20 Aug 2015
In SRF's five-part 2015 schizophrenia genetics update, reporter Michele Solis surveys leaders in the field about milestones, challenges, and current research.
August 21, 2015. As the genetic risk factors underlying schizophrenia come into focus, the findings blur the categories of mental illness. All types of genetic risk factors for schizophrenia—from common single nucleotide polymorphisms (SNPs) to rare copy number variants—include variants that boost risk for other disorders, too. These shared genetic roots do not surprise most researchers.
"Genes don't know about psychiatric diagnoses; they know about development and function of the brain," says Daniel Weinberger of the Lieber Institute for Brain Development in Baltimore, Maryland. "The more we can understand our categories of mental illness in terms of how a brain develops, the more we'll understand what these genes mean to mental illness."
In order to explain how to get from a gene-induced vulnerability for mental illness in general to a specific diagnosis such as schizophrenia, researchers will need to consider how different genetic variants combine to build risk. To complicate things, they will need to consider the environment, a sector of risk that teems with so many unknowns that most are content to wrestle with purely genetic puzzles. But the shared genetics undoubtedly point to shared biology and so argue for conceptualizing psychiatric disorders in terms of their disrupted brain processes rather than their observable symptoms. This means grappling again with the nature of schizophrenia by using tools such as brain imaging or in-depth cognitive testing. Any core phenotypes that come to light, in turn, can be marshaled in the hunt for more genes.
"We need to start honing down and refining our phenotypes to really find the remainder of the genes, or even to understand the genes that have been found," said Anil Malhotra of Zucker Hillside Hospital in Glen Oaks, New York.
Carefully phenotyping thousands of people is expensive and time consuming but worth the trouble to some.
"I think with 5,000 subjects who are exquisitely well characterized, you can find out as much or more than other platforms where you have many more subjects but you really don't know much about them," said David Braff of the University of California, San Diego.
Although lumping cases of schizophrenia together without special consideration of their heterogeneous features has dominated the genetics field, Braff sees the two approaches as complementary. "Both strategies are valid. If one thing worked, we'd only be doing one thing, and we'd have resolved this."
Getting to schizophrenia
Overlaps occur among all flavors of genetic variation. For example, both chromosome 16p11.2 duplications and 15q13.3 deletions increase risk for schizophrenia, autism, and intellectual disability. Damaging point mutations found in schizophrenia, for example, in SCN2A and POGZ, are also linked to autism and intellectual disability (Fromer et al., 2014).
Common variants also predispose people to a range of psychiatric disorders. In 2013, the Psychiatric Genomics Consortium (PGC) published a cross-disorder genomewide association study (GWAS) which combined samples with schizophrenia, bipolar disorder, major depressive disorder, autism, and attention deficit-hyperactivity disorder (ADHD) (SRF related news report). Comparing this melting pot to controls revealed four regions containing generic vulnerability factors for mental illness, including genes important for calcium signaling.
Studying genetic signals across disorders can give a kind of taxonomy of mental illness. The greatest shared risk arose between schizophrenia and adult-onset disorders, in particular, bipolar disorder and major depressive disorder (see also SRF related news report).
"How much are these really the same disorders, schizophrenia and bipolar? We've been debating this for a hundred years, swinging back and forth," Kendler said. "This is an area that will need more clarification."
Variants shared by multiple disorders may set a common stage upon which disease-specific risk factors act. In the brain, this stage may take the form of a brain circuit sensitized to stress, for example, which could produce a cascade of ill effects on cognition and emotion regulation. Additional genetic or environmental risk factors may tilt a person toward a specific disorder. Alternatively, how well a brain can compensate for these risk factors may determine the resulting outcome. Another scenario includes modifiers, which by themselves do not impact risk for a disorder but instead influence the form that a risk factor takes.
Yet no one understands how these combine, especially with the unwieldy environment. Perinatal complications, urban birth, season of birth, and famine are among established risk factors for schizophrenia, but these have not yet been integrated into the genetic results. They may leave a signature on the genome in the form of methylation (see SRF related news report), which controls which genes are turned on or off, or somehow subtly alter brain development. Though researchers agree that taking environment into account will be important, studying the environment, and funding those studies, is a challenge.
