In Five Disorders, Genetic Markers Belie DSM-5 Distinctions

July 2013
In Five Disorders, Genetic Markers Belie DSM-5 Distinctions

The new, fifth, edition of the psychiatric bible formally known as Diagnostic and Statistical Manual of Mental Disorders, henceforth DSM-5, went on sale on 22 May 2013, but even before that it was, once again, the subject of some controversy. Not, this time, for turning widespread, if not precisely normal, behavior into a pathological condition, though it does that too: DSM-5 says that children prone to temper tantrums may have “disruptive mood dysregulation disorder.” The controversy, this time, runs far deeper, with a recent publication in The Lancet showing that five distinct disorders—at least as envisaged by DSM-5—share genetic markers.

The whole point of the DSM was to standardize psychiatric diagnoses. Because these are based on behavior and thought patterns, there has always been scope for interpretation, and the DSM sought to bring a measure of conformity to the profession. It offers reasonably hard and fast ways to distinguish various mental disorders, so that patients end up in the correct categories, and part of the point of reaching a correct diagnosis is in order to be able to offer the correct treatment, one that is liable to work. It has always been recognized that there may be some overlap between disorders, but the paper from the Cross-Disorder Group of the Psychiatric Genomics Consortium, published in The Lancet in April 2013, goes far further (“Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis,” Lancet, 381[98975]: 1371-9, 20 April 2013).

FOUR GENETIC VARIANTS

Five different conditions—attention deficit hyperactivity disorder (ADHD), autism, bipolar depression, major depression, and schizophrenia—were characterized by the same four genetic variants. Two of these SNPs (single nucleotide polymorphisms) are in genes that regulate the flow of calcium ions into neurons, and so could plausibly have an impact on behavior. And another, on chromosome 10, has been further linked with coronary artery disease, intracranial aneurysm, and Parkinson’s disease.

These linkages have been brought to light thanks to genome-wide association studies (GWAS), still definitely a hot topic. Indeed, a previous column revealed that schizophrenia and bipolar disorder shared specific genetic markers. [Note: The paper discussed in that column, by S. Ripke et al., appears in the accompanying table here, at #5, along with a selection of highly cited reports on genome-wide association studies and psychiatric disorders, culled from Thomson Reuters Web of Science.]

Selected, Highly Cited Papers on Genome-Wide Analysis and Psychiatric Disorders, 2007-2013

(Listed by citations)

Rank Paper Citations
1 S.M. Purcell, et al., “Common polygenic variation contributes to risk of schizophrenia and bipolar disorder,” Nature, 460(7256): 748-52, 2009. [26 institutions worldwide] 688
2 H. Stefansson, et al., “Common variants conferring risk of schizophrenia,” Nature, 460(7256): 744-7, 2009. [51 institutions worldwide] 481
3 P. Sklar, et al., “Whole-genome association study of bipolar disorder,” Molecular Psychiatry, 13(5): 558-69, 2008. [16 institutions worldwide] 268
4 L.J. Bierut, et al., “Novel genes identified in a high-density genome wide association study for nicotine dependence,” Human Molecular Genetics,” 16(1): 24-35, 2007. [11 US and Australian institutions] 256
5 S. Ripke, et al., “Genome-wide association study identifies five new schizophrenia loci,” Nature Genetics, 43(1): 969-76, 20011. [131 institutions worldwide] 169
6 S. Shifman, et al., “Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women,” PLOS Genetics, 4(2): No. E28, 2008. [12 institutions worldwide] 151
7 P.F. Sullivan, et al., “Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo,” Molecular Psychiatry, 14(4): 359-75, 2009. [17 institutions worldwide] 130
8 B. Franke, et al., “Genome-wide association studies in ADHD,” Human Genetics, 126(1): 13-50, 2009. [7 institutions worldwide] 99
9 J. Lasky-Su, et al., “Genome-wide association scan of quantitative traits for attention deficit hypyeractivity disorder identifies novel associations and confirms candidate gene associations,” Am. J. Medical Genetics B – Neuropsychiat. Genetics, 147B(8): 1345-54, 2008. [23 institutions worldwide] 86
10 R. Anney, et al., “A genome-wide scan for common alleles affecting risk for autism,” Human Molecular Genetics, 19(20): 4072-82, 2010. [81 institutions worldwide] 84

SOURCE: Thomson Reuters Web of Science

Another 2012 paper, by T.G. Schulze, et al., extended the connections to depression. The 2013 Lancet paper, which lumped together 33,332 cases diagnosed with any one of the five disorders and compared them with 27,888 controls, brought in ADHD and autism. In some respects, then, it should not have been that much of a surprise. Psychiatrists have long known that the same patients or family may manifest two or more of the five disorders, and that a patient with one of the conditions in childhood may develop another in adulthood. Perhaps most indicative, the same drug, which presumably targets the same functions, can be effective in several distinct disorders. Nor is it only mental disorders that show this kind of overlap; Crohn's disease and ulcerative colitis, for example, both inflammatory diseases, share several markers.

REALITY VERSUS ARTIFICIALITY

The controversy, thus, is more about what DSM-5 is trying to do versus human reality. Many commenters, including some who worked on DSM-5, have said that the mind and body just don't reflect DSM-5's artificial lines.

"Nature does not define the disorders designated by our current diagnostic labels, all of which were devised by committees of clinicians who were voting on the symptoms," Thomas Insel, director of the National Institute of Mental Health (NIMH), wrote in March 2012.

On the other hand, genetic associations are still far too weak even to be considered as diagnostic tools for mental disorders. Jordan Smoller, of Massachusetts General Hospital in Boston, one of the coordinators of the study, commented that each of the genetic associations "can account for only a small amount of risk for mental illness, making them insufficient for predictive or diagnostic usefulness by themselves." Smoller is nevertheless optimistic that “these results will help us move toward diagnostic classification informed by disease cause.” In the end, that will result in better treatment, just as it has as a result of a more personalized, genetic approach to some cancers.

Better treatment as a result of better diagnosis is still a long way off, but to move in that direction the NIMH has been engaged in an exercise to define what it calls Research Domain Criteria (RDoC). NIMH Director Insel described this as "an experimental approach to the classification of mental disorders that incorporates multiple dimensions: behavior, thought patterns, neurobiological measures, and genetics.” While the ultimate objective is to give psychiatric medicine better diagnostic tools even than DSM-5, for now the goal is to develop a framework for research that will increasingly guide NIMH funding decisions.

On current form, DSM-6 will be due in around 12 years’ time. Long enough, perhaps, for genetics to make a genuine contribution to the diagnosis and, more importantly the treatment, of mental disorders.


Dr. Jeremy Cherfas is a science writer based in Rome, Italy.

The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.