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Recent Autism Gastrointestinal research funded by NIH

24 Jul

There are many parent advocates asking for research into gastrointestinal disorders and autism. My own anecdotal observations have been that these same parent advocates are of the belief that no work is ongoing. There are a number of projects ongoing and I’ve tried in the past to make that point (What projects are being funded in autism research? Part 1: vaccines and GI issues). I found 14 projects, nearly $3M in 2010. I found 11 projects for $1.7M in 2009.

I thought it time to revisit this question. I’m using a different data source–the NIH RePORTER database. Because of that these projects are those funded by NIH. Other Federal groups can and do fund autism research. Also private organizations like Autism Speaks

Below are the projects I found for the past few years. There are projects on epidemiology, treatment and biology.

While I think that the funding agencies could do a better job informing the communities about these projects, I sincerely wish that the parent advocacy groups calling for this research would inform their members that it is going on. I am actually very curious as to why they have not done that.

MECHANISMS OF AUTONOMIC BRAINSTEM DEVELOPMENT ($243,000)

Brainstem and autonomic circuitry, though understudied in neurodevelopmental disorders, are implicated in pathophysiology and co-occurring medical conditions, such as gastrointestinal disturbances (GID). The goal of this R21 project is to fill this knowledge gap, based on significant preliminary data.

CASEIN KINASE 1 INHIBITORS FOR TREATMENT OF AUTISM $349,610

The overall goal of our program is to (1) identify CK1 [Casein Kinase 1] inhibitors suitable for development as therapeutic agents and (2) to use these agents to investigate the suitability of CK1 inhibitors for addressing specific behavioral features of the complex, multi-symptom disorder known as autism.

The CADDRE SEED studies are multiyear but I haven’t listed all the grants. So the amount is much higher than even the substantial sums noted below.

MD CADDRE: STUDY TO EXPLORE EARLY DEVELOPMENT, SEED PHASE II $91,706

MD CADDRE: STUDY TO EXPLORE EARLY DEVELOPMENT, SEED PHASE II $1,600,000

CALIFORNIA CADDRE-SEED PHASE II $1,100,000

NC CADDRE: STUDY TO EXPLORE EARLY DEVELOPMENT (SEED) PHASE II $1,100,000

COLORADO CADDRE STUDY TO EXPLORE EARLY DEVELOPMENT CADDRE_SEED II $1,100,000

PA-CADDRE: STUDY TO EXPLORE EARLY DEVELOPMENT (SEED) PHASE II $1,100,000

SEED will address hypotheses including: ASD phenotypic variation, including the pattern of clustering of core symptoms, timing of onset, cognitive status, and presence of medical and psychiatric co-morbidities; gastrointestinal features; genetic variation and interaction with environmental risk factors (GxE); infection, immune function, and autoimmunity factors; hormonal factors and maternal reproductive characteristics; and sociodemographic and lifestyle factors.

INVESTIGATING THE GUT MICROBIOME FOR NOVEL THERAPIES AND DIAGNOSTICS FOR AUTISM $558,136 (also funded in 2013 for $558,136)

Based on compelling preliminary evidence, this project aims to explore the potential connection between GI barrier defects and altered behavior in preclinical models of autism. Our long-term goal is to explore possible serum biomarkers for ASD diagnosis, and potentially develop a novel probiotic therapy for at least a subset of children with ASD with GI issues.

2013 projects

TREATMENT OF MEDICAL CONDITIONS AMONG INDIVIDUALS WITH AUTISM SPECTRUM DISORDERS $488,568 (also, $339,591 in 2012, $264,726 in 2011, $578,006 in 2010, $535,209 in 2009, and $465,840 in 2008)

The life-long impairments in communication and social function are often complicated by the presence of medical comorbidities, including epilepsy, (and epileptiform discharges), gastrointestinal disturbances and sleep disorders.

REGULATION OF GASTROINTESTINAL NEUROMUSCULAR FUNCTION BY NIBP/NFKB SIGNALING $320,576 (and 2012 $343,747)

The proposed research is relevant to public health because the discovery of a novel function of NIBP/NFkB signaling in enteric neurons and glial cells is ultimately expected to increase the understanding of the pathogenesis of gastrointestinal diseases. It also shed light on the therapeutics for gastrointestinal inflammation and functional disorders.

