Reproductive testing at UCLA leads to healthy babies.

John and Andrea Nelson Meigs and their two-year-old daughter, welcomed a beautiful baby girl, Alexandra, to their family in October 2007. But just weeks after bringing Alexandria home, John and Andrea began to suspect something was wrong. At her two-month checkup, Alexandra wasn’t moving her arms and legs and she was breathing rapidly.

Alexandra was diagnosed with spinal muscular atrophy (SMA). “Spinal muscular atrophy is an illness caused by an abnormal copy of a gene from mom and dad, passed onto the baby. This disease gets worse and worse, and over time, will be fatal for the majority of those infected,” explains Mousa Shamonki, M.D., director of in vitro fertilization and assisted reproduction at UCLA.

During 12 days in the hospital, Alexandra slowly deteriorated and she passed away on New Year’s Day 2008.

When John and Andrea were ready to expand their family a few years later, they sought the help of Shamonki. They had heard how using in vitro fertilization, and the latest reproductive testing and technology, Shamonki and his team would be able to extract sperm and eggs to implant healthy embryos into mothers.

Andrea Nelson Meigs, UCLA patient

“We were fortunate to hear about this option and basically, what it allows you to do is to test the embryos for this genetic disease before they are implanted into the uterus. So before you are pregnant, you can test it to see if the baby is, in fact, affected with the disease,” says Andrea.

“We practice at the cutting edge of medicine to provide the best of care for each and every patient. We treat each patient as an individual. Everyone has a unique story, so our goal is to discover how we can best treat that individual to achieve their goals of having a child,” Shamonki says.

The procedure was successful. John and Andrea are blessed with healthy twins, Calla and Isabella.

“When the babies came out, John was there, in the operating room, and [the nurses] literally were like, baby A, baby B. I just started crying and I couldn’t believe it, I was just in shock. I just thought, wow, we are so lucky, we are so blessed that they are here, and that they are healthy,” Andrea says.

“There’s great science, and then there’s great care. What we found at UCLA was that the two were merged,” John says.

“I was just so happy. Honestly, I had forgotten what it felt like to be that happy,” Andrea exclaims.

Rare study will test a therapy for a genetically predestined disease — before its onset.

Ken Kosik, UC Santa Barbara

After an announcement by federal officials approving clinical trials for the drug crenezumab, researchers searching for a way to treat Alzheimer’s disease are gearing up for a rare study that will allow them to test a therapy for a genetically predestined disease — before its onset.

“This is really incredible,” said UC Santa Barbara neuroscientist Ken Kosik, who is the Harriman Professor of Neuroscience Research in the Department of Molecular, Cellular & Developmental Biology, and co-director of UCSB’s Neuroscience Research Institute. He, along with several other Alzheimer’s experts in the United States and Colombia, will be conducting the five-year, $100 million study, starting early next year.

The scientists will be drawing their study participants from a large family in Medellín, Colombia. It’s a family of about 3,000, with the unfortunate distinction of coming down with the disease early in life — onset begins at around 49 years of age. Unlike the kind of Alzheimer’s that strikes late in life, this particular form has been traced to a specific genetic mutation.

“Almost everybody, if they have the mutation, gets the disease like clockwork,” said Kosik, who first met with members of the family in the early 1990s, just after starting his work with Alzheimer’s as an assistant professor at Harvard University. His interests led him to Bogotá, where he met Francisco Lopera, the Colombian neurologist who told him of the family, and who is another lead researcher on the study.

At the time, there was the interest in starting treatment and research, but the country was in upheaval, caught between political insurgents, drug cartels and internal armed conflicts. Pharmaceutical companies were reluctant to invest or participate in any trials.

Two decades later, not only has turmoil in the country decreased, but the thinking toward treatment of Alzheimer’s disease has shifted from cure to prevention, paving the way for studies such as this one.

“When the brain is severely damaged with full-blown Alzheimer’s disease, it’s very hard to treat. There’s already been a lot of damage and you can’t replace the neurons that have died,” said Kosik.

About two years ago, Kosik received a call to do this study from colleague Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix and another lead researcher. At that time, several Phase 3 trials on what was hoped to be a viable treatment for sufferers of the disease had failed, forcing the neuroscientists to rethink their approach.

What is unique about this opportunity, said Kosik, is that the population being studied is a relatively homogenous group. Family members have the same genetic mutation, the same rural background, similar diets and activities.

“They have said over and over that this disease has been such a burden to them, that they want to participate in a clinical trial,” Kosik said.

The study involves testing candidates for the genetic mutation, taking a record of baseline conditions, administering either the medication or a placebo over a period of time and monitoring the subjects’ progress. In this double-blind trial, neither the subjects nor the investigators will know which subjects have the mutation, or which ones receive the drug or the placebo. A third party will handle that information.

Additionally, a group of participants that don’t have the mutation will be included in the mix, and will receive the placebo –– a measure taken to ensure that the family members in the study don’t know whether or not they have the mutation. In total, 300 members of the family will be participating in the first phase of the study.

Kosik, who has been concentrating on the genetic and ethical side of the research, said he agonized over whether the family members should be told of their genetic status.

“It’s very dangerous knowledge,” said Kosik. “I saw a 23-year-old man who said that if he found out he had the mutation, he would commit suicide.” On the other hand, there are people like the young female family member he encountered who wanted to have children but was terrified at the prospect of passing down the mutated gene.

In the end, he said, since there was no capability for genetic counseling at this early phase, the family members had to agree that they wouldn’t know which ones had the mutation.

“As this program develops, hopefully what some of these funds will be used for is to begin to offer genetic testing and counseling for those who want it,” said Kosik.

There will be several tests to assess whether crenezumab is successful at delaying or even stopping the onset of dementia. The tests will involve cognitive thinking and memory skills. The researchers will also be assessing any changes in emotional state that could signal the emergence of the disease. Added to these evaluations will be physiological examinations and other measurements to determine the health of the brain. Results could come as soon as two years into the study, and there are breakpoints at which the investigators may deem efforts a success or a failure, at which point they may move on to test another drug.

