UCLA scientists have discovered that infants who possess a specific immune gene that too closely resembles their mothers' are more likely to develop schizophrenia later in life. Reported in the October issue of the American Journal of Human Genetics, the study suggests that the genetic match may increase fetal susceptibility to schizophrenia, particularly in females.
HLA-B is one of a family of genes called the human leukocyte antigen (HLA) complex, which helps the immune system distinguish the body's own proteins from those made by foreign invaders, such as viruses and bacteria. The developing fetus inherits one copy of the HLA-B gene from each parent.
"Our findings clearly suggest that schizophrenia risk rises, especially in daughters, when the child's HLA-B gene too closely matches its mother's," explained Christina Palmer, Ph.D, UCLA associate professor of psychiatry and human genetics and a researcher at the Semel Institute for Neuroscience and Human Behavior. "We don't know whether sons who match are not affected -- or are more affected and less likely to come to term."
In 2002, Palmer and her colleagues discovered that infants are twice as likely to develop schizophrenia later in life when they possess a cell protein called Rhesus (Rh) factor that their mothers lack. Later studies found that male babies were more vulnerable to the consequences of Rh incompatibility than female infants.
The UCLA team hypothesized that females must possess a different fetal risk factor that predisposes them to schizophrenia. They decided to focus on HLA-B, which previous studies had linked to prenatal complications, like preeclampsia and low birth weight, that in turn have been associated with schizophrenia.
The researchers studied a group of 274 Finnish families in which at least one child had been diagnosed with schizophrenia or a related psychosis. In this group, 484 offspring had been diagnosed with the disease.
The scientists drew blood samples from everyone and performed DNA analysis, identifying cases in which children's HLA-B genes closely matched their mothers'.
Analysis of the entire sample revealed that daughters whose HLA-B genes matched their mothers' were 1.7 times more likely to develop schizophrenia than children who don't match their mothers'. If this risk could be removed, the researchers calculated that up to 12 percent of the cases of schizophrenia in daughters could be prevented.
"Our findings point out a paradox in pregnancy," said Palmer. "Why doesn't the mother's immune system reject her fetus when it inherits a copy of the HLA gene from the father that substantially differs from hers?
"It seems pretty clear that it's a good thing for the HLA genes of a mother and her fetus to not match," she added. "We suspect that HLA-matching increases a woman's susceptibility to pregnancy complications, which in turn predispose her child to schizophrenia. This is one more piece in the puzzle of identifying genetic markers for the disease."
The UCLA findings will enhance scientists' ability to detect genes that promote adverse prenatal conditions and deepen understanding of how these genes and the prenatal environment act separately and together to increase vulnerability to schizophrenia.
"In the future, we also may be able to produce tailored risk assessments for individuals with personal or family histories of schizophrenia," said Palmer.
Palmer's co-authors included Hsin-Ju Hsieh, Elaine Reed and Janet Sinsheimer of UCLA; J. Arthur Woodward of UC Merced; and Jouko Lonnqvist and Leena Peltonen from the National Public Health Institute and the Department of Medical Genetics at the University of Helsinki. The National Institute of Mental Health, Center of Excellence in Disease Genetics of the Academy of Finland and Helsinki-based Biocentrum funded 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 faculty seeks to develop effective treatments for neurological and psychiatric disorders, improve access to mental health services and shape national health policy regarding neuropsychiatric disorders. See http://www.