ARE AUTISM SPECTRUM DISORDERS ASSOCIATED WITH LEAKY-GUT AT AN EARLY CRITIACAL PER $292,221 (and 2012 $302,820, and 2011 $302,820)

This project seeks to answer fundamental questions about the connection between early development of gastrointestinal (GI) problems (constipation, diarrhea, vomiting, etc.) and autism spectrum disorders (ASD)

From 2011

NEUROIMMUNOLOGIC INVESTIGATIONS OF AUTISM SPECTRUM DISORDERS (ASD) $264,726

A number of anecdotal reports have linked autism with gastrointestinal (GI) dysfunction; most notable among these are reports that autism is associated with “leaky gut” syndrome. Microbial translocation (MT) is the process by which bacteria or microbial byproducts permeate through the wall of the GI Tract (or other abnormally porous mucosal barriers) into the bloodstream. The microbial byproducts would then stimulate the immune system, which could have secondary effects on CNS functioning, or the byproducts could have a direct neurotoxic effect. We conducted assays of MT products in children with autism (from blood and CSF), as well as typically developing children (blood samples only).

and

Our ongoing phenotyping studies will be used to identify a cohort of children with autism who also have significant gastrointestinal symptoms in order to address this potentially important subgroup of patients.

A PRIMATE MODEL OF GUT, IMMUNE, AND CNS RESPONSE TO CHILDHOOD VACCINES $156,634


By Matt Carey

Press Release: Common gene variants account for most genetic risk for autism

23 Jul

This press release is from NIH: Common gene variants account for most genetic risk for autism

Common gene variants account for most genetic risk for autism
Roles of heritability, mutations, environment estimated – NIH-funded study

Most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches, researchers funded by the National Institutes of Health have found. Heritability also outweighed other risk factors in this largest study of its kind to date.

About 52 percent of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6 percent of the total risk.

nimh-20_l

The bulk of risk, or liability, for autism spectrum disorders (ASD) was traced to inherited variations in the genetic code shared by many people. These and other (unaccounted) factors dwarfed contributions from rare inherited, non-additive and spontaneous (de novo) genetic factors. Source: Population-Based Autism Genetics and Environment Study
“Genetic variation likely accounts for roughly 60 percent of the liability for autism, with common variants comprising the bulk of its genetic architecture,” explained Joseph Buxbaum, Ph.D., of the Icahn School of Medicine at Mount Sinai (ISMMS), New York City. “Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together.”

Buxbaum, and colleagues of the Population-Based Autism Genetics and Environment Study (PAGES) Consortium, report on their findings in a unique Swedish sample in the journal Nature Genetics, July 20, 2014.

“Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now detect common as well as rare genetic variation associated with risk,” said Thomas R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH). “Knowing the nature of the genetic risk will reveal clues to the molecular roots of the disorder. Common variation may be more important than we thought.”

Although autism is thought to be caused by an interplay of genetic and other factors, including environmental, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive. Recently, evidence has been mounting that genomes of people with autism are prone to harboring rare mutations, often spontaneous, that exert strong effects and can largely account for particular cases of disease.

More challenging is to gauge the collective impact on autism risk of numerous variations in the genetic code shared by most people, which are individually much subtler in effect. Limitations of sample size and composition made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited, and rare spontaneous variation.
Differences in methods and statistical models also resulted in sometimes wildly discrepant estimates of autism’s heritability – ranging from 17 to 50 percent.

Meanwhile, recent genome-wide studies of schizophrenia have achieved large enough sample sizes to reveal involvement of well over 100 common gene variants in that disorder. These promise improved understanding of the underlying biology – and even development of risk-scores, which could help predict who might benefit from early interventions to nip psychotic episodes in the bud.

With their new study, autism genetics is beginning to catch up, say the researchers. It was made possible by Sweden’s universal health registry, which allowed investigators to compare a very large sample of about 3,000 people with autism with matched controls. Researchers also brought to bear new statistical methods that allowed them to more reliably sort out the heritability of the disorder. In addition, they were able to compare their results with a parallel study in 1.6 million Swedish families, which took into account data from twins and cousins, and factors like age of the father at birth and parents’ psychiatric history. A best-fit statistical model took form, based mostly on combined effects of multiple genes and non-shared environmental factors.

“This is a different kind of analysis than employed in previous studies,” explained Thomas Lehner, Ph.D., chief of NIMH’s Genomics Research Branch. “Data from genome-wide association studies was used to identify a genetic model instead of focusing just on pinpointing genetic risk factors. The researchers were able to pick from all of the cases of illness within a population-based registry.”

