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Archive - Aug 17, 2013

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Genome Study Assesses Genetic Overlaps Between Major Mental Disorders

The largest genome-wide study of its kind has determined how much five major mental illnesses are traceable to the same common inherited genetic variations. Researchers, funded in part by the National Institutes of Health, found that the overlap was highest between schizophrenia and bipolar disorder; moderate for bipolar disorder and depression and for ADHD and depression; and low for schizophrenia and autism. Overall, common genetic variation accounted for 17-28 percent of risk for the illnesses. "Since our study only looked at common gene variants, the total genetic overlap between the disorders is likely higher," explained Naomi Wray, Ph.D., University of Queensland, Brisbane, Australia, who co-led the multi-site study by the Cross Disorders Group of the Psychiatric Genomics Consortium (PGC), which is supported by the NIH's National Institute of Mental Health (NIMH). "Shared variants with smaller effects, rare variants, mutations, duplications, deletions, and gene-environment interactions also contribute to these illnesses." Dr. Wray, Kenneth Kendler, M.D., of Virginia Commonwealth University, Richmond, Jordan Smoller, M.D., of Massachusetts General Hospital, Boston, and other members of the PGC group report on their findings online on August 11, 2013 in the journal Nature Genetics. "Such evidence quantifying shared genetic risk factors among traditional psychiatric diagnoses will help us move toward classification that will be more faithful to nature," said Bruce Cuthbert, Ph.D., director of the NIMH Division of Adult Translational Research and Treatment Development and coordinator of the Institute's Research Domain Criteria (RDoC) project, which is developing a mental disorders classification system for research based more on underlying causes.

Elimination of Cilia Suppresses Cyst Growth in Models of Polycystic Kidney Disease (PKD)

A study by Yale researchers and colleagues has uncovered a new and unexpected molecular mechanism in the development of polycystic kidney disease (PKD). The study was published online on July 28, 2013 in Nature Genetics. PKD is a life-threatening genetic disorder that causes multiple cysts to form on the kidneys — enlarging them, cutting off proper urine flow, and causing kidney failure in half of affected people by age 60. It affects more than 12 million people worldwide. Cilia are the hair-like structures on the surface of many human cells that can either move things along – dirt out of the lungs, or an egg from the ovary to the uterus – or sense the environment, such as vision in the retina or smell in the nose. Recent research has implicated defects in the sensory cilia — often caused by genetic mutations — in many human diseases, including cancer, cardiac disease, blindness, and kidney disease. In the kidney, disruption of sensory cilia can cause kidney cysts. The polycystin-1 and polycystin-2 (also known as PC1 and PC2) proteins are key players in the normal functioning of the kidneys. Earlier research has shown that when either if these proteins is lost or mutated, cysts grow in the kidneys and cause almost all cases of autosomal dominant PKD (ADPKD) in humans. Working in mice, the Yale team and colleagues found that cysts grew when the cilia were intact but lacked polycystin protein — but, surprisingly, cysts stopped growing despite the absence of polycystins when the cilia were disrupted or eliminated. The activity of this pathway, and the timing of the loss of polycystin proteins and the cilia, determined the severity of both early- and adult-onset PKD, the researchers found.

Chemical Reverses Effects of Parkinson's-Disease Mutation in Cells

University of California-San Francisco (UCSF) scientists working in the lab used a chemical found in an anti-wrinkle cream to prevent the death of nerve cells damaged by mutations that cause an inherited form of Parkinson’s disease. A similar approach might ward off cell death in the brains of people afflicted with Parkinson’s disease, the team suggested in a study reported in the August 15, 2013 issue of the journal Cell. The achievement marks a pharmacologic milestone as the first highly specific targeting of a member of an important class of enzymes called kinases to increase rather than to inhibit their activity, according to UCSF chemist Kevan Shokat, Ph.D., the senior scientist on the study. The research raises hope that similar pharmaceutical strategies might be used for combating other diseases, including diabetes and cancer, he said. Mutations that cause malfunction of the targeted enzyme, PINK1, are directly responsible for some cases of early-onset Parkinson’s disease. Loss of PINK1 activity is harmful to the cell’s power plants, called mitochondria, best known for converting food energy into another form of chemical energy used by cells, the molecule ATP. In Parkinson’s disease, poorly performing mitochondria have been associated with the death of dopamine-producing nerve cells in a region of the brain called the substantia nigra, which plays a major role in control of movement. Loss of these cells is a hallmark of Parkinson’s disease and the cause of prominent symptoms including rigidity and tremor. A UCSF team led by Dr. Shokat, a Howard Hughes Medical Institute Investigator, used the chemical, called kinetin, to increase mutant PINK1 enzyme activity in nerve cells to near normal levels.