In the larger picture, Kosik sees a shift in how Alzheimer’s disease may be diagnosed. Currently, clinical diagnosis is contingent upon the presence of cognitive impairment, which has been too late for treatment with today’s medications. If the disease could be found early using genetic markers, a clinical diagnosis could be made sooner.

But, Kosik cautions against going to the other extreme –– for instance, the genetic bias of finding the mutation in a 10-year-old boy and diagnosing an otherwise healthy individual with a fatal disease.

“It’s a shifting line right now,” he said. “It’s an extremely interesting area.”

Findings spark hopes for development of new therapies.

Beate Ritz, UCLA

UCLA researchers may have found a key to determining which Parkinson’s disease patients will experience a more rapid decline in motor function, sparking hopes for the development of new therapies and helping identify those who could benefit most from early intervention.

In a study published today (May 15) in the peer-reviewed online journal PLoS ONE, the researchers found that Parkinson’s sufferers who possess two specific variants of a gene known to be a risk factor for the disease had a significantly speedier progression toward motor decline than patients without these variants.

“This is a relatively small study, with 233 patients, but the effects we’re seeing are actually quite large,” said Dr. Beate Ritz, vice chair of the department of epidemiology at the UCLA Fielding School of Public Health and the study’s primary investigator.

The SNCA gene is a well-known risk factor for Parkinson’s disease, and higher levels of the α-synuclein protein made from this gene are associated with greater disease severity in familial cases of Parkinson’s. The researchers examined two risk variants, the REP1 263bp promoter and rs356165. They recruited Parkinson’s disease patients shortly after they were diagnosed from three Central California counties and followed 233 of those patients for an average of 5.1 years.

They found that carriers of the Rep1 263bp variant had a fourfold higher risk of faster motor decline. They observed an even stronger trend in progression toward motor decline when both the Rep1 263bp and rs356165 variants were present in patients.

When doctors currently see Parkinson’s disease patients, they can’t predict how rapidly their motor function will deteriorate — how quickly, for instance, they will reach a point when they need a wheelchair or other aids, said Dr. Jeff Bronstein, professor of neurology at the David Geffen School of Medicine at UCLA.

“But if our results are confirmed,” Bronstein said, “these gene variants can now identify patients who are likely to have faster progression.”

And because of these differences in the rate of disease progression, researchers can test potential therapies in individuals carrying the genetic variations, obtaining faster results on the efficacy of those drugs, said co-author Shannon Rhodes, a researcher in epidemiology at the UCLA Fielding School of Public Health. “Plus,” she said, “you’re helping the people who are the most affected.”

Ritz, who is also a professor of neurology at the David Geffen School of Medicine at UCLA, said there are probably other markers that need to be identified, because not all patients with the variants in question become fast progressors. In addition, the results need to be replicated, so future studies with many more subjects are needed.

“Since motor symptom severity predicts increased mortality (in Parkinson’s disease) independent of age and disease duration, identifying genetic predictors of faster motor decline is critical to pinpointing biological mechanisms as targets for therapies and identifying patients who will most benefit from early interventions,” the authors write. “While replication of our results in similarly well-characterized population-based incidence PD cohorts that have been longitudinally followed is still needed, our findings strongly suggest that α-synuclein and related pathogenic pathways have great promise as potential disease modifying and therapeutic targets.”

The National Institutes of Health, the Michael J. Fox Foundation for Parkinson’s Research and the American Parkinson Disease Association funded this research.

Dr. Yvette Bordelon, an assistant clinical professor of neurology at the David Geffen School of Medicine at UCLA, was also a co-author of this study.

The UCLA Fielding School of Public Health is dedicated to enhancing the public’s health by conducting innovative research, training future leaders and health professionals, translating research into policy and practice, and serving local, national and international communities.

The David Geffen School of Medicine at UCLA ranks among the nation’s elite medical schools, producing doctors and researchers whose contributions have led to major breakthroughs in health care. With more than 2,000 full-time faculty members, nearly 1,300 residents, more than 750 medical students and almost 400 Ph.D. candidates, the medical school is ranked seventh in the country in research funding from the National Institutes of Health and third in the United States in research dollars from all sources.

NIH grant to UC Riverside’s Frances Sladek aims to bring personalized medicine a step closer.

Frances Sladek, UC Riverside

Aside from identical twins, no two individuals are completely identical genetically. Most differences between individuals are due to single nucleotide changes or polymorphisms (SNPs) — DNA sequence variations — in the genome.

SNPs, the most common type of genetic variation among people, are being increasingly recognized as playing a major role in phenotype variations, such as eye and hair color, basal body weight, muscle tone, responsiveness to alcohol consumption, as well as susceptibility to diseases such as cancer, diabetes, heart disease and mental disorders.

The more scientists know what SNPs’ functions are, the easier it would be to understand the tremendous variability in individuals’ responses to drug treatments such as why some drugs are life-saving for some people but cause serious side effects in others.

Frances Sladek, a professor of cell biology and toxicologist at the University of California, Riverside, has received a $1.5 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health to support a four-year research project that will allow her to examine the effect SNPs have on a special class of proteins called nuclear receptors that bind DNA and regulate the expression of many important genes in response to hormones, vitamins and drugs.

“Many SNPs introduce structural or functional changes in the proteins encoded by genes,” explained Sladek, the grant’s principal investigator.  “Other SNPs, the vast majority, are outside of the protein-coding portion of the gene; they are often found in the regulatory regions of genes — regions that determine the level of gene expression.  We will characterize both types of SNPs to help predict disease susceptibility and response to drug treatments.  Such a characterization will help lay the foundation for personalized medicine, ultimately leading to more effective and hence less costly health care costs.”

Sladek’s lab will use a powerful new technology, called protein binding microarrays, to identify SNPs in DNA sequences to which nuclear receptors bind.  By integrating a range of biochemical, molecular, genomic and bioinformatics approach, the researchers will examine nuclear-receptor-DNA binding and how SNPs influence it.

The team will make publicly available all their results on a UC Riverside website dedicated to the project, as well as on other public databases.  The researchers are also developing web-based tools for target gene prediction, an evolving science of efficiently identifying the regions of genomic DNA that regulate the expression of genes.