Now that the genetic architecture is better understood, the researchers are identifying specific genetic risk factors detected in the sample, such as deletions and duplications of genetic material and spontaneous mutations. Even though such rare spontaneous mutations accounted for only a small fraction of autism risk, the potentially large effects of these glitches makes them important clues to understanding the molecular underpinnings of the disorder, say the researchers.

“Within a given family, the mutations could be a critical determinant that leads to the manifestation of ASD in a particular family member,” said Buxbaum. “The family may have common variation that puts it at risk, but if there is also a de novo [spontaneous] mutation on top of that, it could push an individual over the edge. So for many families, the interplay between common and spontaneous genetic factors could be the underlying genetic architecture of the disorder.”

Witnesses for Congressional hearing on autism announced

28 Nov

Thursday the US House Committee on Oversight & Government Reform will hold a hearing on autism: 1 in 88 Children: A Look Into the Federal Response to Rising Rates of Autism.

The witness list has been made public on the committee’s website:

Alan Guttmacher, M.D.
Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health

Coleen Boyle, Ph.D.
Director of the National Center on Birth Defects and Developmental Disabilities
Centers for Disease Control and Prevention

Mr. Bob Wright
Co-Founder
Autism Speaks

Mr. Scott Badesch
President
Autism Society

Mr. Mark Blaxill
Board Members
SafeMinds

Mr. Bradley McGarry
Coordinator of the Asperger Initiative at Mercyhurst
Mercyhurst University

Mr. Michael John Carley
Executive Director
Global & Regional Asperger Syndrome Partnership

Mr. Ari Ne’eman
President
Autistic Self Advocacy Network

NIH awards $100 million for Autism Centers of Excellence Program

7 Sep

The U.S. National Institutes of Health (NIH) Have awarded $100 million over five years to the next Autism Centers of Excellence (ACE). The press release discussing the groups and their focus is below:

NIH awards $100 million for Autism Centers of Excellence Program
Nine grantees receive research funding over next five years

The National Institutes of Health has announced grant awards of $100 million over five years for the Autism Centers of Excellence (ACE) research program, which will feature projects investigating sex differences in autism spectrum disorders, or ASD, and investigating ASD and limited speech.

The disorders are complex developmental disorders that affect how a person behaves, interacts with others, communicates and learns. According to the Centers for Disease Control and Prevention, ASD affects approximately 1 in 88 children in the United States.

NIH created the ACE Program in 2007 to launch an intense and coordinated research program into the causes of ASD and to find new treatments.

“The ACE program allows NIH institutes to leverage their resources to support the large collaborative efforts needed to advance the broad research goals of the Interagency Coordinating Committee Strategic Plan for ASD research,” said Alice Kau, Ph.D., of the Intellectual and Developmental Disabilities Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), one of five institutes funding the ACE program. “This year, the program has expanded to such areas as children and adults who have limited, or no speech, possible links between ASD and other genetic syndromes, potential treatments and the possible reasons why ASD are more common among boys than girls.”

In addition to the NICHD, the NIH institutes that support the ACE program are the National Institute on Deafness and Other Communication Disorders, the National Institute of Environmental Health Sciences, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

The nine awards for 2012 will support research at individual centers or at research networks, which involve multiple institutions, dedicated to the study of ASD.

Grants were awarded to research teams led by the following investigators:

2012 Center Grants

Susan Bookheimer, Ph.D. (University of California, Los Angeles)—This research group will use brain imaging technology to chart brain development among individuals having genes suspected of contributing to ASD. The researchers hope to link genetic variants to distinct patterns of brain development, structure and function in ASDs. Researchers in this center also are investigating treatments that will improve social behavior and attention in infants and acquisition of language in older children with ASD.

Ami Klin, Ph.D. (Emory University, Atlanta)—The Emory team will investigate risk and resilience in ASD, such as identifying factors associated with positive outcomes or social disability, starting in 1-month-old infants and will begin treatment in 12 month olds in randomized clinical trials. Through parallel studies in model systems, the researchers will chart brain development of neural networks involved in social interaction. This center will increase understanding of how ASD unfolds across early development.

Helen Tager–Flusberg, Ph.D. (Boston University)—Many individuals with ASD fail to acquire spoken language, and little is known about why this is so. This research team will use brain imaging technologies in an effort to understand why these individuals do not learn to speak, with the goal of helping them to overcome this limitation. The research team will also test new approaches to help young children with ASD acquire language.