"In my view, it's going to be important to put genes and environment together," Kendler said. "The trouble is, there are very few good environmental risk factors for schizophrenia you can measure when you talk to an affected person."
A new Danish project, called the Initiative for Integrative Psychiatric Research (iPSYCH), is poised to systematically explore gene-environment interactions. The national registries in Denmark track information on every resident's education, health, and other demographics, as well as genetic information obtained from blood samples collected at birth. One project will monitor the children of people with schizophrenia or bipolar disorder, pulling together measures of cognition, brain imaging, environment, and genetics to find the mix that leads toward or away from particular disorders.
Recognizing that the road from a risk variant to schizophrenia is a long and winding one, some researchers have gravitated toward understanding intermediate phenotypes that are presumed to lie closer to genes. These reflect concrete features of brain function measured, typically, with cognitive testing, electroencephalography, or magnetic resonance imaging (MRI). Dubbed "endophenotypes" by Irving Gottesman (Shields and Gottesman, 1972; see SRF online discussion), they are by definition heritable, and so might yield clearer genetic signals than the diagnostic category of schizophrenia, as well as extract the malfunctioning brain circuits.
A similar perspective was adopted five years ago by the National Institute of Mental Health (NIMH) with its Research Domain Criteria (RDoC). The initiative offers a framework for researchers to move beyond the traditional, symptom-based classifications of psychiatric disorders to focus on questions oriented around their underlying biology. For example, instead of studying schizophrenia, a project may study the brain circuits underlying social cognition or auditory hallucinations (see SRF webinar).
"It certainly is reinforcing what I've been selling," said Gottesman of RDoC, though he worries that its implementation in the NIMH's grant structure is premature.
For the past 10 years, Braff has led the Consortium on the Genetics of Schizophrenia (COGS), which has pursued cognitive and electrophysiological endophenotypes. From 100 original candidates, the group has homed in on 12 they consider the most important (see SRF related news report; SRF related conference report).
But collecting this fine-grained phenotypic data is time consuming, requiring participants to spend two days in the lab and ultimately taking 10 years to characterize 5,000 people. A GWAS of the sample is expected to be finished in the next year, which could point to the genetic contributors to endophenotypes such as working memory. Sequencing of the COGS samples is also underway.
Braff fully expected it would take this long. "These are really long-term projects. We have to have a lot of patience and diligence," he said.
The most direct readout of the brain may come from brain scans. Measuring the sizes of brain regions with structural MRI, or the flow of activity between regions with functional MRI, may illuminate brain-based endophenotypes that could build bridges between genes and brains. The field of imaging genetics demands sample sizes larger than typically seen for straight imaging studies. Pooling data from many sites, such as is done by the ENIGMA Network will be essential.
"Brain imaging is still a wide open game, there are lots of techniques out there, and you're still inferring a lot," Malhotra said. "But as we're better able to visualize brain structure and function, I think phenotype will matter more and more to schizophrenia genetics."
Beyond their application to genetics, some endophenotypes may be useful biomarkers that could carve out new classifications of disorders. For example, at the 2015 International Congress on Schizophrenia Research, the Bipolar Schizophrenia Network on Intermediate Phenotypes (B-SNIP) reported three new "biotypes" based on measures of cognitive function, eye movement control, and responses to auditory stimulation (see SRF related news report). Alternatively, some biomarkers might delineate subsets of people with schizophrenia. Still others may predict treatment response: Malhotra and colleagues recently reported that changes in functional connectivity between the striatum and the cortex upon taking antipsychotics were greater in people who got more relief from the medicine (see SRF related news report).
Ultimately, endophenotypes may prove more useful in helping researchers understand the biology of risk variants identified by standard case-control GWAS than in identifying schizophrenia's genes.
"Everyone genuflects to say these are really complex disorders, but to date we haven't had the stunning advance by dividing these disorders into something that was meaningful," Kendler said.
With so many possible genes and phenotypes, biologists may be left scratching their heads on which leads are best to follow. The next and final story—"Part 5, Plan of Action"—explores opinions about how to prioritize these leads, how to use them to tailor treatments to individuals, and how the landscape of schizophrenia genetics research will change as team science takes hold.—Michele Solis.