“We hope these tools will advance the long-term goal of fast-tracking research linking nuclear receptors to disease and drug metabolism, and thereby help personalize medicine and ensure that drugs that target nuclear receptors can be used in a more effective fashion,” Sladek said.

DNA, situated in the cell’s nucleus, carries the genetic information of a cell and consists of thousands of genes. Each gene serves as a recipe on how to build a protein molecule. Proteins perform important tasks for the cell functions or serve as building blocks. When proteins are needed, the corresponding genes are made into RNA (single-stranded molecules that can adopt very complex three-dimensional structures) via a process called transcription for which proteins, called transcription factors, are needed.  Nuclear receptors are transcription factors that regulate the expression of a wide range of genes involved in nearly all aspects of human physiology and disease.

“We have much to learn about the nuclear-receptor-DNA interaction and the factors that influence it,” Sladek said. “While nuclear receptors have been investigated heavily for their role in physiology and disease and are themselves targets of many successful drugs, we still do not have a complete understanding of their role in disease susceptibility nor in individual responses to drug treatments.  This grant will allow us to better define what kind of sequences the nuclear receptors bind to, and help with other ways of examining what kind of genes the nuclear receptors regulate.”

Sladek will be joined in the research by the following colleagues at UCR: Tao Jiang, a professor of computer science and engineering and the grant’s co-principal investigator; Thomas Girke, an associate professor of bioinformatics; and two postdoctoral researchers.

Cancer Genomics Hub will manage, analyze “big data” gathered by cancer researchers.

The emerging field of “personalized” or “precision” medicine holds great promise in the fight against cancer. If scientists can identify the genetic changes that drive each patient’s cancer cells, they can use that information to develop targeted treatments. But achieving this goal will require massive amounts of genomic and clinical data and a sophisticated infrastructure to manage and analyze the data.

David Haussler, UC Santa Cruz

The University of California, Santa Cruz, has now completed a first step in building this infrastructure, said UC Santa Cruz bioinformatics expert David Haussler. Haussler’s team has established the Cancer Genomics Hub (CGHub), a large-scale data repository and user portal for the National Cancer Institute’s cancer genome research programs. CGHub’s initial “beta” release is providing cancer researchers with efficient access to a large and rapidly growing store of valuable biomedical data. The project is funded by the National Cancer Institute (NCI) through a $10.3 million subcontract with SAIC-Frederick Inc., the prime contractor for the Frederick National Laboratory for Cancer Research.

In personalized care, doctors design treatments to target specific genetic changes found in a patient’s cancer cells. Researchers are trying to catalog all the genetic abnormalities found in different types of cancers and find connections between specific genetic changes and how patients respond to different treatments. The scale and complexity of the information being gathered creates a critical challenge in the area of data management.

Although recent studies using genetically targeted treatments have shown promising results, much more research is needed to enable their widespread use, Haussler said. “There won’t be one magic bullet, because cancer is not one disease, or even 100 diseases. Every instance of cancer is different. We have to improve our understanding of the molecular biology of cancer and develop computer algorithms so that we can analyze the genetic changes in each individual patient. It will take time. But with cancer genomics, we will eventually know our enemy completely.”

Haussler’s team assembled the first draft of the human genome sequence in 2000 and created and maintains the UCSC Genome Browser, a Web-based tool that is used extensively in biomedical research and serves as the platform for several large-scale genomics projects. His group’s contributions to cancer genomics research include creation of a Cancer Genomics Browser for analyzing data from large-scale cancer studies.

Haussler’s group built CGHub to support all three major NCI cancer genome sequencing programs: The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and the Cancer Genome Characterization Initiative (CGCI). TCGA is a collaborative effort led by NCI and the National Human Genome Research Institute to map the genomic changes that occur in at least 20 major types and subtypes of adult cancer. The TARGET program is a related effort focusing on the five most common childhood cancers, and the CGCI makes available genomic data from HIV-associated cancers and certain lymphoid and childhood cancers.

These programs are laying the foundation for personalized cancer care by creating a database that scientists around the world can use to connect specific genomic changes with clinical outcomes. Haussler’s group has been closely involved in data analysis for TCGA.

“TCGA is allowing us for the first time to look at cancer in full molecular detail,” Haussler said. “Cancer is a disease caused by disruption of DNA molecules within the cell. When life starts, every cell in the body has the same DNA. In the course of a person’s lifetime, however, some cells may accumulate changes in their DNA that cause them to go rogue and multiply without control, creating the disease we call cancer. For the first time now, we are able to look into an individual patient’s cancer cells and see all the genetic disruptions, among which are the molecular drivers of that person’s cancer.”

There are currently only a few situations in which doctors can prescribe a treatment plan based on the specific genetic mutations in a patient’s cancer cells. That is expected to change as projects like TCGA, TARGET and CGCI yield a comprehensive catalog that researchers can use to find new targets for medicines and discover clues to improve patient outcomes. But there is an urgent need for an efficient and user-friendly portal to give researchers access to the data. The NCI genome projects are producing staggering amounts of data.

“The scale of this is far beyond anything faced in medical research before,” Haussler said. “Each genome file, the DNA record from a tumor or normal tissue, is 300 billion bytes. And for every case there are two of these files, the cancer genome and the normal genome. Add to this RNA sequence data, and the prospect of deeper sequencing in the future, and we must plan for up to a terabyte (1,000 billion bytes) for each case.”

TCGA currently generates about 10 terabytes of data each month. For comparison, the Hubble Space Telescope amassed about 45 terabytes of data in its first 20 years of operation. TCGA’s output will increase tenfold or more over the next two years. Over the next four years, if the project produces a terabyte of DNA and RNA data from each of more than 10,000 patients, it will have produced 10 petabytes of data (a petabyte is 1,000 terabytes). And TCGA is just the beginning of the data deluge, Haussler said, noting that 10,000 cases is a small fraction of the 1.5 million new cancer cases diagnosed every year in the United States alone.

