the amygdala and the hypothalamus areas found in the brains of humans with major depression and bipolar disorder.

The study results appear to be another significant example of  an emerging paradigm shift away from viewing psychiatric and mental disorders as purely genetically determined toward an understanding of such disorders, including autism disorders, as arising from gene-environment interaction.  Future studies are likely to reflect this paradigm shift:

"Previous studies have suggested that the prenatal immune response to a microbe—be it a major illness or just transient flulike symptoms barely noticed by the pregnant woman—may be responsible for the increased incidence of adult psychopathology in humans. But this hypothesis, Pletnikov said, has been difficult to prove. Using this mouse model, he suggested, is a valuable way to study the relationship between gene-environment interactions and mental illness, and should be replicated to find more of these interactions to gain a better understanding of these relationships.

Future studies, he said, will try to sort out whether different timing or stimulating different parts of the immune system might lead to specific types of mental illness, and will explore the consequences of other environmental adverse events such as stress or drug abuse."

 
The John Hopkins University Gazette article by Stephanie Desmon of John Hopkins Medicine lists several supporters of the study including Autism Speaks.

New Autism Genetic Data Released By John Hopkins and Autism Consortium

More detailed autism genetic data was released yesterday in a coordinated effort by the Autism Consortium and Johns Hopkins' McKusick-Nathans Institute of Genetic Medicine. As stated in the Autism Consortium and John Hopkins press releases the data was released to the world research community prior to publication in an effort to speed up research into causes of and cures for autism.

It is also interesting that parent driven organizations like Autism Speaks have been directly involved in the organization of this massive effort. The distrust of parent autism advocates and autism advocacy organizations demonstrated by Canada's CIHR does not seem to be shared by similar American agencies. The Autism Consortium DNA samples for the genome wide scans of DNA variation were provided by the Autism Genetic Resource Exchange (AGRE), a program of Autism Speaks.

The Autism Consortium consists of researchers from from Beth Israel Deaconess Medical Center, Boston Medical Center, Boston University, Boston University School of Medicine, Broad Institute of MIT and Harvard, Cambridge Health Alliance, Children’s Hospital Boston, Harvard University, Harvard Medical School, Massachusetts General Hospital, Massachusetts Institute of Technology, McLean Hospital and Tufts-New England Medical Center. The Autism Consortium web site can be found at www.autismconsortium.org. More information about the Johns Hopkins' McKusick-Nathans Institute of Genetic Medicine can be found at http://www.hopkinsmedicine.org/geneticmedicine/

From the Autism Consortium press release

Autism Consortium releases data on genes involved in autism to researchers worldwide

BOSTON – OCTOBER 22, 2007 – The Autism Consortium, a group of researchers, clinicians and families dedicated to radically accelerating research and enhancing clinical care for autism, announced today that it has completed the first genome scan for Autism Spectrum Disorders (ASD) through its Autism Gene Discovery Project and has released the reference data set to a database that autism researchers around the world can use. The scan was conducted using new, high resolution technology developed by Affymetrix on genetic data from more than 3,000 children with ASD and their families.

“Today’s release of genetic and phenotypic data on autism marks a significant achievement for the autism research community,” said Thomas Insel, Ph.D., Director of the National Institute for Mental Health. “Progress in finding the causes and cures for autism spectrum disorders rests in large part on improving the rapid access and sharing of data and resources That the Consortium is making the data available to the scientific community even before its own researchers have fully analyzed the information, demonstrates their high degree of commitment to and leadership in advancing autism research.”

Along with complementary data generated by Dr. Aravinda Chakravarti at Johns Hopkins and provided to the NIMH this week, these data provide the most detailed look to date at the genetic variation patterns in families with autism.

From the John Hopkins Press Release:

Hopkins Researchers Release Genome Data on Autism; Most Detailed Look at Genetic Contributions to Date

BALTIMORE, Oct. 22 (AScribe Newswire) -- Researchers at Johns Hopkins' McKusick-Nathans Institute of Genetic Medicine today are releasing newly generated genetic data to help speed autism research. The Hopkins data, coordinated with a similar data release from the Autism Consortium, aims to help uncover the underlying hereditary factors and speed the understanding of autism by encouraging scientific collaboration. These data provide the most detailed look to date at the genetic variation patterns in families with autism.

