When Anne Bassett told colleagues in the late 1980s that she was planning to study the genetics of schizophrenia, they winced. “People thought I was going into a field without a lot of promise,” she says.
To some degree those people were right. Schizophrenia seemed to have an inherited component, because it was known to run in families, yet no one seemed to be able to find its genetic roots. Even as DNA sequencing technologies advanced, and genes associated with Huntington’s disease, cystic fibrosis, and other inherited disorders were identified, schizophrenia researchers were coming up empty-handed.
It was an early hint at the now notorious complexity of schizophrenia genetics. The diversity of symptoms in patients was similarly inscrutable. “Anybody who thought schizophrenia was easy has never seen a patient with the disorder,” says Patrick Sullivan, who studies the genomics of psychiatric disease at the University of North Carolina School of Medicine. “It’s called a complex trait for a damned good reason.”
A person diagnosed with schizophrenia can fall victim to an array of ills: delusions, hallucinations, social withdrawal, depression, cognitive disabilities, and more. Today, geneticists are finding that same heterogeneity in the DNA of patients with the disorder. “What we’re talking about is a serious brain disease that can involve all regions of the brain,” says Bassett. “It’s going to be every bit as complex as cancer.”
In fact, according to recent genome-wide association studies (GWAS), schizophrenia and the related bipolar disorder may actually be the most genetically complex neurological disorders plaguing humans. Over the last five years, large-scale GWAS have identified a handful of alleles associated with a risk of developing schizophrenia and/or bipolar disorder, but each accounts for only a very small percentage of the risk. For every risk allele identified, there may be 1,000 more pieces of the genetic puzzle that are still missing, not to mention the environmental factors thought to significantly contribute to each disorder.
But even a little knowledge is better than nothing, researchers argue. “We still have a lot of work to do, but we are at a different place than we were even five years ago,” says Jordan Smoller, a psychiatrist at Harvard Medical School. “We’ve gone from very little to at least something.”
“Now we’re moving,” agrees Bassett, currently director of clinical genetics at the Centre for Addiction and Mental Health in Toronto. Despite the dire predictions of her naysayers, she has identified numerous novel schizophrenia risk alleles—and other researchers are confirming the findings. “For the first time, we’re starting to see serious, compelling replication of results within our field,” she says.
Genes at fault
In 2005, University of California, San Diego, researcher Jonathan Sebat was eager to start using a new genome-wide screening method called a microarray. It employs tiny spots of DNA attached to a solid surface as probes to detect genetic sequences. At the time, sequencing of individual mutations, or single nucleotide polymorphisms (SNPs), was very difficult to do with a microarray, so Sebat decided to search for copy number variants (CNV), or genome “hiccups,” in which a chunk of DNA is copied numerous times. Though CNVs had not been explicitly linked to disease at the time, Sebat suspected they might underlie disease susceptibility in schizophrenia. “You can’t escape the heterogeneity, but you can grapple with it,” says Sebat.
In 2008, Sebat’s team found that CNVs occur three times as often in people with schizophrenia as in their healthy counterparts, and four times as often in people whose schizophrenia had been diagnosed before age 18. But schizophrenic patients did not share CNVs at the same locations in the genome; each had his own distinctive genome alterations.1
There have long been two theories of the genetic cause of schizophrenia. Some, like Sebat, have argued that the disorder is caused by a few mutations, each with a strong effect, that are unique to each patient. Other researchers have suggested that the disorder results from a crowd of common variants shared among patients, each with a subtle effect. Today, the data are pointing toward the latter.
The most common of the CNVs associated with schizophrenia is a 1.5- to 3-megabase deletion on chromosome 22 in a region of the genome that normally contains 30 to 40 genes, many of which are not well characterized. Approximately 25 percent of people with this mutation exhibit psychosis, but the deletion, called 22q11.2, is found in only 1 percent of schizophrenia cases. Despite this low proportion, however, no other genetic mutation has been found that accounts for a greater share of the risk than this particular deletion. Most mutations that are associated with schizophrenia are found in fewer than 1 in 1,000 patients, and those are still the low-hanging fruit, says Sebat. There are probably many more mutations that contribute to the disease, but they’re found at far lower frequencies—on the order of 1 in every 30,000 cases.