New data compression schemes are expected to reduce the total storage space needed, so the CGHub repository is designed initially to hold 5 petabytes and to allow further growth as needed. That is still a massive amount of data, and CGHub will need to accommodate transfers of extremely large data files.

Managed by the UCSC team, the CGHub computer system is located at the San Diego Supercomputer Center. It is connected by high-performance national research networks to major centers nationwide that are participating in these projects, including UCSC. Haussler’s team designed and oversees the storage and computing infrastructure for the repository, which has an automated query and download interface for large-scale, high-speed use. It will eventually also include an interactive web-based interface to allow researchers to browse and query the system and download custom datasets.

It may take years for cancer genomics research to bring about major changes in cancer care. The first step, and the focus of the NCI cancer genomics programs, is to determine which genomic changes are involved in each type of cancer and to understand the molecular and clinical effects of those changes. Then biomedical researchers must identify or develop treatments to block those effects.

“Right now, cancer research needs something on a very large scale, like the Large Hadron Collider in physics,” Haussler said. “Instead of bringing subatomic particles together in high-energy collisions and computing their behavior, we’re bringing cancer genomes together in a common database and computing the disease drivers.”

CGHub program director is Robert Zimmerman, and project team members include technical director Mark Diekhans; operations manager Linda Rosewood; hardware systems lead Erich Weiler; engineering lead Chris Wilks; engineering consultant Brian Craft; and networking consultants Brad Smith and Jim Warner. The core code, including GT software for downloading data, was licensed from Annai Systems. The cancer genomics group at UCSC also includes co-principal investigator Joshua Stuart, an associate professor of biomolecular engineering at UCSC; assistant research scientist Jing Zhu; engineers Kyle Ellrott, Teresa Swatloski and Singer Ma; user testing engineer Mary Goldman; postdoctoral scholars Adam Ewing, Benedict Paten and Daniel Zerbino; research associate Charlie Vaske; and graduate students Tracy Ballinger, Steve Benz, Daniel Carlin, James Durbin, Ted Goldstein, Mia Grifford, Sam Ng, Amie Radenbaugh,  Zack Sanborn and Chris Szeto.

The CGHub project is 100 percent funded by the National Institutes of Health, in the amount of $10.3 million using prime contract HHSN261200800001E, from the Frederick National Laboratory for Cancer Research.

UCLA researchers shed light on cause of rare disease that attacks the brain and spine.

Joanna Jen, UCLA

Researchers at UCLA have been searching for the cause of a rare disease that virtually no one has ever heard: PCH1, or pontocerebellar hypoplasia type 1, which attacks the brain and the spine.

It’s a particularly cruel disorder, occurring mostly in infants, who begin manifesting symptoms at or soon after birth, with poor muscle tone, difficulty feeding, growth retardation and global developmental delay.

Now, thanks to the cooperation of a California family stricken by the disorder and a state-of-the-art genomic sequencing lab at UCLA, Dr. Joanna Jen, a UCLA professor of neurology, and colleagues discovered a specific mutation of a gene that is responsible for PCH1 in this family, then confirmed mutations in the same gene in several other PCH1 families around the world.

The study appears today (April 29) in the online edition of the journal Nature Genetics.

The diagnosis of PCH1 is often delayed or never made because the combination of cerebellar and spinal motor-neuron degeneration is very rare and not commonly recognized. The discovery of the gene, EXOSC3 (exosome component 3), showed that it is critically important in the normal development and survival of neurons, especially in the cerebellum, and for motor neurons in the spine, which innervate or stimulate muscles.

Five years ago, Jen began working with a family living in Southern California with four boys who were neurologically afflicted. They were floppy at birth, suffered from progressive muscle wasting and were never able to stand, walk or speak. Today, they range in age from 9 to the teens, and none weighs more than 50 pounds.

The family was referred to Jen because of her special interest in rare neurological disorders. As Jen reviewed the medical history and examined the children to reach a clinical diagnosis, she began searching for the causative gene in collaboration with Dr. Stanley Nelson, a professor and vice chair of the UCLA Department of Human Genetics.

Nelson, who also directs the UCLA Clinical Genomics Center, and his graduate student Michael Yourshaw, used a new technique called exome sequencing. The exome is the part of the genome that directs those proteins that are actually expressed — that is, it provides the genetic blueprint for functional genes. Exome sequencing searches just the protein-coding regions in the genome to pinpoint disease-causing mutations. In this way, they were able to quickly survey some 22,000 protein-encoding genes to identify a defect in the EXOSC3 gene in this single California family.

To confirm their finding, Jen reached out to other neurologists around the world, eventually verifying the presence of the same defective gene in eight other families stricken with PCH1. And by using a model of the disease in zebrafish, Jijun Wan, a UCLA research scientist in neurology, found that preventing the EXOSC3 gene from expressing in zebrafish caused embryonic maldevelopment and poor movement reminiscent of human clinical features. These symptoms were largely reversed when the researchers injected normal EXOSC3, suggesting that it was indeed the mutations that disrupted normal function.

The EXOSC3 gene encodes a core component of the RNA exosome complex, which is essential for all organisms and which is emerging as the major cellular machinery in the processing of RNA to regulate gene expression, Jen said. There is increasing appreciation for the diversity of RNAs, she noted, as it is becoming clear that the majority of genomic information is transcribed into RNA.

“When we began this study, mutations in the RNA exosome had not been associated with any human disease,” Jen said. “Relatively little is known about the human RNA exosome. It is surprising that a gene that is expressed in every cell should have such a selective detrimental impact on the cerebellar and spinal motor neurons.

There is increasing focus on RNA metabolism in motor neuron diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, and spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, Jen said. The discovery of defects in the RNA exosome causing combined SMA and PCH further emphasizes the importance of the regulation of RNA metabolism.

“The discovery may lead to potential targets for treatment and in addition enhances our understanding of the biological function of the RNA exosome,” said Jen. She is working with other neurologists to better define the clinical spectrum of EXOSC3-associated PCH1.

“It is remarkable that all of the affected children in this family have survived beyond infancy. We are grateful for the generosity of the family in sharing their experience and participating in research to improve the lives of other children who are similarly affected,” said Jen.