"Autism is a difficult enough genetic mystery for which we need all of the best minds and approaches to help unravel the role of genes in this neuropsychiatric illness," says Aravinda Chakravarti, Ph.D., director of the Center for Complex Disease Genomics at Hopkins.

Chakravarti and his team analyzed whole genomes from 1,250 autistic individuals, their siblings and parents; these samples were collected across the United States by many researchers under the aegis of the National Institute of Mental Health, part of the National Institutes of Health. Mark Daly, Ph.D., a senior associate member of the Broad Institute of Massachusetts Institute of Technology and Harvard, is part of the Autism Consortium which released data acquired collected similarly from 3,000 individuals who are either affected by autism spectrum disorders (ASD) or are family members of individuals with autism.

"We're releasing raw genotype data so that other qualified researchers can take a look at it even as we're still beginning our own analysis," says Daly.

"It is really something of a landmark to have pre-publication data from our laboratories available to autism researchers. We are doing so in the spirit of the human genome project where such data releases were critical to progress long before final results were available. We are carefully looking at our collaborative findings as we continue to search for definitive information about which genes are important in causing autism spectrum disorders," says Chakravarti, who has collaborated with Daly for many years. "We hope to identify the most likely candidates over the next few months."

Too Soon to Write Off a Possible Mercury (Thimerosal) Autism Link ?

I have personally never been a believer in possible alleged mercury (thimerosal) autism link. Primarily because I accept the overwhelming consensus in the world scientific community that there is no link. Second, because I don't believe in the conspiracy angle of those who postulate a mercury autism link. Third, for personal reasons, my son displayed unusual behavior, which we have documented in a large photograph collection, since birth. None the less I think that Michael Wagnitz has made a very interesting argument for the mercury vaccine connection. Mr. Wagnitz is a chemist with 20 years experience working trace metal analysis who argues that recent findings of clinical studies examining brain tissue, blood, urine and human cells make a strong case for thimerosal as the agent causing the neuroinflammation which has been found in the brains of deceased autistic persons. The following article in the Madison Wisconsin Capital Times is worth a read. It will be interesting to read critiques of Mr. Wagnitz' theory but for now at least maybe it is worth waiting for more study before writing off the mercury-autism link.


Michael Wagnitz: Research supports mercury-autism link

By Michael Wagnitz

It was reported repeatedly in 2006 that the link between mercury-containing vaccines and autism has been disproven. Yet if one looks at the most recent research coming from some of our major universities, one may draw the opposite conclusion.

What we have learned in the last couple of years is that the underlying medical condition of autism is neuroinflammatory disease. In a study conducted at John Hopkins University, brain tissue from deceased autistic patients was examined. The tissue showed an active neuroinflammatory process and marked activation of microglia cells. Neuroinflammatory disease is synonymous with an activation of microglia cells.

A study done at the University of Washington showed that baby primates exposed to injected thimerosal (50 percent mercury), at a rate equal to the 1990s childhood vaccine schedule, retained twice as much inorganic mercury in their brains as primates exposed to equal amounts of ingested methylmercury. We know from autometallographic determination that inorganic mercury present in the brain, following the dealkylation of organic mercury, is the toxic agent responsible for changes in the microglial population and leads to neuroinflammation.

Recently it was shown that in more than 250 examined patients, atypical urinary porphyrins were almost three times higher in autistic patients than controls. Porphyrins are precursors to heme, the oxygen-carrying component of blood. Mercury inhibits the conversion of porphyrins to heme. When the patients were treated to remove mercury, urinary porphyrins returned to normal levels.

In a study done at the University of Arkansas, autistic children were found to have significantly lower levels of the antioxidant glutathione. Glutathione is the major antioxidant needed for the elimination of mercury at the cellular level. This may explain why some children are more severely affected by thimerosal in vaccines than others.

While all the government-conducted epidemiological (statistical) studies show no link between thimerosal and autism, the clinical studies examining brain tissue, blood, urine and human cells show a completely different picture.

Michael Wagnitz is a Madison resident with more than 20 years of experience as a chemist working with trace metal analysis.

Published: February 27, 2007



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