Blaming your mother’s genes

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).

Saving the Autistic Mouse – with Schizophrenia

Mouse ‘models’ for psychiatric disorders, strains of mice genetically engineered by ‘knocking out’ a specific gene that mediates expression of the disorder, provide invaluable information regarding the genetic, developmental, physiological, and neurological causes of mental diseases in humans.  One of the first mouse models relevant to autism was generated via knockout of a gene called FMR1, whose loss of function in humans causes an autistic spectrum condition called Fragile X syndrome (Kooy et al. 1996; Hagerman et al. 2009).

Amazingly, such mice can now be ‘rescued’ – that is – restored to essentially normal function for cognitive tasks that were formerly much impaired, via treatment with drugs that down-regulate one of their brain receptors for glutamate, called mGLUR5 (Dölen et al. 2007; Hagerman et al. 2009).  Fragile X mice can also be rescued by knocking out one copy of the actual gene that codes for mGLUR5, which reduces the brain’s production of this receptor and thus mimics the impact of pharmaceutical treatment (Dölen et al. 2007). (more…)

The Dawn of Darwinian Psychopharmacology

We usually consider medicine as a predictive scientific endeavor, as methodical in application as noble in purpose.  But for some diseases, such as schizophrenia, the first treatments showing any effectiveness, including lithium, chlorpromazine, and even electroconvulsive therapy, were discovered entirely by accident.  After the discovery of the first antipsychotic treatments, a period of allegedly rational schizophrenia drug development ensued, focusing on drugs that block the brain dopamine receptor DRD2 that was considered, based on very limited evidence, as the critical lock for chemical antipsychotic keys.  Some of the drugs worked – more or less, with serious side effects.  Truly rational drug development, however, required understanding of the causal basis of disease, which for brain diseases like schizophrenia requires, to a considerable extent, understanding the dark inner workings of the brain itself.

But the causal basis of one relatively-simple brain disease, Fragile X syndrome, has, in the past few months, been deciphered – a true milestone in the touted medical march from brain to computer, lab bench to bedside. Afflicting about 1 in 3000 children, Fragile X is the most-common known cause of both intellectual disability and autism.  A series of studies, led by researchers including Gul Dölen and Mark Bear at MIT (Dölen and Bear 2008) and Randi Hagerman at UC Davis (Hagerman et al. 2009), has identified the core neuronal defect caused by mutation of the fragile X gene, and shown they can fix it – literally cure it (Figure 1) – in mice.  The fix involves (more…)

Chasing Darwin’s Dulcinea

Heredity is particulate, but development is unitary.  Everything in the organism is the result of the interactions of all genes, subject to the environment to which they are exposed.

T. Dobzhansky 1961, p. 111

The chief analytical ultimacy in the new life sciences enterprise is represented by the capability of shifting scientific reduction to the smallest relevant molecular level for understanding life.

R. D. Alexander, 2008

I have no doubt that in reality the future will be vastly more surprising than anything I can imagine. Now my own suspicion is that the universe is not only queerer than we suppose, but queerer than we can suppose.

J. B. S. Haldane, 1927, p. 286

Kenneth Weiss, in his deeply-scholarly review of recent progress in the genetics of diseases mediated by effects from many genes, suggests that researchers are stalking ever-smaller, more elusive genetic prey – variants slightly increasing risk of disease – with ever-more powerful technological and analytic weapons.  He reminds us that population-genetic theory from nearly a century ago predicted just such a multitude of infinitesimal, variable effects as we are now observing, and that more research efforts might be better deployed other places than genome scans with more genetic markers, cases and controls.

I agree, and suggest that we try spending more money and research effort on true evolutionary disease genetics.   True, in that we must draw tightly together, for the first time, two disparate fields: (1) the study of the molecular and phenotypic selective pressures that have given rise to modern humans, (2) the study of the genetic and environmental underpinnings of polygenic disease. Disease risk, like our other traits, has evolved, but you would hardly know it from reading the pages of American Journal of Medical Genetics, Molecular Psychiatry, or other disease-genetic journals whose authors either ignore evolutionary principles or view them with deep suspicion as untestable speculation. Positive selection, antagonistic pleiotropy, and intragenomic conflicts are all expected to generate pervasive effects on disease risk but are virtually unexplored – as are, we must admit, the workings of the genome itself.  The genome’s machinations will surely turn out to be queerer than we can now imagine, but we must still try to reduce their vast complexities, by attacking with not just more nucleotide data at the bottom, but also with evolutionary concepts and methods across all levels from DNA to development, physiology, morphology and cognition.  A Darwin’s Dulcinea can be seen to embody love of this evolutionary venture, to understand our evolved selves, and our malaises, from single nucleotide polymorphism to brain.  Is this quest hopeless? If so, ultimately, nothing will make sense.

Alexander, R. D.  (2008) On ultimacy in the life sciences.  Unpublished Essay.

Dobzhansky, T. (1961) In: J. S. Kennedy (Ed.). Insect Polymorphism. London: Royal Entomological Society.

Haldane, J. B. S. (1927) Possible Worlds and Other Papers.

Chatto and Windus: London, 1932, reprint.

Behind Blue Eyes

Eye color phenotypes  (from Eiburg et al. 2008)

Perhaps the main lesson we eventually learn in school is how little we actually know. In elementary genetics, we were taught that there are two alleles for eye color, blue and brown, with brown dominant, allowing simple assessment of whether we were more likely fathered by dad or the mailman. In these simple Mendelian days, eye color was not considered to be a focus for natural selection, except perhaps in the context of an associated trait, pale skin, being favored to help accrue vitamin D in the high, dark latitudes of northern Europe. Only over the past few months has a series of publications begun to reveal the true complexities of human eye-color genetics, genomics, selection and evolution. In the context of tantalizing data linking eye color to social behavior, rather than just skin and hair color, these studies show that the metaphor of eyes as windows to souls may be more than poetic. (more…)