There were multiple authors on the paper in addition to first authors Wan and Yourshaw, and Nelson and Jen. Please see the paper for names and affiliations. Multiple sources provided funding for the study, including the National Institutes of Health.

The Clinical Exome Sequencing Service within the recently established UCLA Clinical Genomics Center in the department of laboratory medicine and pathology provides fully CLIA-compliant whole-exome sequencing that can now be ordered on campus.

The UCLA Department of Neurology, with over 100 faculty members, encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer’s disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks in the top two among its peers nationwide in National Institutes of Health funding.

Second study identifies brain-development genes associated with intercranial volume.

Charles DeCarli, UC Davis

Two research studies, co-led by UC Davis neurologist Charles DeCarli and conducted by an international team that included more than 80 scientists at 71 institutions in eight countries, has advanced understanding of the genetic components of Alzheimer’s disease and of brain development. Both studies appear in today’s (April 15) edition of the journal Nature Genetics.

The first study, based on a genetic analysis of more than 9,000 people, has found that certain versions of four genes may speed shrinkage of a brain region involved in making new memories. The brain area, known as the hippocampus, normally shrinks with age, but if the process speeds up, it could increase vulnerability to Alzheimer’s disease, the research suggests.

The second paper identifies two genes associated with intracranial volume — the space within the skull occupied by the brain when the brain is fully developed in a person’s lifespan, usually around age 20.

DeCarli is an internationally renowned pioneer in the field of neuroimaging of the aging brain who has been at the forefront of developing and using quantifiable imaging techniques to define the relationship between structure and function in the healthy aging brain and to characterize the changes associated with vascular and Alzheimer’s dementias. He is professor of neurology and director of the UC Davis Alzheimer’s Disease Center and the UC Davis Imaging of Dementia and Aging Laboratory.

Genetic variants of hippocampus study

The gene variants identified in the first study do not cause Alzheimer’s, but they may rob the hippocampus of a kind of “reserve” against the disease, which is known to cause cell destruction and dramatic shrinkage of this key brain site. The result is severe loss of memory and cognitive ability.

Scientists calculated that hippocampus shrinkage in people with these gene variants accelerates by about four years on average. The risk of Alzheimer’s doubles every five years beginning at age 65, so a person of that age would face almost twice the Alzheimer’s risk if he or she had these versions of the gene.

Looked at another way, if a person with one of these variants did get Alzheimer’s, the disease would attack an already compromised hippocampus and so would lead to a more severe condition at a younger age than otherwise, the research suggests.

“This is definitely a case of ‘bigger is better,’” said DeCarli. “We already know that Alzheimer’s disease causes much of its damage by shrinking hippocampus volume. If someone loses a greater-than-average amount of volume due to the gene variants we’ve identified, the hippocampus is more vulnerable to Alzheimer’s.”

Why the aging hippocampus normally decreases in volume is unclear. The new research shows that the genes most strongly linked to shrinkage are involved in maturation of the hippocampus and in apoptosis, or programmed cell death — a continual process by which older cells are removed from active duty.

The scientists suggest that if the gene variants they identified do affect either maturation or the rate at which cells die, this could underlie at least some of the increased rates of hippocampus shrinkage.

“Either by making more or healthier hippocampal neurons or preventing them from dying with advancing age, the healthy versions of these genes influence how people remember as they get older,” said DeCarli. “The alternate versions of the genes may not fully provide these benefits.”

The researchers hope that they can find ways to protect the hippocampus from premature shrinkage or slow its decline by studying the normal regulation of the proteins coded by these genes.

The genetic analysis draws on what is known as a genome-wide association study — research aimed at finding the common genetic variants associated with specific diseases or other conditions. Different versions of a gene usually come down to changes in just one of the tens of thousands of DNA “letters” that make up genes. These one-letter differences are known as single-nucleotide polymorphisms, or SNPs.

The research involved more than 80 scientists at 71 institutions in 8 countries. Many researchers are needed for such a study in order to put together the large samples, or cohorts, of people whose genetic makeup is to be investigated, to measure the hippocampus from magnetic resonance pictures of the brain and for the labor-intensive statistical analysis of the findings.

The study used a very large assemblage of genetic and disease data called the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, or CHARGE. The consortium brings together several population-based cohorts in the United States and Europe.

The cohort was made up of 9,232 dementia-free volunteers with an average age of 67. The study identified four different gene variants associated with hippocampus volume decline. One, known as rs7294919, showed a particularly strong link to a reduced hippocampus volume, suggesting that this gene is very important to hippocampus development or health.

The findings were then assessed in two other cohorts. One, including both normal and cognitively compromised people with an average age of 40, showed that three of the suspect SNPs were linked to reduced hippocampus volume. Analysis of results from the third group, comprised primarily of older people, showed a significant association between one of the SNPs and accelerated memory loss.

“With this study, we have new evidence that aging, the hippocampus and memory are influenced by specific genes,” DeCarli said. “Understanding how these genes affect the development and aging of the hippocampus may give us new tools to delay memory loss with advanced age and possibly reduce the impact of such diseases as Alzheimer’s disease.”

Intracranial-volume study

While the first study deals with the genetic associations with brain shrinkage, the second deals with associations impacting intracranial volume, which is an indirect measure of the size of the brain at full development.

Though brain volume and intracranial volume are both highly heritable, the genetic influences on these measures may differ. To assess the genetic influence on these two measures, researchers in the second study performed a genome-wide association study on cross-sectional measures of intracranial volume and brain volume in 8,175 elderly in the CHARGE consortium.

They found no associations for brain volume, but they did discover that intracranial volume was significantly associated with two loci: rs4273712, a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21.

“Since geneticists are already familiar with the other functions of these same genes, associating these particular genes with intracranial volume may help us better understand brain development in general,” said DeCarli. “For instance, we know that one of these genes has played a unique evolutionary role in human development, and perhaps we as a species are selecting this gene as a way of providing further advances in brain development.”

Both studies involved international teams representing scores of institutions, funded by a variety of NIH grants as well as grants from agencies around the world. Please refer to the papers for complete lists of authors, affiliations, and funding sources.”

