Genetics seems to be a subject of particular interest for everyone. News stories often emerge in the mainstream press that report on the latest genetic research into different disorders, including psychiatric disorders. However, it is not always clear what the results of these studies really mean in terms of their implications for clinical practice.
This article explores how the current state of knowledge regarding genetics might be used to help psychiatrists diagnose psychiatric disorders or predict their onset.
A big picture perspective
Research data from family, twin, and adoption studies show that psychiatric disorders (such as depression, schizophrenia, anxiety, and bipolar disorder) are complex (or multifactorial) disorders that typically arise as a result of the combined effects of genetic and environmental factors.1 Psychiatric disorders are etiologically heterogeneous. Thus, even within a single discrete diagnostic category, each individual will have accumulated different combinations of contributing genetic and environmental influences that ultimately result in illness manifestation. Although very broad, this knowledge provides intuitive yet fundamental information that is of relevance to clinical practice—no genetic test can predict with certainty who will and who will not become mentally ill. Despite this, there remains considerable value in identifying the genetic variants that increase risk of psychiatric disorders—for example, the potential to refine nosology and diagnosis of psychiatric disorders, improve treatments, and identify those at risk. Thus, there has been considerable research in this area.
Contextualizing current research
Some of the first attempts to identify specific genetic variations that could predict the risk of a psychiatric disorder used linkage studies. This strategy aims to identify regions of chromosomes that are transmitted together with the phenotype in question (eg, psychiatric disorders) through generations of a family. Linkage studies are incredibly powerful when searching for genes that play a large role in a particular phenotype. For example, in the 1980s, linkage studies were responsible for locating the genes responsible for both cystic fibrosis and Huntington disease. However, when applied to the study of psychiatric disorders, linkage studies offered only equivocal results. Attempts to replicate initial findings produced only partial or conditional success. The disappointing data drove psychiatric geneticists to consider whether the genes that contribute to the development of psychiatric disorders were typically of an effect size that was not large enough to be detected by linkage studies.
The traditional association study, which is theoretically more powerful for detecting genes of smaller effect, was logically the next approach in an attempt to identify genetic variations that confer vulnerability to psychiatric disorders. Traditional association studies test individual genetic variants to determine whether they occur more frequently in persons with psychiatric disorders than in those who are not affected. However, again, extensive research using this approach generated largely equivocal results.
Genome-wide association studies
By the early 2000s, technological developments made genome-wide association studies (GWAS) possible. A GWAS typically involves testing half a million individual genetic variations (single nucleotide polymorphisms [SNPs]) for association with the phenotype in question at the same time. This study approach requires very large sample sizes and very stringent thresholds for statistical significance, but it is theoretically very powerful for detecting variations of small effect.
There was much anticipation that the genes that had generated the most support from traditional linkage and association techniques would be confirmed by the results of GWAS. The data from the first, relatively small studies, however, did not deliver this result: few genetic variants surpassed the stringent criteria for statistical significance, and fewer still were variants that had been previously suggested by traditional linkage and association approaches. Many attributed these outcomes to inadequate sample sizes. Consequently, international collaborations were established, and huge data-sets (involving more than 50,000 individuals) were accumulated for powerful genome-wide association investigations of psychiatric disorders.2,3 These studies identified genetic variations that met stringent criteria for genome-wide statistical significance and showed that in some cases the same variation seemed able to contribute toward vulnerability for more than one psychiatric disorder.
Dr Austin is Associate Professor of Psychiatry and Medical Genetics on the Faculty of Medicine at the University of British Columbia, and is a research scientist at the BC Mental Health and Addictions Research Institute in Vancouver. She reports no conflicts of interest concerning the subject matter of this article.
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