THURSDAY, Aug. 9, 2018 — Evolutionary changes in the human brain may be responsible for psychiatric illnesses such as schizophrenia and bipolar disorder, new research suggests.
The researchers identified long, noncoding stretches of DNA (called “repeat arrays”) in a gene that governs calcium transport in the brain. Their findings were published Aug. 9 in the American Journal of Human Genetics.
“Changes in the structure and sequence of these nucleotide arrays likely contributed to changes in CACNA1C function during human evolution and may modulate neuropsychiatric disease risk in modern human populations,” senior author David Kingsley said in a journal news release. Kingsley is a professor of developmental biology at Stanford University in California.
The study authors suggested that the findings could lead to improved treatment for patients with schizophrenia and bipolar disorder, which affect about 3 percent of people worldwide.
Classifying patients based on their repeat arrays may help identify those most likely to respond to current calcium channel drugs, which so far have produced mixed results, Kingsley said.
He added that more research is needed to determine whether patients with a genetic variation of CACNA1C have too much or too little calcium channel activity.
The repeat arrays in the CACNA1C gene occur only in humans. Kingsley said that suggests the arrays may have given humans an evolutionary advantage, even if they increased the risk of conditions such as schizophrenia and bipolar disorder.
The U.S. National Institute of Mental Health has more on schizophrenia.
Posted: August 2018
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Researchers have recently begun to realize that biological sex plays a key role in disease risk. Sex plays a role in hypertension, diabetes, arthritis—and in many neurological and psychiatric disorders. Depression and anxiety affect females more, while neurodevelopmental disorders, including autism spectrum disorders, early onset schizophrenia, and attention deficit hyperactivity, affect more males. Males are also more sensitive to prenatal insults, such as gestational stress, maternal infection and drug exposure.
To better understand the molecular underpinnings of this disparity, Tracy Bale of the University of Maryland School of Medicine, along with several colleagues, focused on a molecule that plays a key role in placental health. In a study of mice, they found that the molecule, O-linked N-acetylglucosamine transferase (OGT) works by establishing sex-specific patterns of gene expression.
The study was published this week in the journal Nature Communications.
OGT seems to work via an epigenetic modification that broadly controls transcription, H3K27me3. Epigenetics is the study of changes in how genes are expressed. Dr. Bale showed that high levels of H3K27me3 in the female placenta produce resilience to stress experienced by the mother. This indicates at least one molecular pathway that allows females to be more resilient to maternal stress than males.
“This pathway could help explain why we see this profound neurodevelopmental difference in humans,” said Dr. Bale. “OGT and H3K27me3 in the placenta are crucial to a lot of protein encoding that occurs during pregnancy, and so this process has a lot of downstream effects. The OGT gene is on the X chromosome, and seems to provide a level of protection for the female fetus to perturbations in the maternal environment.”
Dr. Bale has focused much of her research on the links between stress and subsequent risk for neurodevelopmental disorders, including autism and schizophrenia in offspring. Her previous work on the placenta has found novel sex differences that may predict increased prenatal risk for disease in males.
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