The UC Davis Alzheimer’s Disease Center is one of only 29 research centers designated by the National Institutes of Health’s National Institute on Aging. The center’s goal is to translate research advances into improved diagnosis and treatment for patients while focusing on the long-term goal of finding a way to prevent or cure Alzheimer’s disease. Also funded by the state of California, the center allows researchers to study the effects of the disease on a uniquely diverse population. For more information, visit alzheimer.ucdavis.edu.

UCLA-launched partnership identifies genes that boost or lessen risk of brain atrophy, mental illness, Alzheimer’s disease.

Paul Thompson, UCLA

In the world’s largest brain study to date, a team of more than 200 scientists from 100 institutions worldwide collaborated to map the human genes that boost or sabotage the brain’s resistance to a variety of mental illnesses and Alzheimer’s disease.

Published April 15 in the advance online edition of the journal Nature Genetics, the study also uncovers new genes that may explain individual differences in brain size and intelligence.

“We searched for two things in this study,” said senior author Paul Thompson, professor of neurology at the David Geffen School of Medicine at UCLA and a member of the UCLA Laboratory of Neuro Imaging. “We hunted for genes that increase your risk for a single disease that your children can inherit. We also looked for factors that cause tissue atrophy and reduce brain size, which is a biological marker for disorders like schizophrenia, bipolar disorder, depression, Alzheimer’s disease and dementia.”

Three years ago, Thompson’s lab partnered with geneticists Nick Martin and Margaret Wright at the Queensland Institute for Medical Research in Brisbane, Australia, and with geneticist Barbara Franke of Radboud University Nijmegen Medical Centre in the Netherlands. The four investigators recruited brain-imaging labs around the world to pool their brain scans and genomic data, and Project ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) was born.

“Our individual centers couldn’t review enough brain scans to obtain definitive results,” said Thompson, who is also a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA. “By sharing our data with Project ENIGMA, we created a sample large enough to reveal clear patterns in genetic variation and show how these changes physically alter the brain.”

In the past, neuroscientists screened the genomes of people suffering from a specific brain disease and combed their DNA to uncover a common variant. In this study, Project ENIGMA researchers measured the size of the brain and its memory centers in thousands of MRI images from 21,151 healthy people while simultaneously screening their DNA.

“Earlier studies have uncovered risk genes for common diseases, yet it’s not always understood how these genes affect the brain,” Thompson said. “This led our team to screen brain scans worldwide for genes that directly harm or protect the brain.”

In poring over the data, Project ENIGMA researchers explored whether any genetic variations correlated to brain size. In particular, the scientists looked for gene variants that deplete brain tissue beyond normal in a healthy person. The sheer scale of the project allowed the team to unearth new genetic variants in people who have bigger brains, as well as differences in regions critical to learning and memory.

When the scientists zeroed in on the DNA of people whose images showed smaller brains, they found a consistent relationship between subtle shifts in the genetic code and diminished memory centers. Furthermore, the same genes affected the brain in the same ways in people across diverse populations from Australia, North America and Europe, suggesting new molecular targets for drug development.

“Millions of people carry variations in their DNA that help boost or lower their brains’ susceptibility to a vast range of diseases,” said Thompson. “Once we identify the gene, we can target it with a drug to reduce the risk of disease. People also can take preventive steps through exercise, diet and mental stimulation to erase the effects of a bad gene.”

In an intriguing twist, Project ENIGMA investigators also discovered genes that explain individual differences in intelligence. They found that a variant in a gene called HMGA2 affected brain size, as well as a person’s intelligence.

DNA comprises four bases: A (adenine), C (cytosine), T (thymine) and G (guanine). People whose HMGA2 gene held a letter “C” instead of a “T” at a specific location on the gene possessed larger brains and scored more highly on standardized IQ tests.

“This is a really exciting discovery, that a single letter change leads to a bigger brain,” Thompson said. “We found fairly unequivocal proof supporting a genetic link to brain function and intelligence. For the first time, we have watertight evidence of how these genes affect the brain. This supplies us with new leads on how to mediate their impact.”

Because disorders like Alzheimer’s, autism and schizophrenia disrupt the brain’s circuitry, Project ENIGMA will next search for genes that influence how the brain is wired. Thompson and his colleagues will use diffusion imaging, a new type of brain scan that maps the communication pathways between cells in the living brain.

Project ENIGMA received funding from hundreds of federal and private agencies around the world. Thompson’s UCLA co-authors included first author Jason Stein, Derrek Hibar, Rudy Senstad, Neda Jahanshad, Arthur Toga, Rita Cantor, Dr. Nelson Freimer, Roel Ophoff, Kristy Hwang, Dr. Liana Apostolova and Dr. Giovanni Coppola.

The UCLA Department of Neurology, with over 100 faculty members, encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer’s disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks in the top two among its peers nationwide in National Institutes of Health funding.

Bart Weimer, Hao Zhang will co-direct world’s largest genome sequencing organization.

Bart Weimer, UC Davis

Bart Weimer, a professor in the Department of Population Health and Reproduction in the UC Davis School of Veterinary Medicine, and Hao Zhang, chief operating officer of BGI Americas, have been appointed co-directors of BGI@UCDavis, a partnership between UC Davis and BGI, the world’s largest genome sequencing organization.

Weimer and Zhang will be responsible for the day-to-day operations of the center, to be located on UC Davis’ Sacramento campus.

“Professor Weimer brings a wide range of experience both in genomic science and industry partnerships to this role. This exciting joint venture will benefit greatly from his leadership,” said Harris Lewin, vice chancellor for research at UC Davis.

The center will be managed by a steering committee, of which Weimer and Zhang will be members, and a governance committee. The two committees will include both UC Davis and BGI personnel, consistent with the closely collaborative nature of this partnership.

The co-directors will also act as liaisons to their respective institutions to develop projects and look for opportunities to bring BGI’s capabilities to bear on scientific problems and challenges in areas including human and animal health, agriculture and the environment.