2012 Network Grants

Connie Kasari, Ph.D. (University of California, Los Angeles)—This network will compare two types of intensive, daily instruction for children with ASD who use only minimal verbal communication. Earlier research has shown that even after early language-skills training, about one-third of school aged children with ASD remain minimally verbal. Researchers plan to enroll 200 children in four cities: Los Angeles, Nashville New York City, and Rochester, N.Y.

Kevin Pelphrey, Ph.D. (Yale University, New Haven, Conn.)—A team of researchers from Yale, UCLA, Harvard, and the University of Washington will investigate the poorly understood nature of ASD in females. The project will study a larger sample of girls with autism than has been studied previously, and will focus on genes, brain function, and behavior throughout childhood and adolescence. The objectives are to identify causes of ASD and develop new treatments. According to the U.S. Centers for Disease Control and Prevention, ASD are almost 5 times more common among boys (1 in 54) than among girls (1 in 252).

Joseph Piven, M.D. (University of North Carolina at Chapel Hill)—This research group previously used brain imaging to show atypical brain development at age 6 months in infants who were later diagnosed with ASD. The group now plans to follow another group of infants at risk for ASD. In this study, they will do more frequent scans throughout infancy and until age 2, to gain a greater understanding of early brain development in children with ASD.

Abraham Reichenberg, Ph.D. (Mount Sinai School of Medicine, New York City)—Researchers in this network will embark on an ambitious attempt to understand how genetic and environmental factors influence the development of autism. The researchers will analyze detailed records and biospecimens from 4.5 million births involving 20,000 cases of ASD, from 7 countries (the United States, Australia, Denmark, Finland, Israel, Norway, and Sweden.) The analysis will span three generations and involve grandparents, parents, aunts, uncles, and siblings and cousins.

Mustafa Sahin, M.D., Ph.D. (Harvard Medical School, Boston) and Darcy Krueger, M.D., Ph.D. (Cincinnati Children’s Hospital and University of Cincinnati)—This network will recruit patients with tuberous sclerosis complex, a rare genetic disease that causes tumors in the brain and other vital organs. Patients with tuberous sclerosis complex have an increased risk for developing autism. The researchers will track brain development in infants diagnosed with tuberous sclerosis complex, to gain insights into how autism develops.

Linmarie Sikich, M.D. (University of North Carolina at Chapel Hill)—The researchers will test whether treatment with oxytocin nasal spray can improve social interaction and communication in children with ASD. Oxytocin is a neuropeptide (used by brain cells to communicate) and has been associated with social behaviors. The researchers plan to enroll 300 children with ASD between 3 and 17 years old from Boston, Chapel Hill and Durham, N.C.; Nashville, New York City, and Seattle.

Additional information about ASD is available at http://health.nih.gov/topic/Autism.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; intellectual and developmental disabilities; and medical rehabilitation. For more information, visit the Institute’s website at http://www.nichd.nih.gov/.

About the National Institutes of Health (NIH): 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. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.


By Matt Carey

Note: this was originally published without a title

Most Children with ASD Diagnosed After Age 5, Use Multiple Services and Medications

25 May

A study just out from US National Institute of Mental Health researchers analyzes a survey they performed. Even today half of sad children identified are not diagnosed until after age 5. Half of autistic school age kids are using some form of psychotropic medicine.

The study is discussed here:

Most Children with ASD Diagnosed After Age 5, Use Multiple Services and Medications

And that discussion is quoted below:

Fewer than one out of five school-aged children with special health care needs were diagnosed with autism spectrum disorder (ASD) by age 2, according to new data from an NIMH-funded study. These diagnoses were made by a variety of health care providers, and most children in the study used multiple health care services (such as speech or language therapy) and multiple medications.

Background

Identifying ASD at an early age allows children to start treatment sooner, which can improve their later development and learning, and may also reduce a child’s need for specialized services or treatments later in life.

To determine the experiences of school-aged children with special health care needs, Lisa Colpe, Ph.D., M.P.H., and Bev Pringle, Ph.D., of the NIMH Division of Services and Intervention Research, collaborated with colleagues who conducted more than 4,000 telephone interviews with parents or guardians of a child between the ages of 6-17 who had a confirmed diagnosis of ASD, intellectual disability, and/or developmental delay.

