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Psychiatric Genetics: Applications in Clinical Practice
Reviewed by JOHN I. NURNBERGER
Am J Psychiatry 2009;166:377-379. doi:10.1176/appi.ajp.2008.08081237
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edited by Jordan W. Smoller, M.D., Sc.D., Beth Rosen Sheidley, M.S., C.G.C., and Ming T. Tsuang, M.D., Ph.D., D.Sc. Arlington, Va., American Psychiatric Publishing, 2008, 337 pp., $60.00.

Psychiatric genetics is a field in transition. Over the past century, there has been a long history of studies based on standard genetic epidemiological methods that can be subsumed under the headings of family studies, twin studies, adoption studies, and high-risk studies. This is “classic” psychiatric genetics, and it has established that most of the conditions we treat in psychiatry appear to be highly heritable. Schizophrenia, bipolar disorder, major depression, autism, obsessive-compulsive disorder, and other common psychiatric conditions tend to run in families and to be more frequent among close relatives of an affected person than in distant relatives. However, the genetics of these conditions do not seem to be simple, or Mendelian, in nature. Although important single genes have been identified for certain conditions (e.g., fragile X syndrome and Lesch-Nyhan syndrome), the disorders of major importance seem to be genetically complex, with environmental factors interacting with many genes of small effect (an increase of approximately 10% to 40% risk). It has been difficult to unambiguously identify these genes and understand how they interact with each other and with nongenetic influences, including—for instance—birth trauma, abuse and neglect, viral infections, and stressful life events. We now appear to have methods capable of providing the answers to many of these questions in the laboratory. Genome-wide association studies enable the testing of essentially every gene in the genome simultaneously for each gene’s relationship to illness. The “fly in the ointment” has been the requirement for very large samples (in the tens of thousands) of well-defined cases and comparison subjects in order to overcome the limitations of statistical power. These methods, together with other more potent but experimental candidate gene strategies using biological markers or endophenotypes, search for rare variants and small areas of chromosomal duplication or deletion, and investigations of gene expression changes are now in the process of redefining the genetic landscape for psychiatry. It appears likely that in the future we will have “panels” of genes of interest that will help estimate quantitative risk for individuals and families but likely few overwhelmingly powerful single gene effects.

Psychiatric Genetics: Applications in Clinical Practice fits into this context. The editors are experts in psychiatric genetic epidemiology (Smoller and Tsuang) and genetic counseling (Sheidley). The authors include well-published experts (e.g., David Pauls, Deborah Blacker, Stephen Faraone, and Paul Appelbaum) in related areas. The emphasis is on making genetic concepts and advances useful for practicing clinicians. Given the complexity of the field and the limited knowledge about the role of specific single genes at the present time, producing a book such as this is a challenge. However, the book makes the point that the available information (primarily regarding familial aggregation of disorders) is important and clinically useful and that the range of questions that patients ask about genetics cannot really be addressed without the background provided by this or other similar texts. In a larger context, the book stresses the importance of clinicians understanding the scientific context of genetic findings and their social, legal, and ethical implications as part of continuing professional development. Informed discussion of these issues is provided.

The initial section includes introductory chapters on psychiatric genetics and genetic counseling. There is a very interesting discussion on risk communication. Recipients of genetic counseling information often misinterpret risk when it is presented in terms of conditional probabilities (if this, then that?). For instance, if the true positive rate for a test for colorectal cancer is 50% and the false positive rate is 3% and the actual prevalence of the disorder is 0.3%, what is the predictive value of a positive test? It turns out to be a lot more effective to communicate this information in terms of natural frequencies: Out of 10,000 people, 30 will have colorectal cancer. Of these, 15 will have a positive test; of the other 9,970, approximately 300 will also have a positive test; and therefore the positive predictive value of the test is only 5%. Very few people, including physicians, could produce the correct answer from the initial statement, but most could follow the second. Relative risk figures are also criticized, since they may appear to magnify effects that are actually small. For example, a three-fold increase in risk for a birth defect may sound more ominous than an increase in absolute risk from 1/10,000 to 3/10,000. These lessons in perception are rightfully emphasized as a function of the human brain in relation to risk evaluation. They deserve to be amplified by additional research in this area, since complex communication and decision making in the face of genetic information will become more the rule than the exception in the molecular genetic era.

