Frontiers in Psychiatric Research

These are exciting times for genetics research: Science magazine chose our new appreciation of human genetic diversity as the scientific breakthrough of the year 2007.¹ The year brought a new genetic bonanza with the announcement of the 1000 Genome Project, a plan to capture human diversity by obtaining the entire genome sequence information of 1000 individuals. This project will create massive new human genome data that will serve as "a gold-standard reference set for analysis of human genetic variation."² This work will be conducted by 3 National Human Genome Research Institute–funded sequencing centers in the United States, the Wellcome Trust Sanger Institute in the United Kingdom, and the Beijing Genomics Institute in Shenzhen, China.

We are witnessing the birth of a new industry of personal genomics.³ The way things stand now, this is still a poorly regulated industry to which private individuals are already subscribing because genotyping services are available at a relatively reasonable price. Subscription rates will probably soar in the near future, and if this happens, this industry is likely to flourish as a result of lower prices, high demand, and decreased costs because of the affordability of whole genome sequencing technology that may soon reach its goal of full genome sequencing for $1000.⁴

Human genetic diversity

This research field has started to come of age with the recent achievement of several milestones:

• The completion of the sequencing of the human genome in 2001 and the first human genome references in 2003.^5,6

• The mapping of human haplotypes of the most common form of genetic variations (eg, single nucleotide polymorphism [SNP]) with the release of the HapMap and its second-generation map of more than 3.1 million SNPs.^7-9

• The reduction in genotyping costs and an increase in analytical and bioinformatics capabilities as a result of technological and methodological advances.

These milestones have changed the way researchers investigate the association between diseases (phenotype) and genes (genotype); instead of querying a few gene variations per study, ie, candidate gene approach, we can now survey SNPs in the whole genome by using the whole genome association (WGA) scan approach.¹⁰ A WGA scan can compare more than 1 million SNPs at a time for each individual.

The first human genome reference sequences were derived from a few "celebrity" individuals (eg, James Watson, Craig Venter) and could not have captured the magnitude of genetic variations.^6,11,12 Our whole genome contains about 3.2 billion bases, and we may differ from each other by 1 base every 100 to 300 bases. We all have variations in our genes that are qualitative (difference in bases like the SNPs), but we also have quantitative differences: we have duplications of DNA sequences and deletions of large DNA segments, which are broadly referred to as structural variations or copy number variations and may cause disease.^13,14 During this past year, studies have shown that our genomes have many more variations than we had previously thought: individual genomes may differ by as many as 9 million bases. Wong and colleagues¹⁵ described more than 3600 copy number variants in 95 study participants. Our DNA similarities define humankind, but countless DNA qualitative and/or quantitative variations make each of us unique.

Recent genetic advances in common complex disorders

The identification of the genetic susceptibility to common diseases and complex traits has been challenging.^16,17 After an initial period of uncertainty and low yield for WGA studies, this approach is finally bringing new insight into the understanding of common complex disorders. Last year, several findings were reported that implicated new genes or DNA sequences in the risk of type 2 diabetes mellitus, cancer, heart disease, Crohn disease, and bipolar disorder.¹⁸ Because they are based on scan comparisons of thousands of healthy and unhealthy people, these studies are much more powerful than earlier ones.

A recent impressive study by the Wellcome Trust Case Control Consortium, a collaboration of 24 geneticists in the United Kingdom, surveyed 3000 controls and 14,000 persons with 7 common diseases, including bipolar disorder, and reported independent replications of their findings.¹⁹ Those studies increase the tally to more than 100 new DNA markers that have been found to be associated with chronic illnesses. These findings bring new hope to the field, since we may be on the brink of understanding the pathophysiological mechanisms of common complex disorders, which include virtually all the chronic diseases of unknown causes with no known curative treatment. Most psychiatric disorders are included among these common disorders. However, because researchers still do not understand the function and relevance of many genes and their regulatory regions, it may take several years to fully grasp the meaning of some of these findings

Genetic findings and clinical psychiatry

Recent genetic findings in psychiatry are summarized in the Table. The results of psychiatric genetics and genomics have been difficult for clinical psychiatrists to interpret. There are at least 2 main reasons for this problem: inconsistent replication of findings of genotype-phenotype associations and complex genetic research methodology and analyses.²⁰ Although these difficulties are apparent in mental health research, they pervade the field of genomics of common complex disorders, in which the role of a single gene variant is very small, and consequently, the genetic contributions to a disorder are the compounded effect of multiple genes. It is unlikely that a single study will definitively establish a valid genotype-phenotype association. Therefore, each study is a valuable discovery tool and requires replication. This is a consequence of the immense number of variations that are tested in a scan, which increase the chances of spurious associations.

Another reason for the disconnect between genetic research and clinical practice in psychiatry is that gene variations may have different frequencies depending on ethnicity; therefore, patients with disease and control populations ideally need to be drawn from comparable genetic backgrounds and environmental conditions, and researchers have to consider the confounding factor of population stratification. In addition to WGA, other strategies may be necessary to identify the genes associated with diseases, because the WGA approach does not address rare variants or extra copies of genes.

What will these new discoveries bring to psychiatry? We may quickly transition from having a few candidate genes of known functions, to a plethora of candidate genes/gene regions in several chromosomes, to a handful of replicated genes/gene regions of poorly defined functions. To make matters worse, it is believed that most genetic variations probably contribute incremental increases in disease risk. Thus, most genes that increase the risk for a psychiatric dis- order may not have the same effect as the recently described macular degeneration variant that raises the risk for macular degeneration by 2 to 3 times in those carrying 1 copy of the gene variant. (The Table shows that most genes associated with psychiatric conditions would only slightly raise the odds ratio above 1.)