These survey interviews were a part of the Pathways to Diagnosis and Services Study, sponsored by NIMH using funds available from the American Recovery and Reinvestment Act of 2009 (Recovery Act). Additional collaborators on this project include the National Center for Health Statistics at the Centers for Disease Control and Prevention (CDC) and the Maternal and Child Health Bureau at the Health Resources and Services Administration (HRSA).

Results of the Study

Key findings include:
The median age when school aged children with special health care needs and ASD were first identified as having ASD was 5 years.
Those identified as having ASD at younger than 5 years were diagnosed most often by generalists (such as pediatricians, family physicians, and nurse practitioners) and psychologists. Those identified later than 5 years were diagnosed primarily by psychologists and psychiatrists.

Nine out of ten school-aged children with special health care needs and ASD used at least one health care service, such as behavioral intervention or modification services, sensory integration therapy, cognitive based therapy, occupational therapy, physical therapy, social skills training, or speech or language therapy.

Social skills training and speech or language therapy were the most commonly used service, each used by almost 60 percent, or three out of five, of these children.

More than half of school-aged children with special health care needs and ASD used at least one psychotropic medication. “Psychotropic medication” refers to any medication used to treat a mental disorder.
Almost 33 percent of these children used stimulant medications
25 percent used anti-anxiety or mood-stabilizing medications
20 percent used antidepressants.

Further findings are available in the NCHS Data Brief and Frequently Asked Questions.

Significance
The new data detail the experiences of young children with ASD, describing when they are first identified as having ASD, who is making those identifications, and the services and medications the children use to meet their developmental needs.

What’s Next
NIMH encourages researchers to access and analyze the new dataset to produce more studies on the early life experiences and the diagnostic, service, and treatment issues relevant to children with ASD and special health care needs. The Pathways to Diagnosis and Services Study dataset can be accessed at http://www.cdc.gov/nchs/slaits/spds.htm.

Reference
Pringle BA, Colpe LJ, Blumberg SJ, Avila RM, Kogan MD. Diagnostic History and Treatment of School-Aged Children with Autism Spectrum Disorder and Special Health Care Needs. NCHS data brief, no 97. Hyattsville, MD: National Center for Health Statistics. 2012.

Thomas Insel: The New Genetics of Autism – Why Environment Matters

4 Apr

Thomas Insel is the director of the National Institute of Mental Health (NIMH) and the chair of the Interagency Autism Coordinating Committee (IACC) in the U.S..

His article can be found here (The New Genetics of Autism – Why Environment Matters) and I have quoted it in full bellow. (As a government publication I feel that it is appropriate to use the entire piece):

Last week’s autism news was about prevalence. The CDC reported a 78 percent increase in autism prevalence since 2002. This week’s autism news is about genetics—three papers in Nature describe new genes associated with autism. For many people, these two stories seem contradictory or, at best, unrelated. Increasing prevalence suggests environmental factors like chemicals and microbes changing over the past decade, whereas genes change over generations. Why is anyone looking for genetic causes when there is such a rapid increase in prevalence? Shouldn’t every research dollar be invested in finding the environmental culprit rather than searching for rare gene variants?

The simple answer is that some autism is genetic. Autism, like schizophrenia and mood disorders, includes many syndromes. Indeed, we should probably speak of the “autisms.” Some of these autisms are single gene disorders, such as Fragile X, tuberous sclerosis, and Rett syndrome. While these rare genetic disorders account for less than 5 percent of children within the autism spectrum, children with any of these disorders are at high risk for autism, roughly a 30-fold higher risk than the general population and higher than any of the other known risk factors. Recent genomics research has discovered that many children diagnosed within the autism spectrum have other genetic mutations that have not yet been designated as named syndromes. Each of these mutations is rare, but in aggregate they may account for 10 – 20 percent or more of what we have been calling the autisms.1

The new papers published today in Nature use an approach called whole exome sequencing, mapping every base of DNA across the exome—the 1.5 percent of the genome known to code for protein. The three research groups are members of the Autism Sequencing Consortium (ASC), an international team of autism genetics researchers. All three look for de novo or spontaneous mutations, changes in DNA sequence that are not found in either parent. Recent sequencing studies in the general population have demonstrated that each of us diverges genomically from our parents — the process of reproduction introduces variation even beyond the random mixture of the genomes we inherit from mom and dad. People with autism and schizophrenia are far more likely to have large de novo copy number variants, sometimes a million bases of DNA that are abnormally duplicated or deleted and not found in either parent.
These new papers go beyond the previous discovery of de novo copy number variants to identify de novo single base changes associated with autism. This is tough sailing because there are so many of these changes in all of us and most of these single base changes have no impact. These studies tried to improve the odds of success by focusing on individuals from families with no one else affected (these are called “simplex” families), and sometimes comparing the individual with autism to a sibling without autism. The results are intriguing.