“There’s a famous line from Tolstoy: ‘All happy families are alike; each unhappy family is unhappy in its own way,’ ” says Sebat. “That applies directly to schizophrenia: there are a multitude of ways in which you can disrupt cognition and produce psychosis.”
Now that technology allows easier scrutiny of SNPs, Patrick Sullivan and colleagues at the University of North Carolina this year performed the largest schizophrenia GWAS to date, scanning the genomes of more than 59,000 people, including 7,500 schizophrenia patients. The team identified 22 risk alleles for schizophrenia, 13 of which were identified for the first time. Based on the number of patients studied and the low risk contribution of each identified allele, Sullivan extrapolates there may be between 6,300 and 10,200 SNPs associated with schizophrenia. “We finally have an idea as to how many puzzle pieces there are. We’ve got 22 pieces, maybe of the corners and edges,” he says. “Now we need to get the rest of the edges together. We need to find, say, 2,000 of these 6,000 loci. If we do that, we’ll actually have a good fix on the pathways involved.”
And that is the ultimate goal—to use schizophrenia-associated genes flagged by GWAS to identify pathways underlying the disease. Some of the SNPs recently identified affect molecules involved in synaptic function, such as neurexin, a presynaptic protein. Other SNPs alter components of glutamate signaling and genes that regulate protein synthesis and cell growth. Of Sullivan’s 22 variants, one plays a role in a microRNA pathway and two are components of a calcium channel signaling pathway. (See illustration below.)
The old notion that a schizophrenic simply has a chemical imbalance in the brain is outdated, says Sebat. “I suspect that this universe of rare mutations will start to condense into constellations of genes that are involved in similar pathways,” says Sebat. “There won’t be one schizophrenia pathway, but we have the very beginnings of a molecular understanding now.”
http://www.the-scientist.com/?articles.view/articleNo/38034/title/The-Psychiatrist-s-Jigsaw/
To some degree those people were right. Schizophrenia seemed to have an inherited component, because it was known to run in families, yet no one seemed to be able to find its genetic roots. Even as DNA sequencing technologies advanced, and genes associated with Huntington’s disease, cystic fibrosis, and other inherited disorders were identified, schizophrenia researchers were coming up empty-handed.
It was an early hint at the now notorious complexity of schizophrenia genetics. The diversity of symptoms in patients was similarly inscrutable. “Anybody who thought schizophrenia was easy has never seen a patient with the disorder,” says Patrick Sullivan, who studies the genomics of psychiatric disease at the University of North Carolina School of Medicine. “It’s called a complex trait for a damned good reason.”
A person diagnosed with schizophrenia can fall victim to an array of ills: delusions, hallucinations, social withdrawal, depression, cognitive disabilities, and more. Today, geneticists are finding that same heterogeneity in the DNA of patients with the disorder. “What we’re talking about is a serious brain disease that can involve all regions of the brain,” says Bassett. “It’s going to be every bit as complex as cancer.”
In fact, according to recent genome-wide association studies (GWAS), schizophrenia and the related bipolar disorder may actually be the most genetically complex neurological disorders plaguing humans. Over the last five years, large-scale GWAS have identified a handful of alleles associated with a risk of developing schizophrenia and/or bipolar disorder, but each accounts for only a very small percentage of the risk. For every risk allele identified, there may be 1,000 more pieces of the genetic puzzle that are still missing, not to mention the environmental factors thought to significantly contribute to each disorder.
But even a little knowledge is better than nothing, researchers argue. “We still have a lot of work to do, but we are at a different place than we were even five years ago,” says Jordan Smoller, a psychiatrist at Harvard Medical School. “We’ve gone from very little to at least something.”