The next section delves into specific disorders. This is presaged by a rather startling table in Chapter 1, which ranks 51 DSM-IV-TR disorders according to heritability from twin studies. I would not have guessed, for instance, that narcissistic personality disorder was more heritable than anorexia or major depression or that dysthymia was the sole disorder studied showing no evidence of heritability. The references are not provided, and thus we cannot independently verify this ranking, but I would guess that a table of family study results would show a different distribution. The editors feature the following four classes of psychiatric disorders: childhood onset disorders, psychotic disorders, mood and anxiety disorders, and Alzheimer’s disease. These are certainly good choices, but a number of disorders are not addressed, principally substance use disorders, which we know to be substantially heritable. The schizophrenia chapter is a well-documented and authoritative effort from Anne Bassett at the University of Toronto. However, it is somewhat weighted toward the 22q11.2 deletion syndrome (i.e., velocardiofacial syndrome), which accounts for only approximately 1% of cases of schizophrenia. Genes such as dysbindin, neuregulin, and DISC1, which feature prominently in most reviews and may provide more proximate clues to important biological pathways in schizophrenia, are mentioned in a table. The other disorder-specific chapters are comprehensive and balanced, and, overall, there is a good accounting of the progress of the field of psychiatric genetics in approximately 120 pages. There is an interesting contribution on the neuropsychiatric aspects of genetic disorders (see Mendelian) from Dr. Christine Finn at Harvard, which is a valuable reference for the practicing psychiatrist who may receive referrals related to the behavioral aspects of Huntington’s disease or Prader-Willi syndrome.

The last section includes several special topics. Koukopoulos et al. at Massachusetts General Hospital provide one of the best chapters I’ve read on the teratogenicity and treatment of psychiatric disorders during pregnancy. The conclusion of this chapter states that “psychotropic medications may be used during pregnancy when the risk of untreated psychiatric illness in the mother outweighs the potential risks of fetal drug exposure” (p. 248). This provides an appropriate perspective on the risks and benefits to the mother and child. Focusing purely on the risk of medications ignores the concerns regarding fetal and maternal exposure to episodes of illness. The literature in this area is well summarized, and practical therapeutic suggestions are included. The chapter on ethical, legal, and social implications by Hoge and Appelbaum is a brief and historically informed summary of a complex area. Many interesting questions are introduced, which can probably be expanded in future editions. The book provides a look ahead at the future of psychiatric genetics that concentrates on the genetics of treatment response and the development of genetic testing for psychiatric illnesses.

I would recommend this book, with the few caveats previously noted, to colleagues, students, and the scientifically minded layperson. It is the first volume I’ve read that effectively merges expertise in psychiatric genetics and genetic counseling. There is a lot of summary information in table form that will be useful as a reference for clinicians and investigators. The text is appropriately conservative in its data interpretation and is clearly written to be accessible to a knowledgeable layperson. It is somewhat audacious in its focus on clinical application, but the accumulated genetic epidemiology of psychiatric disorders is now quite mature and can bear the scrutiny of evidence-based medicine. Before long, the empirical risk figures will be supplemented with information on specific single genes from ongoing efforts in laboratories around the world. Then we’ll be ready for a bigger book.

+Dr. Nurnberger is currently editing a book on a similar topic and has authored a book on this topic.

+Book review accepted for publication September 2008 (doi: 10.1176/appi.ajp.2008.08081237).

+Reprints are not available; however, Book Forum reviews can be downloaded at http://ajp.psychiatryonline.org.

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