Shared Risk Factors in Multiple Psychiatric Disorders

[[{"type":"media","view_mode":"media_crop","fid":"13920","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_3528999163116","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"652","media_crop_rotate":"0","media_crop_scale_h":"118","media_crop_scale_w":"160","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]The aggregation of psychiatric diagnoses in individual psychiatric patients, ie, the presence of multiple disorders in one individual, is a curious and sometimes disturbing observation in psychiatry. Several explanations have been put forward to explain this, including the clustering of different disorders in some unlucky individuals, overlap in symptomatic expression of different disorders, inadequate or inaccurate diagnostic criteria, incompetent diagnosticians, and shared biological underpinnings. Now comes evidence that there may indeed be shared risk factors across multiple psychiatric disorders.

A group of scientists in the Cross-Disorder Group of the Psychiatric Genomics Consortium, led by Jordan Smoller, MD, performed a meta-analysis of multiple genetic data sets that encompass 33,332 psychiatric patients and 27,888 non-psychiatric controls.¹ Patients who were in the sample had diagnoses of bipolar disorder (BPD), schizophrenia, MDD (unipolar depression), autism spectrum disorders, and ADHD. The researchers applied multinomial logistic regression analyses to the association of single nucleotide polymorphism (SNP, pronounced “snip”) markers across the entire genome (genome-wide analysis). They found that 4 areas of the human genome on the short of chromosome 3 (3p21) and the long arm of chromosome 10 (10q24), and SNPs within 2 calcium channel genes (CACNA1C and CACNB2) had some association with all 5 disorders. The results have multiple implications.

The findings suggest that psychiatric diagnoses may have symptomatic and syndromal overlap because they share the same pathoetiologic genes. In other words, the reason a psychiatric patient has 2 or 3 different diagnoses may be because of a single genetic contribution, or a small set of shared genetic contributions. This would go a long way to explain why so many psychiatric patients have so many psychiatric comorbidities.

One of the most important contributions of this report is the idea of pleiotropy of genes.² Pleiotropy is the ability of different abnormalities of the same gene to cause different clinical manifestations in different conditions. The best example of this is the L-type voltage-dependent calcium channel (CACNA1C), which has been associated with BPD, schizophrenia, MDD, and Timothy syndrome.^3-6 Abnormalities in the CACNA1C protein coding are also associated with hypertension, arrhythmias and sudden cardiac death, and seizure disorders.^7-9 Thus, pleiotropy may also help explain the increased presence of associated medical illnesses in psychiatric disorders. Pleiotropy certainly complicates the understanding of pathogenic processes, but it is an important concept. The introduction of the concept of pleiotropy into our search for causes of psychiatric disorders is a huge step forward.

However, one needs to also be aware of the limitations of these data. First, it is important to understand the design. The study used unique markers in the genome to determine which section of the chromosome is related to illness. Thus, in addition to the 2 calcium channel genes that may have pleiotropic actions, the data suggest that a gene or group of genes, close to 4 nonspecific markers, on chromosomes 3 and 10 are related to the 5 psychiatric diseases studied. Given that genes tend to reside in clusters that are related to their function, it could very well be that there are independent genes for each one of these conditions that all reside in the same general area. If this were true, the data would still explain why comorbid diagnoses exist, since sections of DNA tend to travel together. The study does not reveal what the genes on chromosomes 3 and 10 might be, or what they might do. Those investigations would occur in the future if this finding was replicated.

One of the most important limitations of this study is that it reports an association. There are many phenomena that are associated with but not caused by each other. For example, a specific SNP that has been related to bipolar illness was found to have no functional significance when investigated further.¹⁰ In other words, associations must always be confirmed by experiments that examine the potential causal connection between the gene and the associated condition. This limitation seriously constrains the conclusions that can be drawn from the study.

The most important finding of genetic studies is the documentation of the extent of assortative mating in psychiatric patients. Random mating may be how Gregor Mendel uncovered some of the principles of heredity, but it is not the rule in human mating behavior.¹¹ Rather, human mating is not at all random. Among people with BPD, the likelihood of pairing with an individual with a family history of a mood disorder is approximately 70%.^12,13

Assortative mating occurs with all psychiatric conditions. What that means is within any population, genes from people with mood disorders are continuously concentrated from one generation to the next. This is true for all genes, not just ones responsible for causing the illness. Thus, when you perform a study that relies only on finding an association between the illness and a gene, you can expect to find many false leads. Since this study used only people from Europe, a small continent where this phenomenon of in-breeding has been happening for thousands of generations, the likelihood of false leads increases. So one must be careful with the conclusions drawn, even with exciting studies such as this one.

The promise of molecular psychiatry is great. Ongoing work will clarify diagnoses and pathophysiology and will focus treatment. This study has raised the fascinating possibility that many psychiatric disorders share the same genes, but that these genes may cause different phenotypes under different circumstances to produce a wide array of interrelated signs and symptoms.

Disclosures:

Dr El-Mallakh is Professor and Director of the Mood Disorders Clinical and Research Program, and Dr Tasman is Professor and Chairman in the department of psychiatry and behavioral sciences at the University of Louisville School of Medicine, Louisville, Ky. They report no conflicts of interest concerning the subject matter of this article.

References:

1. Cross-Disorder Group of the Psychiatric Genomics Consortium; Smoller JW, Craddock N, Kendler K, et al. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis [published correction appears in Lancet. 2013;381:1360]. Lancet. 2013;381:1371-1379.

2. Nasrallah HA. Pleiotropy of psychiatric disorders will reinvent DSM. Curr Psychiatry. 2013;12:7.

3. Ferreira MA, O’Donovan MC, Meng YA, et al; Wellcome Trust Case Control Consortium. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008;40:1056-1058.

4. Hamshere ML, Walters JT, Smith R; The Schizophrenia Psychiatric Genome-wide Association Study Consortium, Wellcome Trust Case Control Consortium+, Wellcome Trust Case Control Consortium 2. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry. 2013 Mar 5; [Epub ahead of print].

5. Green EK, Grozeva D, Jones I, et al; Wellcome Trust Case Control Consortium. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry. 2010;15:1016-1022.

6. Depil K, Beyl S, Stary-Weinzinger A, et al. Timothy mutation disrupts the link between activation and inactivation in Ca(V)1.2 protein. J Biol Chem. 2011;286:31557-31564.

7. Gillis J, Burashnikov E, Antzelevitch C, et al. Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome. Am J Med Genet A. 2012;158A:182-187.

8. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm. 2010;7:1872-1882.

9. Navedo MF, Cheng EP, Yuan C, et al. Increased coupled gating of L-type Ca2+ channels during hypertension and Timothy syndrome. Circ Res. 2010;106:748-756.

10. Gao Y, Galante M, El-Mallakh J, et al; BiGS Consortium. BDNF expression in lymphoblastoid cell lines carrying BDNF SNPs associated with bipolar disorder. Psychiatr Genet. 2012;22:253-255.

11. Buston PM, Emlen ST. Cognitive processes underlying human mate choice: the relationship between self-perception and mate preference in Western society. Proc Natl Acad Sci U S A. 2003;100:8805-8810.

12. Mathews CA, Reus VI. Assortative mating in the affective disorders: a systematic review and meta-analysis. Compr Psychiatry. 2001;42:257-262.

13. Merikangas KR, Spiker DG. Assortative mating among in-patients with primary affective disorder. Psychol Med. 1982;12:753-764.