Scoping Schizophrenia?Human genetics: Hit or miss?
Schizophrenia Magazine
(Naturenews.com)?Five years ago, human geneticists rallied around an emerging concept: Technology had granted the ability to compare the genomes of individuals by looking at tens of thousands of known single-letter differences scattered across them. These differences, called single nucleotide polymorphisms (SNPs), served as reference points of common variation between individuals. The idea was that common variants in the genome might contribute to the genetics of common diseases.
Genome-wide association studies (GWAS) could scan SNPs in thousands of people, with and without a disease. When a DNA variant can be associated with the risk of developing a disease, it signals that something in that area of the genome might be partly responsible. With such ?hits? would presumably flow a better mechanistic understanding of disease, genetic-testing abilities, and even treatment.
?Many researchers really grabbed on to the common variant hypothesis, and in some cases it worked,? says Jonathan Haines, director of the Vanderbilt University Medical Center?s Center for Human Genetics Research in Nashville, Tennessee. But, he adds, ?it hasn?t panned out to be as pervasive an explanation as we thought.?
Schizophrenia genetics has been a mire of false starts. Scores of candidate gene association studies had identified promising targets, but few held up to further scrutiny. So the excitement around approaching the disease in an unbiased genome-wide study was high. But the first four schizophrenia GWAS reported no statistically significant associations. Then, in research published last year, researchers performed scans in roughly 500 people with the disorder and 3,000 healthy controls. When 12 of the hits that turned up were examined in 16,000 more individuals, a signal started to emerge: Three variants were significant, but only one of them was in a gene, ZNF804A, which encodes a protein with unknown function.
Having a potential candidate gave researchers something concrete to work with. One group took 115 healthy people, a little less than half of whom had two copies of the high-risk ZNF804A variant, and compared their brain activity using functional magnetic resonance imaging (fMRI), a method that reveals local blood oxygenation and presumably electrical activity in the brain in real time. Those with the variant, they found, had abnormal connectivity between certain brain areas, impairing ?the degree in which they talk to one another,? says Andreas Meyer-Lindenberg, the director of the Central Institute of Mental Health in Mannheim, Germany, who led the study. Healthy adults with the variant were showing schizophrenia-like brain activity even though they showed no outward signs of disease.
Combining genetic and brain imaging data to study psychiatric disease is not new. Since 2001, researchers have used the strategy to link imaging data to candidate gene findings in schizophrenia, depression, and autism. Meyer-Lindenberg?s study is the first to use a genetic loci identified through GWAS for follow-up with fMRI. ?We?ve now applied [the technique] to a variant that has definitive support as being a schizophrenia risk gene. That wasn?t available before,? says Meyer-Lindenberg.
Part of the problem when seeking schizophrenia-related genes is that, unlike fetal haemoglobin levels for example, the definition of the trait both within and between studies can differ. Also the spectrum and severity of schizophrenia symptoms varies between individuals and are sometimes subjective from a clinical perspective. That?s why fMRI is attractive. The researchers hope to get closer to quantitative measures of psychiatric disorders. ?It makes sense to have a biological level of analysis on which these genetic associations can be studied,? says Daniel Weinberger, the director of the genes, cognition, and psychosis program at the National Institute of Mental Health in Bethesda, Maryland, who pioneered the method in the 1990s.
The ZNF804A association from GWAS has been replicated in some studies but not others. And there are few clues to the mechanism by which this gene might contribute to brain connectivity. It was the group of Michael O?Donovan, a professor of psychological medicine at Cardiff University, England, that made the initial discovery using GWAS. The team is now carrying out a series of experiments to determine which DNA sequences and other proteins it binds, and how variants might alter gene expression.
Schizophrenia Magazine
(Naturenews.com)?Five years ago, human geneticists rallied around an emerging concept: Technology had granted the ability to compare the genomes of individuals by looking at tens of thousands of known single-letter differences scattered across them. These differences, called single nucleotide polymorphisms (SNPs), served as reference points of common variation between individuals. The idea was that common variants in the genome might contribute to the genetics of common diseases.
Genome-wide association studies (GWAS) could scan SNPs in thousands of people, with and without a disease. When a DNA variant can be associated with the risk of developing a disease, it signals that something in that area of the genome might be partly responsible. With such ?hits? would presumably flow a better mechanistic understanding of disease, genetic-testing abilities, and even treatment.
?Many researchers really grabbed on to the common variant hypothesis, and in some cases it worked,? says Jonathan Haines, director of the Vanderbilt University Medical Center?s Center for Human Genetics Research in Nashville, Tennessee. But, he adds, ?it hasn?t panned out to be as pervasive an explanation as we thought.?
Schizophrenia genetics has been a mire of false starts. Scores of candidate gene association studies had identified promising targets, but few held up to further scrutiny. So the excitement around approaching the disease in an unbiased genome-wide study was high. But the first four schizophrenia GWAS reported no statistically significant associations. Then, in research published last year, researchers performed scans in roughly 500 people with the disorder and 3,000 healthy controls. When 12 of the hits that turned up were examined in 16,000 more individuals, a signal started to emerge: Three variants were significant, but only one of them was in a gene, ZNF804A, which encodes a protein with unknown function.
Having a potential candidate gave researchers something concrete to work with. One group took 115 healthy people, a little less than half of whom had two copies of the high-risk ZNF804A variant, and compared their brain activity using functional magnetic resonance imaging (fMRI), a method that reveals local blood oxygenation and presumably electrical activity in the brain in real time. Those with the variant, they found, had abnormal connectivity between certain brain areas, impairing ?the degree in which they talk to one another,? says Andreas Meyer-Lindenberg, the director of the Central Institute of Mental Health in Mannheim, Germany, who led the study. Healthy adults with the variant were showing schizophrenia-like brain activity even though they showed no outward signs of disease.
Combining genetic and brain imaging data to study psychiatric disease is not new. Since 2001, researchers have used the strategy to link imaging data to candidate gene findings in schizophrenia, depression, and autism. Meyer-Lindenberg?s study is the first to use a genetic loci identified through GWAS for follow-up with fMRI. ?We?ve now applied [the technique] to a variant that has definitive support as being a schizophrenia risk gene. That wasn?t available before,? says Meyer-Lindenberg.
Part of the problem when seeking schizophrenia-related genes is that, unlike fetal haemoglobin levels for example, the definition of the trait both within and between studies can differ. Also the spectrum and severity of schizophrenia symptoms varies between individuals and are sometimes subjective from a clinical perspective. That?s why fMRI is attractive. The researchers hope to get closer to quantitative measures of psychiatric disorders. ?It makes sense to have a biological level of analysis on which these genetic associations can be studied,? says Daniel Weinberger, the director of the genes, cognition, and psychosis program at the National Institute of Mental Health in Bethesda, Maryland, who pioneered the method in the 1990s.
The ZNF804A association from GWAS has been replicated in some studies but not others. And there are few clues to the mechanism by which this gene might contribute to brain connectivity. It was the group of Michael O?Donovan, a professor of psychological medicine at Cardiff University, England, that made the initial discovery using GWAS. The team is now carrying out a series of experiments to determine which DNA sequences and other proteins it binds, and how variants might alter gene expression.
