"Previous studies reported a link between mothers and infants who are Rh-incompatible and a higher rate of schizophrenia in the children later in life," said Dr. Christina Palmer, a research scientist at the UCLA Neuropsychiatric Institute. "Our research is the first to take a genetic approach to examining this increased risk."
Rh factor is a protein that sits on the surface of each red blood cell. A person is Rh-positive when Rh factor is present and Rh-negative when Rh factor is not. The gene that codes for the Rh protein is called Rhesus D factor (RHD).
When a pregnant woman is Rh-negative and her fetus is Rh-positive, her immune system can attack the child's red blood cells. This deprives the brain of oxygen and can cause jaundice.
"In heavy doses, oxygen deprivation and jaundice can cause serious brain damage," said Palmer, an assistant professor-in-residence of psychiatry and biobehavioral sciences. "Even more subtle consequences may set the stage for abnormal brain development and schizophrenia down the road."
In 1970 a prophylactic injection became available for Rh-negative pregnant women whose Rh factors did not match their fetuses'. Now widely used, the drug prevents women's immune systems from destroying their babies' red blood cells.
Still, a large number of Rh-incompatible children living today were born before prophylaxis was available. The UCLA team decided to conduct the first gene-based study of whether Rh incompatibility increased these children's susceptibility to schizophrenia. Prior research on this topic had been limited to birth records. "Many studies have shown that mothers of children who develop schizophrenia experience a higher rate of fetal distress and obstetric complications," Palmer said. "We hypothesized that stressors produced by Rh incompatibility in the prenatal environment -- such as oxygen deficiency to the brain -- could predispose a child for schizophrenia later in life."
To test their theory, the UCLA team collaborated with Dr. Leena Peltonen, UCLA professor of human genetics. She mapped out the genetic make-up of 181 Finnish families in which at least one family member had been diagnosed with schizophrenia. Except for three cases, all of the children in the sample were born before the introduction of prophylaxis in 1970.
Dr. Janet Sinsheimer, UCLA associate professor of human genetics and biomathematics, created a new statistical test to determine if maternal-fetal Rh incompatibility increased the likelihood of schizophrenia. UCLA colleagues Palmer, Sonia Minassian and J. Arthur Woodward used the test to scrutinize the chromosomal location of RHD and analyzed the gene's data from the Finnish subjects' DNA.
Palmer and her colleagues discovered that when a mother is Rh-negative and her fetus is Rh-positive, the child is more than twice as likely to develop schizophrenia than infants born from different maternal-fetal Rh combinations.
"We found evidence that the Rh-positive children of Rh-negative mothers possess more than double the risk for developing schizophrenia later in life," Palmer said. "This suggests that the RHD gene is a risk factor for this mental disorder."
"The next important step will be to look at Rh incompatibility in people born after 1970 to test whether prophylaxis has reduced their risk of schizophrenia."
A board-certified genetic counselor, Palmer emphasizes that the UCLA findings should not panic mothers who don't share Rh compatibility with their children. "A two-fold increase is no cause for alarm," she said. "Schizophrenia is a complex disorder that likely stems from a combination of several genetic and environmental factors. It is doubtful that Rh incompatibility alone causes the disorder."
She encouraged Rh-negative women to take advantage of Rh-incompatibility prophylaxis, receive good prenatal care and review their family histories for schizophrenia.
Schizophrenia is a disabling brain disease that afflicts 1 percent of the worldwide population and more than 2 million Americans. Palmer estimates that Rh incompatibility accounts for about 4 percent of these cases. People with schizophrenia may suffer from hallucinations, delusions, disordered thinking and loss of emotional affect. Medication can treat certain symptoms, but less than one in five people completely recovers from the disorder.
The National Institute of Mental Health funded the UCLA study. In addition to the UCLA team, Palmer's co-authors included Joni Turunen, Tiina Paunio and Jouko Lonnqvist.
The UCLA Neuropsychiatric Institute is an interdisciplinary research and educational 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.
Journal
American Journal of Human Genetics