There is no breakthrough or single gene that is a major new cause of autism. But the role of genetics becomes even more evident when these single base changes are considered. For instance, an individual with autism is nearly 6-fold more likely to have a functional variant in genes expressed in the brain. Sanders et al. estimate as many as 14 percent of affected individuals have such a risk variant.2 This 14 percent is in addition to the 10–20 percent with a large copy number variant or identified genetic syndrome. O’Roak et al. find that 39 percent of these variants are related to a specific biochemical pathway, important for brain signaling.3 And Neale et al., while cautioning that the net effect of all of these changes still leave much of the risk for autism unexplained, note the roles of a few specific genes as genuine risk factors.4

Stepping back from this flood of genomic information, what is most important? First, these reports along with previous publications confirm that genetic risk is both complex and substantial. While individual genes appear to confer limited risk, the aggregate effect of spontaneous coding mutations across the genome is now estimated to increase the risk of autism by 5–20-fold.4 Complex genetics does not mean modest effects.

Second, the kinds of small and large genetic changes associated with autism are common in everyone. Risk is conferred not by the size of the mutation or the number of mutations (we all have many) but by the location. Increasingly, we see that interference with the genes involved in development of synapses confer risk; a similar change upstream or downstream does not.
A third point takes us back to the questions we started with. It is important to understand that de novo mutations may represent environmental effects. In other words, environmental factors can cause changes in our DNA that can raise the risk for autism and other disorders. One of these papers reports that spontaneous changes are four times more likely to show up in paternally inherited DNA and are correlated with paternal age.2 The father’s germline, his sperm cells, turn over throughout the lifespan. Presumably, with advancing paternal age, there are a greater number of spontaneous mutations and a greater likelihood that some of these will affect risk genes. Environmental factors and exposures can cause sperm cells to develop mutations that are not found in the father’s somatic, or body cell, DNA, but these new, spontaneous mutations can be passed to the next generation, raising the risk for developing autism. In the initial report of the relationship between autism and paternal age, boys with autism were 6-fold more likely to have a father in his 40s vs his 20s. In girls with autism, this difference went up to 17-fold.5 Paternal age has, of course, increased in the past few decades. This does not explain the increasing prevalence of autism, but it may contribute.

Is autism genetic or environmental? These new studies suggest it can be both. Genetics will not identify the environmental factors, but it may reveal some of the many syndromes within the autism spectrum (as in other neurodevelopmental disorders), it can define risk (as in other medical disorders), and it should yield clues to the biology of autism (revealing potential targets for new treatments). These three new papers on spontaneous mutations are an important milestone in a long journey. In parallel we need to find environmental factors, recognizing that there will be many causes for the autisms and many roads to find them.

Finally, an unavoidable insight from these new papers is that autism even when genetic may be spontaneous and not inherited in the sense that one or both parents carry some reduced form of the syndrome. Perhaps this insight will finally reduce the “blame the parents” legacy perpetuated for too long in the absence of scientific evidence.

References
1Geschwind DH. Genetics of autism spectrum disorders. Trends Cogn Sci. 2011 Sep;15(9):409-16. Epub 2011 Aug 18. PubMed PMID: 21855394.1
2Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. April 5, 2012. Nature.
3O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. April 5, 2012.
4Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shair K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 5, 2012.
5Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, Rabinowitz J, Shulman C, Malaspina D, Lubin G, Knobler HY, Davidson M, Susser E. Advancing paternal age and autism. Arch Gen Psychiatry. 2006 Sep;63(9):1026-32. PubMed PMID: 16953005.

NIMH’s Top 10 Research Advances of 2011

5 Jan

Below is a blog post, NIMH’s Top 10 Research Advances of 2011, from the blog of Tom Insel, director of the National Institute of Mental Health (NIMH) in the U.S..

Tom Insel is the chair of the Interagency Autism Coordinating Committee (IACC), which creates the Strategic Plan for autism research funded by the U.S. government.

It is very interesting to see how often autism research is noted in the list below.

Item 3: Ricardo Dolmetsch’s work using stem cells to study autism and Timothy syndrome. (discussed here on Left Brain/Right Brain)

Item 4: De Novo Genetic Variants and autism

Item 8: NDAR, the National Database for Autism Research

and

Item 10: Public Private Partnerships.

