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Maternal-Fetal HLA-B Genotype Match May Increase Risk of Schizophrenia

7 September 2006. Being too much like your mother may be a risk factor for schizophrenia, at least as far as the immune system is concerned. In the October issue of the American Journal of Human Genetics, Christina Palmer and colleagues at the University of California, Los Angeles, and in Finland report that the risk for the disorder increases for offspring whose human leukocyte antigen (HLA)-B genotype too closely matches their mother’s.

The effect seems to be restricted to female offspring, who have a 1.7 times greater chance of developing schizophrenia spectrum disorders with HLA-B genotype similar to the maternal genotype. The authors suggest that this HLA genotype matching could increase risk indirectly, by contributing to pre- or perinatal insults that, in turn, disrupt normal brain development.

Back to the womb
The idea that the immune systems of mother and child could interact to increase the risk of schizophrenia has precedent. Palmer and her colleagues at UCLA, as well as other research groups, have reported that mismatches between maternal and fetal blood cell rhesus (Rh) status (Rh+ or Rh-) can increase risk of schizophrenia, particularly in male offspring (Hollister et al., 1996; Palmer et al., 2002; Insel et al., 2005). In cases of Rh incompatibility, antibodies from the mother’s immune system mount attacks on the fetus’s blood cells, potentially perturbing neurodevelopment.

In the case of HLA genes, the thinking is somewhat the opposite, that is, that it’s better for the mother and child to be mismatched. HLA proteins are found on cell surfaces, where they “present” antigens, typically bits of foreign substances to the immune system for inspection and possible mobilization. The HLA molecules themselves are antigens and signal to the immune system that a given cell is “self” and should not be attacked.

Strangely enough, in order for a successful implantation and healthy gestation to occur, it may be necessary for the mother’s immune system to be sensitized to (i.e., produce antibodies to) fetal HLA antigens derived from the paternal genes. This has been surmised from the observation that antibodies to fetal cells are commonly found in the maternal circulation. It is not clear why this would be useful, nor are the biological mechanisms understood, but there is evidence, albeit inconsistent, that when HLA genotypes are too similar between mother and offspring, there is an increased risk of complications such as preeclampsia, low birth weight, brain defects, and even fetal loss.

HLA genotype and schizophrenia risk
Given the well-documented association of pre- and perinatal insults with schizophrenia, Palmer and colleagues decided to examine the relationship between HLA genotype and the disorder. Of the many HLA genes found on chromosome 6 (near a locus implicated in schizophrenia linkage studies), they focused on HLA-A, -B, and -DRB1. “HLA genotyping is expensive and tricky to perform. We focused on these three genes specifically because they have been associated in the past in some studies with prenatal complications, schizophrenia, or both,” Palmer told SRF.

The researchers genotyped 274 families, with 484 offspring diagnosed with schizophrenia (n = 372), schizoaffective psychosis disorder (n = 70), or schizophrenia spectrum disorder (n = 42). They first looked at the HLA genotypes of the parents and children for evidence of a risk allele acting only through the child's genotype to increase susceptibility to schizophrenia, but found no statistically significant evidence in either linkage or association testing.

They then turned their attention to different combinations of maternal and fetal genotype. A potential hurdle for Palmer and colleagues would seem to be that HLA genes are wealthy in polymorphisms—HLA-B, for example, was reported to have the highest number of polymorphisms in the human genome (Mungall et al., 2003). However, subsets of the HLA alleles are functionally “identical,” allowing the authors to group them together as single “alleles.”

The researchers found a significantly increased risk of schizophrenia for matched maternal-fetal HLA-B genotype (x2 = 9.1, 2df; P = .01), but not for HLA-A or -DRB1. The relative risk for female offspring was 1.7 (95 percent CI 1.22–2.49), and for male offspring 1.1 (95 percent CI 0.76–1.6).

Although the biological mechanisms whereby matched maternal-fetal HLA genotype could contribute to disease is unknown, there is precedent for studying maternal-fetal HLA status in neurodevelopmental disorders: a link has been reported between maternal-fetal HLA matching and risk of autism (Stubbs et al., 1985). “[B]ecause HLA matching has been found in some studies to increase the risk of prenatal complications, the presence of an HLA-B [maternal fetal genotype] matching effect suggests that susceptibility to schizophrenia may be increased by an adverse prenatal environment, because the matching effect could be associated with pregnancy complications rather than with schizophrenia per se,” Palmer and colleagues write.

The source of the gender differences is not clear, but the authors note research indicating that male fetuses may be more vulnerable to preeclampsia, a complication that has been linked to HLA-B matching. “Thus, the effects of preeclampsia on schizophrenia may be more likely to be observed among females because fewer males are likely to survive the effects of preeclampsia,” the authors write.—Hakon Heimer.

Palmer CGS, Hsieh H-J, Reed EF, Lonnqvist J, Peltonen L, Woodward JA, Sinsheimer JS. HLA-B Maternal-Fetal Genotype Matching Increases Risk of Schizophrenia. Am J Hum Genet 79(4):710-16.

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