“What we know for sure is there isn’t one or a few causes. That’s all we can say for linkage studies,” Need said.
Candidate Gene Studies
In candidate gene studies, “researchers select individual genes that make sense biologically, or because they are in linkage regions, or both,” Need said. Then they look for differences in the frequency of different variants in people with schizophrenia and without.
However, “these types of studies can be confounded by population differences between cases and controls, small sample size and positive publication bias. Few if any of the hundreds of genes implicated in candidate gene studies are likely to have real effects.”
The Schizophrenia Gene Resource is a database of all the genes implicated in schizophrenia. Currently, the number of genes implicated by candidate gene studies is 281 (here’s the list).
Genome-Wide Association Studies (GWAS)
In genome-wide association studies (GWAS), researchers examine specific gene variants that may be associated with schizophrenia. They compare large groups of people with schizophrenia to healthy controls. In other words, “This is the genetic equivalent of trying to find the person responsible for a crime by fingerprinting everyone in town,” writes one UK neuroscientist on his blog Neuroskeptic.
In 2009, three of the biggest GWAS studies were published in Nature. One study from the International Schizophrenia Consortium compared 3,322 Europeans with schizophrenia with 3,587 people without the condition. They found the strongest association on chromosome 22 on the gene that codes for the protein myosin. They also found an association on chromosome 6p at the major histocompatibility complex (MHC).
A second study used the Molecular Genetics of Schizophrenia sample, consisting of 2,681 people of European descent with schizophrenia and 2,653 without, along with 1,286 African American people with schizophrenia and 973 without. They also found an association between chromosome 6p and schizophrenia.
In the last study, researchers part of the SGENE-plus consortium analyzed a sample of 2,663 people with schizophrenia and 13,498 healthy controls. Like the others, they implicated the MHC region on chromosome 6p. When they increased their sample by adding subjects from the latter studies, they also found two other gene variants on the MHC region and two variants on other chromosomes not found in the other studies.
These studies caused quite the stir, but for different reasons — depending on who you asked. UK’s The Independent, for instance, declared that researchers had “unlocked the secrets of schizophrenia.” Press releases referred to the studies as “landmark” and “breakthroughs.” Many science writers, however, were unimpressed, slamming such overly enthusiastic interpretations.
As Nicholas Wade of The New York Times wrote:
Schizophrenia too seems to be not a single disease, but the end point of 10,000 different disruptions to the delicate architecture of the human brain.
Yes, that discovery is a landmark. The kind that says you have 10,000 miles yet to go.
The march of science is not direct but two steps forward, one step back. This was the step back. But it was a completely necessary one…
(This is another critique from the Neuroskeptic blog.)
Need acknowledged that the “increased risk [conveyed by any one of these associated variants] is minuscule.” One of the papers also reported that the combined effects of thousands of gene variants with very tiny effects could account for up to 30 percent of the risk for schizophrenia.
Still, while these findings don’t bring us closer to predicting schizophrenia, they do pinpoint molecular pathways that may be involved, she said. Take the implication of the major histocompatibility complex (MHC). Researchers have been studying MHC’s role in schizophrenia since the 1970s. While the MHC region has a variety of functions, most are involved in immune function, such as recognizing foreign substances in the body. This region has been linked to about 100 different diseases, including type 1 diabetes and multiple sclerosis.
Many researchers have theorized that exposure to infections may contribute to schizophrenia. A 2006 study of Danish people with schizophrenia and their parents found that nine autoimmune diseases were more common in the schizophrenia sample than in controls. Twelve were more common in parents with affected kids than in controls. Also, a history of any autoimmune disease was associated with a 45 percent increased risk for schizophrenia. However, Kári Stefánsson, CEO of deCode Genetics in Iceland who also led one of the Nature studies, told the Associated Press: “It’s guilt by association; it’s not really a link.”
Rare Gene Variants
Rare variations in genes may explain why researchers have struggled to find specific genes that cause schizophrenia. GWAS only examine common variants, but the same technology can allow the detection of large rare variations, called copy number variations (CNVs). These are regions of the chromosome that are either deleted or duplicated.
(For instance, if a normal sequence is W, X, Y, Z, a deletion might look like: W, Y, Z; a duplication might look like: W, W, X, Y, Z.)
There were two noteworthy studies published in Nature in 2008 that found the same deletions in schizophrenia patients. One study found three deletions on chromosomes 1 and 15: 1q21.1, 15q11.2 and 15q13.3. The International Schizophrenia Consortium also found deletions on chromosomes 15q13.3 and 1q21.1. Also, according to the authors, “As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients.”
These deletions are so rare that they only occurred in less than 1 percent of the schizophrenia sample. But, according to the researchers’ calculations, these deletions increased schizophrenia risk 12- and 15-fold.
“Several regions, and even one single gene (NRXN1) have now been associated with schizophrenia through CNV studies,” Need said. Curiously, every variant associated with schizophrenia also has been linked to other seemingly very different brain conditions including mental retardation, autism and even epilepsy, she added.
The next natural step for researchers, Need said, is to begin sequencing the entire genome to locate smaller rare variations. She and her colleagues at Duke have already sequenced 60 to 70 genomes, and 150 exomes (just the coding parts of the genome). Interestingly, just a year ago, it would’ve taken six weeks to sequence one genome and a hefty amount of $40,000. (The first-ever genome cost $3 billion and took more than a decade.) Now it takes about two weeks and costs around $5,000 (an amount that’s steadily decreasing).
A Dearth of Definitive Answers
With an amazing array of advanced tools, you may be wondering why researchers haven’t already discovered the driving forces behind schizophrenia. In a few words, “There aren’t any [easy answers],” Need said.
Schizophrenia is a highly heterogeneous disease. And with each investigation into its causes, we realize just how colossal its complexities are.
It would be great to be able to put schizophrenia into a neat box with several clear-cut causes, but that’s not the reality. Need believes that there may be anywhere between 100 and 10,000 genes with mind-damaging mutations. But how they function depends on a person’s other genes and their environment. A lot of factors may “modify these strong effects and differ between families,” she said.
The goal, according to Need, isn’t “to understand why every single patient gets schizophrenia” but to be able to find other paths to target medication. Right now, drugs used to treat schizophrenia affect the dopamine system, but they aren’t effective for everyone and have difficult side effects. In other words, researchers want “to have enough clues to zoom in on specific molecular pathways to target for treatment.”