At NIMH and in our broad research community, this has been a year of exciting discoveries and scientific progress, as we strive to make a difference for those with mental illness. Here are 10 breakthroughs and events of 2011 that are changing the landscape of mental health research.
1. Complexity: Discovering New Sources of Genetic Variance.

The discovery of two new sources of genetic variation may have an enormous impact on mental health research.

Students in “Genetics 101” learn that messenger RNA precisely mirrors the DNA sequence from which it was transcribed. However, recent studies suggest a far more complex transmission of information. NIMH-funded researchers compared corresponding RNA and DNA sequences in 27 individuals, and found more than 10,000 sequence sites where the RNA and DNA of the same individual did not match (1). These RNA-DNA mismatches were found in multiple study participants and in different types of cells, including brain and skin cells.
Another study presents what may be the most extraordinary discovery of 2011: somatic ‘retrotransposition’ can alter brain tissue (2). Retrotransposons are mobile genetic elements that can copy and insert themselves within a genome causing mutations in dividing cells. Although these insertions rarely lead to harmful effects when they occur in germ line cells (sperm and egg), they are frequently harmful if they occur in somatic cells, such as neurons. While nearly all studies of the genetics of mental illness have focused on germ line DNA, this new discovery suggests that DNA variation occurring in the developing brain could contribute to mental illness, just as mutations in mature tissues contribute to cancer. These surprising findings suggest a whole new frontier for the biology of mental illness.

2. Transcriptome: Developing Brains Have Unique Molecular Signatures.

Messenger RNAs, or transcripts, are intermediate products that carry the message from DNA, the genetic blueprint, to create proteins, and ultimately, the many different cell types throughout the brain. Each gene can make several transcripts, which are expressed in patterns unique to each of us. To better understand how these patterns of gene expression influence the developing brain, NIMH supported the first map of how RNA expression changes across the life span through two parallel studies of postmortem brains, ranging in age from two weeks after conception to 80 years old (3, 4). The researchers found that nearly 90% of genes are expressed differently during prenatal development, infancy, and childhood. While each of these stages has a distinct transcriptional identity, the fetal brain looks like a different organ compared to the postnatal brain, with 60% of genes expressed differently and 83% of transcripts processed to make unique proteins. Many of the genetic variations associated with mental illness appear to have a specific effect on the form of the gene expressed uniquely during fetal life.
3. Induced Pluripotent Stem Cells: Disease in a Dish.

In 2011, induced pluripotent stem cells (iPSCs) enabled a new round of findings on anomalies in neurodevelopment underlying disorders of mental health. The technology permits scientists to take adult cells and reprogram them to have the capabilities of stem cells to divide and differentiate into specific cell types. Growing iPSCs from adults with diagnosed disorders permits direct observation in cell culture of how the development of neurons is altered in these disorders from the very earliest stages. Scientists studying cells from patients with Timothy syndrome, a condition in which children often show autism-like symptoms, and Fragile X syndrome, an inherited cause of intellectual disability, found the kinds of changes in developing neurons that would disrupt their ability to form normal neural networks and tissues (5, 6). Strikingly, observations of iPSCs derived from patients with schizophrenia showed changes in neurons at stages that would correspond to very early development, years before symptoms emerge (7, 8). These reprogrammed cells also offer a means of medications testing; in these studies, scientists were able to observe the effects of medications in cells from patients with Timothy syndrome and schizophrenia.
4. De Novo Genetic Variants.

This year scientists looking at families with only one case of autism found that up to eight percent of cases in these families were the result of de novo (unique to the person affected) copy-number variants—stretches of DNA that were either multiplied or truncated (9, 10). Analysis of the gene regions affected by these variants implicated a network of genes involved in the development of synapses and neuronal function (11). Another study, focusing specifically on sequences of DNA that code for protein, yielded other de novo genetic changes in one-case families (12). While providing information on genetic contributors to a significant fraction of sporadic autism cases, the work also reveals gene regions for future investigation and ultimately, information on functional changes underlying autism that will offer clues to therapy.
5. Epigenomics: How Experience Alters Behavior.