“Now we’re moving,” agrees Bassett, currently director of clinical genetics at the Centre for Addiction and Mental Health in Toronto. Despite the dire predictions of her naysayers, she has identified numerous novel schizophrenia risk alleles—and other researchers are confirming the findings. “For the first time, we’re starting to see serious, compelling replication of results within our field,” she says.
Genes at fault
In 2005, University of California, San Diego, researcher Jonathan Sebat was eager to start using a new genome-wide screening method called a microarray. It employs tiny spots of DNA attached to a solid surface as probes to detect genetic sequences. At the time, sequencing of individual mutations, or single nucleotide polymorphisms (SNPs), was very difficult to do with a microarray, so Sebat decided to search for copy number variants (CNV), or genome “hiccups,” in which a chunk of DNA is copied numerous times. Though CNVs had not been explicitly linked to disease at the time, Sebat suspected they might underlie disease susceptibility in schizophrenia. “You can’t escape the heterogeneity, but you can grapple with it,” says Sebat.
In 2008, Sebat’s team found that CNVs occur three times as often in people with schizophrenia as in their healthy counterparts, and four times as often in people whose schizophrenia had been diagnosed before age 18. But schizophrenic patients did not share CNVs at the same locations in the genome; each had his own distinctive genome alterations.1
There have long been two theories of the genetic cause of schizophrenia. Some, like Sebat, have argued that the disorder is caused by a few mutations, each with a strong effect, that are unique to each patient. Other researchers have suggested that the disorder results from a crowd of common variants shared among patients, each with a subtle effect. Today, the data are pointing toward the latter.
The most common of the CNVs associated with schizophrenia is a 1.5- to 3-megabase deletion on chromosome 22 in a region of the genome that normally contains 30 to 40 genes, many of which are not well characterized. Approximately 25 percent of people with this mutation exhibit psychosis, but the deletion, called 22q11.2, is found in only 1 percent of schizophrenia cases. Despite this low proportion, however, no other genetic mutation has been found that accounts for a greater share of the risk than this particular deletion. Most mutations that are associated with schizophrenia are found in fewer than 1 in 1,000 patients, and those are still the low-hanging fruit, says Sebat. There are probably many more mutations that contribute to the disease, but they’re found at far lower frequencies—on the order of 1 in every 30,000 cases.
“There’s a famous line from Tolstoy: ‘All happy families are alike; each unhappy family is unhappy in its own way,’ ” says Sebat. “That applies directly to schizophrenia: there are a multitude of ways in which you can disrupt cognition and produce psychosis.”
Now that technology allows easier scrutiny of SNPs, Patrick Sullivan and colleagues at the University of North Carolina this year performed the largest schizophrenia GWAS to date, scanning the genomes of more than 59,000 people, including 7,500 schizophrenia patients. The team identified 22 risk alleles for schizophrenia, 13 of which were identified for the first time. Based on the number of patients studied and the low risk contribution of each identified allele, Sullivan extrapolates there may be between 6,300 and 10,200 SNPs associated with schizophrenia. “We finally have an idea as to how many puzzle pieces there are. We’ve got 22 pieces, maybe of the corners and edges,” he says. “Now we need to get the rest of the edges together. We need to find, say, 2,000 of these 6,000 loci. If we do that, we’ll actually have a good fix on the pathways involved.”
And that is the ultimate goal—to use schizophrenia-associated genes flagged by GWAS to identify pathways underlying the disease. Some of the SNPs recently identified affect molecules involved in synaptic function, such as neurexin, a presynaptic protein. Other SNPs alter components of glutamate signaling and genes that regulate protein synthesis and cell growth. Of Sullivan’s 22 variants, one plays a role in a microRNA pathway and two are components of a calcium channel signaling pathway. (See illustration below.)
The old notion that a schizophrenic simply has a chemical imbalance in the brain is outdated, says Sebat. “I suspect that this universe of rare mutations will start to condense into constellations of genes that are involved in similar pathways,” says Sebat. “There won’t be one schizophrenia pathway, but we have the very beginnings of a molecular understanding now.”
http://www.the-scientist.com/?articles.view/articleNo/38034/title/The-Psychiatrist-s-Jigsaw/