New study finds placenta health affects risk of schizophrenia
A team of researchers led by Drs. Gianluca Ursini and Daniel R. Weinberger found the placenta plays a key role for risk for schizophrenia and other neurodevelopmental disorders. In contrast to prior studies which focused on how genes related to behavioral disorders directly alter prenatal brain development, this novel research found that many genes associated with risk for schizophrenia appear to alter early brain development indirectly, by influencing the health of the placenta. Researchers also found evidence the placenta appears to be at least part of the explanation for the sex bias associated with these disorders.
This new scientific frontier, with far-reaching implications for maternal and child health, creates the possibility that scientists can more accurately predict who is at risk of mental illness, and develop strategies to prevent or lessen their occurrence by increasing the resiliency and health of the placenta. Nature Medicine, 2018.
A promising new treatment for a form of autism spectrum disorder
Dr. Brady Maher’s lab studied the TCF4 mutation in a rare form of autism called Pitt-Hopkins Syndrome to understand how the developing cortex is affected by this mutation. His group discovered that the SCN10a sodium channel was upregulated in expression in neurons having this mutation in both cell and animal models and that this is the basis of abnormal neuronal activity found in these models of this disorder. Reducing the abundance of this sodium channel either pharmacologically or by genetic manipulation rescued this physiological abnormality. Neuron, 2016.
We are working with a clinically approved drug that is well tolerated without adverse effects.This drug could be in a clinical trial for Pitt-Hopkins children within two years.
Genetic risk for schizophrenia implicates early life
The discovery of specific genetic factors that contribute to risk for mental disorders represent landmark milestones in the history of psychiatric research.
Using the RNA seq dataset in human brain created in LIBD, Andrew Jaffe and LIBD scientists have shown that the genes associated with risk for schizophrenia regulate specific patterns of gene expression in the developing brain, suggesting that these genes exert pathogenic effects at least in part during early life. Nature Neuroscience, 2015.
Environmental risk for schizophrenia implicates early life
Andrew Jaffe and his co-workers showed that the epigenetic changes associated both with genetic risk for schizophrenia and with the clinical state of having schizophrenia reflect environmental influences that operate principally in early life and not during adulthood around the time of clinical on set of the diagnosis.
This group of investigators also showed that the risk genes for schizophrenia are principally about how “methylated” the genes are, i.e. at least 60% of PGC Genome-wide Association Study (GWAS) loci are significant mEqtls. Nature Neuroscience, 2016
Patterns of RNA editing change across human brain development
The central dogma of biology is that a gene encodes a specific protein. Scientists at the Lieber Institute have discovered that the dogma can be violated after a gene is expressed with specific implications for brain development. RNA editing is increasingly recognized as a molecular mechanism regulating RNA activity and the recoding of proteins.
Lieber scientists reported the first detailed survey of RNA editing across the human genome in brain from prenatal life to old age. The Lieber Team headed by Joo Heon Shin identified three unique patterns of RNA editing across the lifespan: sites that are highly edited throughout life, some that are lowly edited throughout life, and some that show a dramatic pattern of increasing editing from early life to adult life. The increasing pattern has important implications for cortical function, particularly neuronal systems thought to be critical for memory and higher order thought.The developmentally increasing pattern also was disrupted in spinal cord injury and in brain tumors. These results provide new insight into the epitranscriptional regulation of sequence diversity and the modulation of cortical development after transcription. Nature Neuroscience, 2017.
Data Science/Computational Biology
A novel human unique protein is discovered as a risk factor for psychosis
Genetics studies of psychiatric disorders have identified many regions of the human genome where risk genes are found. Most of these regions contain several known genes, but which if any of them are critical for genetic risk is not always clear. Ming Li and colleagues at LIBD identified a previously unknown unique protein called AS3MT-d2d3 that accounts for one of the strongest links to genetic risk for schizophrenia as well as other psychiatric disorders and that is unique to human beings and dramatically turned on in early neuronal development.
The study, led by Director and CEO Daniel R. Weinberger, M.D., highlighted that genes accounting for significant GWAS loci cannot be identified by the physical location of the locus and requires molecular association studies likely in the human brain. This novel protein is being used in our drug development pipeline to find “druggable” targets that might undo the developmental influence of this pathogenic factor. Nature Medicine, 2016