In any one individual, patterns of gene expression vary widely among cells, leading to a diversity of cell types and functions, even though the cells all have the same DNA sequence. Epigenetic processes—heritable changes in gene expression that are not related to DNA sequence—help explain this diversity. Research suggests that epigenetics may also be a sort of programming language through which experience can have lasting effects on behavior, not only in an individual over a lifetime, but across generations. This effect was demonstrated in a 2011 study of male mice exposed to social defeat—repeated bullying by another aggressive male (13). The bullied males developed behavior resembling depression, and in subtle ways, so did their offspring. This was true even though contact between mother and bullied father was brief and took place well before the birth of the young, suggesting that epigenetic mechanisms played a role. Understanding the nature of epigenetic changes opens possibilities for therapy; scientists also showed this year that they could reverse the silencing of a gene involved in a rare neurodevelopmental disorder, a proof of concept for interventions targeting epigenetic processes (14).
6. Grand Challenges in Global Mental Health.

Mental, neurological, and substance use (MNS) disorders account for 13% of the global burden of disease, more than cancer and cardiovascular disease (15). The Grand Challenges in Global Mental Health initiative, led and funded by NIMH, assembled the largest ever international Delphi panel—over 400 participants representing work conducted in 60 countries—to determine priorities for research relevant to MNS disorders (16). The initiative convened an international community of research funders, engaged them in the consensus-building process, and has already resulted in a $20 million (Canadian) commitment to fund research targeting one Challenge. To date, the Grand Challenges have served as a resource for organizations and governments as they select policy and mental health services priorities. Moreover, the Grand Challenges come at a time of increasing recognition of the economic costs of mental illness (17) and the importance of including mental health in global health care (18, 19).
7. Precision Medicine.

In most fields of medicine, focusing on clinical symptoms is no longer adequate for diagnosis. In line with the National Academy of Sciences’ call for the development of a new nosology based on multiple levels of analysis across medicine, NIMH continues to advance the Research Domain Criteria (RDoC) project. Aiming to define basic dimensions of functioning, from genes to neural circuits to behaviors, RDoC will cut across traditional disorder definitions and facilitate rapid progress in basic neurobiological and behavioral research. In psychiatry, as in other fields of medicine, such an integrated understanding of the foundations of mental disorders may lead the development of new or more personalized treatments.
8. NDAR.

For those familiar with the National Database for Autism Research (NDAR) and its mission to accelerate discovery in autism research, the naming of this resource as one of the top three HHS Secretary’s picks in the HHSinnovates program this fall was well-deserved recognition. As the largest database of its kind to date, NDAR provides approved users with simultaneous access to an unprecedented amount of autism research data, tools, and related resources, drawing on records directly submitted to NDAR as well as from four partner databases—the Autism Speaks’ Autism Genetic Resource Exchange (AGRE) and Autism Tissue Program, the Kennedy Krieger Institute’s Interactive Autism Network (IAN), and the NIH Pediatric MRI Data Repository. Approved NDAR users will have access to data from the 25,000 research participants represented in NDAR, as well as 2,500 AGRE families and more than 7,500 participants who reported their own information to IAN. In the two years since its launch, NDAR has managed to set a new standard for data sharing and collaborative research, not only for autism, but other fields as well.
9. New Culture of Discovery: Team Science.

In an age when events in one country can inspire and incite action in another, so too has global research become a more interconnected and collaborative community. Last year, we saw this with the 1000 Connectomes project, which collected resting state fMRI maps of the brain from over 1000 people around the world and made these results broadly accessible via the Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC). This year, we saw this cultural shift toward team science when the Psychiatric Genomic Consortium reported on genetic variants associated with bipolar disorder and schizophrenia based on over 100,000 samples collected from 200 scientists in 65 institutions and 19 countries. Moreover, 2011 was the year when “standardization, integration, and data sharing” became a mantra for all science at NIMH, ensuring that results from individual labs could be leveraged by the global scientific community.
10. Public Private Partnerships.

As the pharmaceutical industry withdrew from psychiatric medication research and development this year, several new public-private efforts began to re-define the pathway for discovering new treatments. Arch2POCM, a public-private partnership comprising academic, industry, and regulatory scientists and clinicians, created a “precompetitive” initiative, free of intellectual property, for identifying new medications for schizophrenia and autism (20). One Mind for Research grew out of Patrick Kennedy’s moonshot for the mind, building an umbrella organization for neuroscience research related to all brain diseases. The Critical Path Institute led the way with common data elements for clinical research and new tools to promote data sharing. In addition, the Biomarkers Consortium brought industry, advocates, FDA, and NIH together to define biomarkers for neuropsychiatric diseases.
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