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Pharmacogenomics: clinical utility closer.

NEW YORK -- The unlocking of the human genome's secrets in recent years has begun to provide new insights into the contributions of genetics to certain psychiatric disorders--with future implications for diagnosis and treatment.

One of the major lessons learned within the past few years is that the genetic variations that make up the less than 1% of difference between individuals--humans are 99% identical--are not limited to sequence variations and include variations in chromosome structure, called copy number variations. These two types of variations are the basis of the genetic contribution to risk for disease, according to Dr. Matthew W. State.

Sequence variations are changes at a single nucleotide that can be common in the population, such as single nucleotide polymorphisms (SNPs). There are approximately 3 million SNPs in the human genome, and some affect transcription or translation; others may serve as markers of inheritance and familial relationships. Alternatively, changes in chromosomal structure were previously thought to be rare and disease causing, but over the last several years, it has become clear that this type of variation also is widespread and may be found in either affected or unaffected individuals.

"It had been dogma for so long that we have two copies of every part of every chromosome that this has been a very profound change," said Dr. State, director of the program on neurogenetics and codirector of the medical genomics program at Yale University, New Haven.

"It used to be that if a child with mental retardation was found to have a piece of DNA missing everyone would say 'QED' [or quod erat demonstrandum, meaning "that which was to be demonstrated"]: The loss of that piece of genetic information is the reason for the retardation. That dogma has been completely transformed.

"We now have the ability to look at the genome with high resolution, and any spot you look at can be missing. We have Swiss cheese genomes, with extra pieces and missing pieces, even in places you would expect to be critically important for brain development," he said.

Experience has shown that purported causal genetic associations with disease demonstrated with the older types of candidate gene studies, which looked at one or a small number of genes, were largely not replicable. Within the last several years, however, whole genome association studies, investigating all known genes simultaneously, have successfully identified hundreds of true risk variants. Much of contemporary genetics is concerned with probabilistic, rather than causal, outcomes determined by these genetic association studies, he explained.

"We have had a decade of experience in getting the studies wrong, but we now have a bright future for getting the studies right," Dr. State said at a psychopharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry.

Pharmacogenomics in Action

These advances have led to the beginnings of clinical use of pharmacogenomics, with genetic variations being seen as contributing to phenotypic differences such as in drug metabolism.

There are essentially two components of pharmacogenomics. Efficacy pharmacogenomics refers to the prediction of response to therapy as influenced by genetic variation, while safety pharmacogenomics is concerned with the influence of genetic variation on drug side effects, Dr. State explained.

"Despite improvements in technology, efficacy pharmacogenomics in child psychiatry is essentially nowhere right now--there is no test you can use that will tell you if a drug is going to be effective in an individual child," he said.

Safety pharmacogenomics, on the other hand, is beginning to have clinical utility. The Food and Drug Administration has approved a test, the AmpliChip, that can genotype for polymorphisms and multiple copies of two cytochrome P450 genes--2D6 and 2C19--which are involved in the metabolism of some antidepressants and antipsychotics.

The 5%-10% of most populations who lack 2D6 are poor metabolizers of tricyclic antidepressants and typical antipsychotics, whereas those with three or more copies are ultrarapid metabolizers and may not respond to the medications, according to Dr. State. A potential clinical application of this test would be for a child with major depression who is not responding to a selective serotonin reuptake inhibitor and is being considered for switching to a tricyclic antidepressant.

"The standard approach of start low, go slow, and get blood levels is fine, but with the genetic test you can be armed in advance with the knowledge that this patient is likely to need lower doses," he said.

Another example of safety pharamacogenic testing is the recommendation by the FDA to genotype Asians, and particularly Han Chinese, for the HLA-B*1502 allele, if treatment with carbamazepine is considered. Cases of carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported among carriers of this allele (Pharmacogenomics 2008; 9: 1543-6).

Diagnostic Testing: Almost Ready

Another area that has been moving ahead very quickly is genetic diagnostic testing for childhood psychiatric disorders.

"What we have been finding is that there is a group of independently rare mutations in genes that are highly correlated with autism or schizophrenia," Dr. State said. One of the most important is a deletion at chromosone 22q11, which occurs in 1 in 4,000 live births and is associated with early-onset psychosis. This mutation also is responsible for the velocardiofacial syndrome (VCFS), which is associated with multiple medical and psychiatric conditions, so the test for 22q11 deletions is being used both for children who appear to have developmental or psychiatric difficulties and for those with the facial and other anomalies typical of VCFS.

For the child with learning difficulties, a positive result always should prompt a work-up for congenital heart abnormalities, and for those with the VCFS abnormalities, it could provide an early warning of later psychiatric symptoms, Dr. State explained.

"By next year, there probably will be four or five more genetic tests for schizophrenia available. Just in the last few months, several chromosomal regions have been identified that are highly correlated with the diagnosis of schizophrenia," he said. These include deletions at 1q21.1, 15q11.2, and 15q13.3 that were identified in a genome-wide search for copy number variations in population-based samples (Nature 2008; 455: 232-6).

Other rare high-penetrant mutations recently identified that increase the risk for schizophrenia are copy number variants at 16p11.2, identified first as a risk factor for autism (N. Engl. J. Med. 2008; 358: 667-75) and 22q11.2 (Schizophr. Bull. 2009; 35: 9-12), which is the VCF locus.

Gene discovery for autism also is advancing rapidly. For example, 16p11 copy number variants have been identified (Hum. Mol. Genet. 2008; 17: 628-38 and N. Engl. J. Med. 2008; 358: 667-75), the first of which is the chromosome 15q11-13 maternal duplication--which is the most common chromosomal abnormality identified in patients with autism spectrum disorders.

"In my view, any child with a new diagnosis of autism should be referred for genetic testing, particularly if there are any manifestations of dysmorphia, seizures, and/or intellectual disability. Approximately 30% of children with autism have associated abnormalities and the yield from genetic testing in these syndromic autism children is particularly high," Dr. State said.

An example is fragile X syndrome, which is the result of a trinucleotide repeat expansion in one region of the genome that can result in autistic behavior, intellectual impairment, and seizures. The mutation prevents the expression of a single protein, the fragile X mental retardation protein.

"What has happened in the last couple of years is that researchers have actually worked out at least part of the neurobiology of that protein, and it turns out that a critical aspect has to do with the turnover of a neurotransmitter receptor, metabotropic glutamate receptor subtype 5 (mGluR5). So some of the deficits in fragile X appear not to be set in stone; it's not bad wiring. It's an ongoing problem in the response of neurons to new information, and we have drugs in [clinical] trials that can target this abnormality," he said.

One such drug is fenobam (F. Hoffmann-La Roche Ltd.), which was developed as an anxiolytic but has been found to be a selective mGluR5 antagonist. It is now being developed as an orphan drug for the treatment of fragile X syndrome (Pediatrics 2009; 123: 378-90). In addition, Seaside Therapeutics, led by Mark Bear, Ph.D., is developing treatments for patients with autism, fragile X, and other disorders of brain development.

"If you had told me even 3 years ago that we would have medications that could potentially treat intellectual disability in fragile X, I would have said that's science fiction," Dr. State said. "So, in conclusion, although the promise of personalized medicine we have been talking about for 10 years remains largely on the horizon, new methods and technologies are rapidly transforming our understanding of disease genes and are likely to do the same for treatments in the not-too-distant future."

Dr. State stated he had no conflicts of interest to disclose.
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Author:Walsh, Nancy
Publication:Clinical Psychiatry News
Date:Mar 1, 2009
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