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.
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.
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