Weimer joined the faculty at UC Davis in 2008 from Utah State University, where he was director of the Center for Integrated BioSystems, which provided core biotechnology services to the campus and conducted genomic science research. He earned his bachelor’s degree from the University of Arizona and his Ph.D. from Utah State, and completed postdoctoral training at the University of Melbourne, Australia. He has worked in both academia and the private sector, including three startup companies based on technology developed in his lab.

In his research, Weimer uses functional genomic techniques to study microbial systems biology, especially of bacteria that can cause foodborne illness.

Zhang was born and educated in China. After he received his bachelor’s degree from Peking University, he moved to the U.S., where he earned his Ph.D. degree from The Ohio State University in 2007. He joined Cambridge, Mass.-based BGI Americas in 2010 as an application biologist before becoming the organization’s chief operating officer. As co-director of BGI, he will be based in Sacramento.

Through BGI, campus researchers will have access to the capabilities and expertise of one of the world’s premier genomics and bioinformatics institutes, while BGI researchers will have the ability to collaborate with UC Davis researchers, thereby benefiting from the university’s diverse resources and expertise, especially in biology, medical sciences, agriculture, the environment and education.

An interim facility with three DNA sequencing machines began operations in renovated space on the Sacramento campus at the end of 2011. The eventual facility, once completed, will house up to 20 such machines. Renovation and construction of the new facility should be complete by end 2012.

About UC Davis

For more than 100 years, UC Davis has engaged in teaching, research and public service that matter to California and transform the world. Located close to the state capital, UC Davis has more than 32,000 students, more than 2,500 faculty and more than 21,000 staff, an annual research budget that exceeds $684 million, a comprehensive health system and 13 specialized research centers. The university offers interdisciplinary graduate study and more than 100 undergraduate majors in four colleges — Agricultural and Environmental Sciences, Biological Sciences, Engineering, and Letters and Science. It also houses six professional schools — Education, Law, Management, Medicine, Veterinary Medicine and the Betty Irene Moore School of Nursing.

New technique reveals another piece of spectrum’s genetic architecture.

Daniel Geschwind, UCLA

There is little argument among experts that autism spectrum disorders (ASD), complex developmental disabilities that vary widely in their severity, are caused by both genetic and environmental factors. Advances in genome sequencing now permit scientists to uncover specific mutations in DNA that are associated with ASD at unprecedented resolution. Such data are vital to understanding the genetic basis of the disorder.

A new study co-authored by UCLA researchers has led to a better understanding of the genetic contribution to autism using this new approach. By comparing siblings with and without ASD, the researchers have discovered a single instance in the affected siblings in which two independent mutations disrupt a gene called SCN2A.

Reporting in today’s (April 4) edition of the journal Nature, Dr. Daniel Geschwind, a UCLA professor of neurology and psychiatry, and colleagues from Yale University, Carnegie Mellon University and the University of Pittsburgh completed “whole-exome sequencing” of 238 parent-child quartets. A quartet is defined as two parents and one child without ASD and one child with ASD.

Instead of the time-consuming process of searching the entire genome of an individual, the researchers turned to the newer technology of whole-exome sequencing, which searches only the protein-coding regions of the genome to pinpoint the mutation that causes a particular disorder.

The researchers compared mutation rates between unaffected individuals and those with ASD within a family, then compared the ASD mutations to the entire cohort. They found multiple variations between the unaffected and affected groups. Specifically, among a total of 279 coding mutations, they identified a single instance in individual children with ASD — and not in siblings — in which two independent mutations disrupt the gene SCN2A. That same mutation was found in all the unrelated children with ASD, confirming its importance.

In addition, the researchers found many other genes with similar mutations occurring only once — these also make promising new candidates for autism susceptibility. Finally, they were able to estimate that there are likely about 1,000 or more genes that contribute to autism risk.

“This work demonstrates that autism, in most cases, has a contribution from several genes, as the average risk imparted by one mutation is typically not sufficient,” said Geschwind, who holds UCLA’s Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and directs the UCLA Center for Autism Research and Treatment. “Overall, these results substantially clarify the genomic architecture of ASD, and this is an important step in attempting to better understand the genetic basis of these disorders.”

A complete list of contributing authors and institutions is available in the Nature paper. Funding was provided by the Simons Foundation.

Autism is a complex brain disorder that strikes in early childhood. The condition disrupts a child’s ability to communicate and develop social relationships and is often accompanied by acute behavioral challenges. Autism spectrum disorders are diagnosed in one in 110 children in the United States, affecting four times as many boys as girls. Diagnoses have expanded tenfold in the last decade.

The UCLA Center for Autism Research and Treatment provides diagnosis, family counseling, clinical trials and treatment for patients with autism. UCLA is one of eight centers in the National Institutes of Health-funded Studies to Advance Autism Research and Treatment network and one of 10 original Collaborative Programs for Excellence in Autism.

Findings suggest that susceptibility to PTSD is inherited, pointing to new ways of screening for and treating the disorder.

Armen Goenjian, UCLA

Why do some people experience post-traumatic stress disorder (PTSD) while others who suffered the same ordeal do not? A new UCLA study may shed light on the answer.

UCLA scientists have linked two genes involved in serotonin production to a higher risk of developing PTSD. Published in the April 3 online edition of the Journal of Affective Disorders, the findings suggest that susceptibility to PTSD is inherited, pointing to new ways of screening for and treating the disorder.

“People can develop post-traumatic stress disorder after surviving a life-threatening ordeal like war, rape or a natural disaster,” said lead author Dr. Armen Goenjian, a research professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA. “If confirmed, our findings could eventually lead to new ways to screen people at risk for PTSD and target specific medicines for preventing and treating the disorder.”

PTSD can arise following child abuse, terrorist attacks, sexual or physical assault, major accidents, natural disasters or exposure to war or combat. Symptoms include flashbacks, feeling emotionally numb or hyper-alert to danger, and avoiding situations that remind one of the original trauma.

Goenjian and his colleagues extracted the DNA of 200 adults from several generations of 12 extended families who suffered PTSD symptoms after surviving the devastating 1988 earthquake in Armenia.

