Perhaps the darkest years of psychiatry spanned the 1950s and 60s, when Bruno Bettelheim’s ‘refridgerator mother’ model for autism clenched the minds of public and clinician alike in its grip of ‘psychogenic’ causation – and the souls of mothers in guilt-ridden anguish. For nearly a generation, cold, distant and inadequate mothering was blamed, until a new focus on the diametric opposite basis for causation – genetics – slowly emerged in the 1970s and 80s with the new era of molecular biology. Bad mothers were replaced by mutations and bad genes – the fault of chance and Mendel, but it has taken over 25 years to develop the molecular-genetic technology to effectively pursue the culprits.
The past several years, and the next few, will in long perspective be seen as historic for psychiatric genetics.For the first time we can genotype virtually the entire genome, for huge samples of psychiatric cases and controls, and inexorably zero in on risk alleles and haplotypes. The last week has seen a key milestone reached: a set of three studies in Nature (ISC 2009; Shi et al. 2009; Stefansson et al. 2009) that provide the first incontrovertible, large-scale evidence that common polygenic variation contributes substantially to the risk of bipolar disorder and schizophrenia. Comparable studies of autism will be close behind, such that we should soon be able to take your genome from a cheek swab – should you be autistic, schizophrenic, or bipolar – and with some confidance or probability find the Maxwellian genetic demons responsible for your atypical cortex, mid-brain and hypothalamus, and the deep loneliness or hallucinated voices.
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.
These considerations should not be so surprising in the context of autism and schizophrenia as neurodevelopmental disorders, given that much, if not most, of crucial large-scale variation among humans in neuroanatomy and function is complete by birth. You can blame your mother’s genes, but it will be more important to genotype and understand them.
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.
International Schizophrenia Consortium, 2009. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature (in press).
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).