Or so it seems. In all three of the Nature studies, the common genetic variants most-strongly associated with schizophrenia risk are in the major histocompatibility region, home for a complex suite of linked HLA (human leukocyte antigen) genes that mediate immune responses to pathogens and other non-self tissues, as well as orchestrating aspects of neurodevelopment and neurological function.
What’s most curious about HLA genes is that they need not actually be inherited to exert profound effects on risk of neurological or other disease – for both autism (Johnson et al. 2009) and rheumatoid arthritis (which is strongly associated with schizophrenia via pleiotropy; Gorwood et al. 2004; Feitsma et al. 2007), disease risk due to HLA variants is a function of the mother’s genotype, not the genotype of the autistic or arthritic offspring. Such so-called maternal effects appear to be mediated by immunological and developmental interactions during pregnancy, such that the non-inherited maternal allele or haplotype exerts profound influences on development of the fetal brain and immune system. What’s worse, such non-inherited maternal haplotypes are expected, under basic evolutionary theory, to benefit from lower maternal investment (or miscarriage) for a given offspring, to which they arede facto unrelated (Haig 2004). You may literally be autistic or insane, or undernourished in utero, due to your mother’s rogue genes and not your own.
Feitsma AL, Worthington J, van der Helm-van Mil AH, et al. 2007. Protective effect of noninherited maternal HLA-DR antigens on rheumatoid arthritis development. Proc Natl Acad Sci U S A. 104:19966-70.
Gorwood P, Pouchot J, Vinceneux P, et al. 2004. Rheumatoid arthritis and schizophrenia: a negative association at a dimensional level. Schizophr Res. 66:21-9.
Haig, D. 2004. Evolutionary conflicts in pregnancy and calcium metabolism–a review. Placenta 25 Suppl A:S10-5.
Johnson WG, Buyske S, Mars AE, et al. 2009 HLA-DR4 as a risk allele for autism acting in mothers of probands possibly during pregnancy. Arch Pediatr Adolesc Med. 163:542-6.
Shi J, Levinson DF, Duan J, et al. 2009. Common variants on chromosome 6p22.1 are associated with schizophrenia.
Nature (in press).
Stefansson H, Ophoff RA, Steinberg S et al. 2009. Common variants conferring risk of schizophrenia. Nature (in press).