In studying the families’ genes, the researchers found that persons who possessed specific variants of two genes were more likely to develop PTSD symptoms. Called TPH1 and TPH2, these genes control the production of serotonin, a brain chemical that regulates mood, sleep and alertness — all of which are disrupted in PTSD.

“We suspect that the gene variants produce less serotonin, predisposing these family members to PTSD after exposure to violence or disaster,” Goenjian said. “Our next step will be to try and replicate the findings in a larger, more heterogeneous population.”

PTSD affects about 7 percent of Americans and has become a pressing health issue for a large percentage of war veterans returning from Iraq and Afghanistan. The UCLA team’s discovery could be used to help screen people who may be at risk for developing PTSD.

“A diagnostic tool based upon TPH1 and TPH2 could enable military leaders to identify soldiers who are at higher risk of developing PTSD and reassign their combat duties accordingly,” Goenjian said. “Our findings may also help scientists uncover alternative treatments for the disorder, such as gene therapy or new drugs that regulate the chemicals responsible for PTSD symptoms.”

According to Goenjian, pinpointing genes connected with PTSD symptoms will help neuroscientists classify the disorder based on brain biology instead of clinical observation. Psychiatrists currently rely on a trial-and-error approach to identify the best medication for controlling an individual patient’s symptoms.

Serotonin is the target of the popular antidepressants known as SSRIs, or selective serotonin re-uptake inhibitors, which prolong the effect of serotonin in the brain by slowing its absorption by brain cells. More physicians are prescribing SSRIs to treat psychiatric disease beyond depression, including PTSD and obsessive–compulsive disorder.

Goenjian’s co-authors included Julia Bailey, Alan Steinberg, Uma Dandekar and Dr. Ernest Noble, all of UCLA, and David Walling and Devon Schmidt of the Collaborative Neuroscience Network. No external grants supported the study.

The Semel Institute for Neuroscience and Human Behavior is an interdisciplinary research and education institute devoted to the understanding of complex human behavior, including the genetic, biological, behavioral and sociocultural underpinnings of normal behavior, and the causes and consequences of neuropsychiatric disorders. In addition to conducting fundamental research, the institute’s faculty seeks to develop effective strategies for the prevention and treatment of neurological, psychiatric and behavioral disorder, including improvement in access to mental health services and the shaping of national health policy.

Genetic atlas provides scientists with new tool for studying, explaining how the brain works.

The first atlas of the surface of the human brain based upon genetic information has been produced by a national team of scientists, led by researchers at the University of California, San Diego, School of Medicine and the VA San Diego Healthcare System. The work is published in Friday’s (March 30) issue of the journal Science.

The atlas reveals that the cerebral cortex — the sheet of neural tissue enveloping the brain — is roughly divided into genetic divisions that differ from other brain maps based on physiology or function. The genetic atlas provides scientists with a new tool for studying and explaining how the brain works, particularly the involvement of genes.

“Genetics are important to understanding all kinds of biological phenomena,” said William S. Kremen, Ph.D., professor of psychiatry at the UC San Diego School of Medicine and co-senior author with Anders M. Dale, Ph.D., professor of radiology, neurosciences and psychiatry, also at the UC San Diego School of Medicine.

According to Chi-Hua Chen, Ph.D., first author and a postdoctoral fellow in the UC San Diego Department of Psychiatry, “If we can understand the genetic underpinnings of the brain, we can get a better idea of how it develops and works, information we can then use to ultimately improve treatments for diseases and disorders.”

The human cerebral cortex, characterized by distinctive twisting folds and fissures called sulci, is just 0.08 to 0.16 inches thick, but contains multiple layers of interconnected neurons with key roles in memory, attention, language, cognition and consciousness.

Other atlases have mapped the brain by cytoarchitecture — differences in tissues or function. The new map is based entirely upon genetic information derived from magnetic resonance imaging (MRI) of 406 adult twins participating in the Vietnam Era Twin Registry (VETSA), an ongoing longitudinal study of cognitive aging supported in part by grants from the National Institutes of Health (NIH). It follows a related study published last year by Kremen, Dale and colleagues that affirmed the human cortical regionalization is similar to and consistent with patterns found in other mammals, evidence of a common conservation mechanism in evolution.

“We are excited by the development of this new atlas, which we hope will help us understand aging-related changes in brain structure and cognitive function now occurring in the VETSA participants,” said Jonathan W. King, Ph.D.,  of the National Institute on Aging, part of the NIH.

The atlas plots genetic correlations between different points on the cortical surface of the twins’ brains. The correlations represent shared genetic influences and reveal that genetic brain divisions do not map one-to-one with traditional brain divisions that are based on structure and function. “Yet, the pattern of this genetic map still suggests that it is neuroanatomically meaningful,” said Kremen.

Kremen said the genetic brain atlas may be especially useful for scientists who employ genome-wide association studies, a relatively new tool that looks for common genetic variants in people that may be associated with a particular trait, condition or disease.

Co-authors of the study are Wes Thompson, Matthew S. Panizzon, UC San Diego Department of Psychiatry; E.D. Gutierrez, UC San Diego Department of Cognitive Science; Terry L. Jernigan, UC San Diego departments of Psychiatry and Cognitive Science; Lisa T. Eyler and Amy J. Jak, UC San Diego Department of Psychiatry and VA San Diego Healthcare System; Christine Fennema-Notestine, UC San Diego departments of Psychiatry and Radiology; Michael C. Neale, Virginia Commonwealth University; Carol E. Franz, UC San Diego Department of Psychiatry and UC San Diego Center for Behavioral Genomics; Michael J. Lyons and Michael D. Grant, Boston University; Bruce Fischl, Harvard Medical School and Massachusetts General Hospital; Larry J. Seidman, Harvard Medical School; and Ming T. Tsuang, UC San Diego Department of Psychiatry, VA San Diego Healthcare System, UC San Diego Center for Behavioral Genomics.

In addition to the NIH, funding for this research came from the VA San Diego Center of Excellence for Stress and Mental Health. VETSA is also supported by the VA Cooperative Studies Program.

Disclosure: Anders M. Dale is a founder and equity-holder in CorTechs Laboratories Inc. and serves on its Scientific Advisory Board.