Depending on disease frequency, an increase of 50% may cause a modest increase in actual individual risk of about 3% to 4%. Genetic risk is likely to act in combination with lifestyle and chronic stressors, such as trauma, and to affect total disease risk, but the size of the combined effect is unclear and most likely varies from case to case. For example, someone with several gene variants that predispose to posttraumatic stress disorder (PTSD) may have a full-blown case of PTSD in the context of a single traumatic event, while another person without genetic predisposition to PTSD may have the full-blown disorder in the context of chronic and repeated abuse.

It is difficult to predict how long it will take before genetic findings alter the way psychiatrists treat patients. In many cases, it has taken several years for genetic findings to lead to changes in therapeutics, even for single-mutation diseases (also called mendelian diseases).

Pharmacogenetic findings and clinical psychiatry

The field of pharmacogenetics has contributed useful tools to the clinical setting. In the past few years, the FDA has added genetic information to the package inserts of drugs in other areas of medicine. In 2003, it changed package insert information for azathioprine and mercaptopurine to include the genetic risk of neutropenia.²¹ In 2005, it included UGT1A1 genotype information and clinical testing of the UGT1A1*28 allele for the drug irinotecan.^22,23 In 2006, it added genetic information to the warfarin label.²⁴ The future may soon bring an integration of pharmacogenomics into clinical practice, similar to that which is happening in cancer research. Discovery of clinically predictive genotypes, haplotypes, and somatic mutations have resulted in FDA-approved pharmacogenetic tests and the initiation of a genotype-guided cancer therapy trial.²⁵

In 2004, the FDA approved the first gene chip for genotyping variations in the genes of 2 metabolizing enzymes of the cytochrome P-450 (CYP) system.²⁶ The 2 genes are the CYP2D6 (29 variations) and CYP2C19 (2 variations) genes, which influence the plasma levels of a significant number (about 25%) of widely prescribed drugs, including most psychiatric drugs. This genotyping test is intended to help clinicians select optimal drug and dosing regimens in conjunction with clinical evaluations and other diagnostic tools. For instance, adherent patients taking standard doses who have low or elevated plasma drug levels may be, respectively, ultrarapid or poor metabolizers because of genetic variations in their CYP enzymes. It is important to take into consideration that about 10% of white persons and 20% of Asian persons are poor metabolizers, and these individuals may be at increased risk for developing a toxic reaction to a drug and/or severe adverse effects.

Clinical guidelines for CYP2D6 and CYP2C19 genotype testing in psychiatry have already been summarized, but no clear indications have been described.²⁷ Genotyping costs are still high in the clinical setting, and information about the impact of genetic variants is imprecise because there are limited controlled (for the effects of diet, medication adherence, and lifestyle) study results on the impact of genetic variants.²⁸ Currently, it remains unclear whether the use of available pharmacogenetic testing is cost-effective in psychiatry, but a patient who is intolerant to several drugs could potentially derive tremendous benefit from CYP genotyping.

Ethical issues in genetics and genomics

A crucial element in genetic research is the debate on the ethics of genetics, because genetic information may be used to discriminate against individuals, which could result in negative financial consequences and privacy infringements. Another sensitive issue is the likely influence of race and ethnicity on genetics and pharmacogenetics. Disease susceptibility might involve different polymorphisms in different populations and personalized medicine may be affected by ethnicity. Genetic research in particular and also clinical research at large may need to focus on individuals of specific ethnic backgrounds. This will change the framework of clinical research and require closer ties with diverse communities.

Ethical principles were formulated by the Human Genetics Commission in 2002: "Each individual is entitled to lead a life in which genetic characteristics will not be the basis of unjust discrimination or inhuman treatment." It is to be hoped that those principles will be sanctioned when the Genetic Information Non-Discrimination Act is approved by Congress and the Senate and signed into law by the president. This act will prohibit insurers from using genetic information to deny benefits or raise premiums, and it will prohibit the use of genetic information to make employment or compensation decisions. Until then, patients will worry about genetic testing and fear disclosing genetic information that could be crucial for their medical care.

Conclusion

Genetic research brings the hope that we may be closer to understanding the pathophysiology of complex disorders and ultimately improve treatment modalities, understand outcomes, and facilitate prevention. Identifying new genes for psychiatric disorders may open up the possibility of novel drug treatments targeted at previously unknown biological pathways. The foremost goal of genetic research is prevention, and genetic information is expected to have a major impact on public health by its use in the prevention of disease or the adverse effects of drugs.

Genomics can improve the practice of psychiatry in 2 ways: by personalizing existing treatments for psychiatric patients and by identifying new targets for the development of novel therapeutic strategies that go beyond the monoamine approaches in current use. Ethical issues need to be addressed at the levels of ethnically targeted genetic testing and at the individual level in terms of ensuring that access to health care is not restricted in any way by a person's genetic makeup. Clinicians need to have a good level of understanding of pharmacogenetics to talk to well- informed inquisitive patients, and clearly, that requirement will increase as this field matures

Disclosures:

Dr Wong reports that she is a member of the scientific advisory board of Signature Genetics (SERYX). Dr Arcos-Burgos reports no conflicts of interest concerning the subject matter of this article. Dr Licinio reports that he is a consultant for Eli Lilly and is a recipient of NIH funding.

References:

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