A World-Renowned Breast Cancer Geneticist Tackles the Genetics of Serious Mental Illness
From The Quarterly, Spring 2014
In 2006, Mary-Claire King, Ph.D., one of the world’s most well-respected geneticists, was awarded a NARSAD Distinguished Investigator Grant to work on schizophrenia genetics.
“I became involved when James Watson, Ph.D. [Nobel laureate for his work with colleagues in discovering the double helix structure of DNA, life’s genetic code book] and Connie and Steve Lieber [President Emerita and Chairman of the Board, Brain & Behavior Research Foundation] asked me to turn my attention to the problem of serious mental illness,” she recalls. It made sense, she says, “because I’m a geneticist, and geneticists have tools to ask important questions about complex illnesses.”
In her early work, beginning in the early 1970s, Dr. King began asking important questions about breast cancer genetics. After 17 years of great persistence, she proved that a specific genetic mutation, passed down from generation to generation, accounted for an important percentage of breast and ovarian cancers. The mutated gene was named BRCA1; another, called BRCA2, was found later. Women who possess a mutated version of either gene have a significantly higher risk of developing breast cancer.
For the past eight years, Dr. King and her team have been bringing their expertise to advance the understanding of genetics in schizophrenia. Like cancer, the causes and pathology of mental illness are highly complex. And like cancer, in addition to inherited genetic risk factors, environmental exposures can play a role in causation. Dr. King is interested in the genetic component of causation. She and her colleagues aim to pinpoint the kinds of genetic mutations that cause pathologies associated with schizophrenia; identify the biological consequences of these mutations at the level of cells and the entire brain; and use this knowledge to inform the development of new targeted treatments.
DECIPHERING GENETIC VARIATIONS
When a sperm fertilizes an egg, a mother and father’s genetic material combines to form the DNA of a new individual. In addition to the parental genetic material, during the process of fertilization a tiny percentage of new genetic variations occur and become a part of the baby’s DNA. Thus, there is a constant stream of new mutations being introduced into human genetic material. These mutations, known as de novo mutations because they do not occur in either parent, account for approximately 175 DNA “letters” per person, per generation. (DNA is made up of four letters, or chemical bases, that combine in various ways to spell out the full genome.) Of the human genome’s three billion letters, most variations “are biologically neutral; they have no effect on our lives at all,” says Dr. King.
“The question becomes,” explains Dr. King, “where do these new mutations happen, in what genes, and which ones among them actually matter?” Dr. King says that de novo mutations might help explain one of the deepest mysteries about schizophrenia: its persistence in the human population. If people with schizophrenia have fewer children, why does the occurrence rate of schizophrenia not decline over time?
In her NARSAD Distinguished Investigator Grant project, Dr. King began work on schizophrenia by comparing the DNA of healthy people (“healthy controls”) with that of patients diagnosed with the illness. When they first started this work, the best technology available at the time enabled them to search for a rare kind of structural mutation of the genome called copy-number variations,* or CNVs. These are often large stretches of the genome that contain extra DNA or missing DNA.
THE FIRST IMPORTANT FINDINGS
Dr. King’s team found rare CNVs in both healthy people and in people with schizophrenia. But these mutations were three to four times more frequent in those with schizophrenia; they were even more likely in those who had severe, early-onset illness. The results, published in the journal Science in April, 2008, were powerful because a pattern emerged: the researchers were able to link specific rare CNVs with the interruption of genes that regulate functions known to be crucial in early brain development. Equally important, the researchers found that the genes being interrupted by the CNVs found in healthy people did not link to these developmental processes; in fact no particular pattern emerged from the impact of CNVs in the healthy controls.
In the past year, Dr. King and colleagues have repeated the experiment with a larger group and with much more advanced technology. Now their sample consists of DNA from entire families: “quad” sets, each with two unaffected parents and two children: one with schizophrenia, the other healthy. This made it possible to precisely study the de novo mutations. “We wanted to know, what are the new mutations occurring in these children with the illness, compared with their well siblings—mutations that neither parent has?”
Their results were published in Cell in August 2013, and again, the results were significant. “We sequenced the full genomes of all four family members in 105 families. The critical discovery: if you look only at mutations that are damaging––a minority of the total––and you ask whether there are more of these in patients, the answer is yes. Disproportionately, the mutations are found in genes affecting aspects of neurodevelopment.”
Dr. King's interpretation of the importance of these results and how they suggest a path toward new therapies of the future are discussed below.
Next Generation Therapies for Schizophrenia: From Specific Genetic Mutations to Targeting Repair Pathways
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.”