From The Quarterly, Spring 2014

Mary-Claire King calls it her “Anna Karenina Hypothesis.” Just as Tolstoy observed that “every unhappy family is unhappy in its own way,” recent results that she and colleagues have obtained suggest that someone who sustains a potentially disease-causing de novo gene mutation is quite possibly the only person in the world with precisely that mutation.  

Incredible as this sounds, it is likely true. Dr. King describes this class of very rare disruptive mutations in her most recent schizophrenia study (published in Cell in 2013) as “essentially private mutations,” so specific are they to those who have them. “We found 55 affected people had 54 different disruptive mutations,” she says. That is, only 1 of the 55 was seen in more than one patient.

Does this mean that every person with schizophrenia caused by a new mutation will need a unique form of therapy to counter the mutated gene’s effects?

Almost certainly not, says Dr. King. “Many thousands of different loss-of-[biological]-function mutations* within the BRCA1 and BRCA2 genes have been identified,” she says. “At the level of individuals, all of these are rare, and each one confers substantially elevated risk for breast and ovarian cancer.” But all of these rare, “severe” mutations affect the same DNA repair pathway, she explains, which makes them targets for a single class of tailored medication (now in development).  

She strongly suspects there is an analogy with rare new mutations in schizophrenia that disrupt genes and may give rise to pathologies associated with the disease. “Of those 54 disruptive mutations I mentioned, 50 of them are components of a single network of genes that we were able to identify,” says Dr. King. “That network acts within the prefrontal cortex of the brain during late gestation. Activity in the network subsides after birth, but then increases again in late adolescence.”

These facts are a source of real hope. It may be true that new mutations are unique to each person, but the genes they are affecting “seem to feed into the same pathways, ones that are important as the brain develops and years later, around the time the behavioral symptoms of schizophrenia tend to emerge,” explains Dr. King. “Once we more fully understand the pathways into which these genes are merging, then wise neurobiologists and pharmacologists will be able to find entry points into them. This is how it has worked with the BRCA genes: knowing the genetics led pharmaceutical researchers to develop what are called PARP inhibitors,” which effectively treat the pathology caused by the BRCA mutations.

Dr. King predicts that “in the future there will be new classes of psychiatric medications; I think they will be pathway-defined; I think the pathways will be gene-defined, and the genes will be mutation-defined.”

Her lab’s current project is its most ambitious so far: looking at the DNA of every person recruited into a large NIMH-curated sample of schizophrenia patients and healthy controls. After fully sequencing 7,000 patient genomes and an equal number of controls, “we’ll be looking for genes and classes of genes affected by new mutations. The more we can find, the more we can contribute to knowledge about pathways, and thus bring us closer to pathway-specific medications.”