General PsychiatryLatest News| Videos
By Michael Smith, North American Correspondent, MedPage Today
Published: February 27, 2013
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
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Action Points
- The findings in this study show that specific single-nucleotide polymorphisms are associated with a range of psychiatric disorders of childhood onset or adult onset.
- In particular, variation in calcium-channel signalling genes seems to play a role in five psychiatric disorders.
Autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia share common genetic underpinnings -- despite differences in symptoms and course of disease, researchers discovered.
In particular, single nucleotide polymorphisms (SNPs) in two genes involved in calcium-channel activity appear to play a role in all five, Jordan Smoller, MD, ScD, of Massachusetts General Hospital in Boston, and colleagues reported online in The Lancet.
The findings come from a genome-wide analysis of 33,332 cases and 27,888 controls in what the authors described as the largest-ever genetic study of psychiatric illness.
The results are "new evidence that may inform a move beyond descriptive syndromes in psychiatry and towards classification based on underlying causes," Smoller said in a statement.
The findings are especially important because of revisions to the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases, which have "reinvigorated debate about the validity of diagnostic boundaries," the authors noted.
Indeed, the findings confirm previous evidence of "abundant pleiotropy in human complex disorders" – meaning the same genetic variant plays a role in several diseases, argued Alessandro Serretti, MD, PhD, and Chiara Fabbri of the University of Bologna in Italy.
For instance, they noted in an accompanying commentary, calcium signaling, a key regulator of the growth and development of neurons, was expected to be highly pleiotropic, an expectation that "has now been confirmed."
But while some gene variants play a role in many disorders, there are almost certainly others that contribute to the "consistent diversity among disorders," Serretti and Fabbri argued.
"Many genes and polymorphisms are expected to confer a liability to individual psychiatric diseases," they wrote.
Nonetheless, they concluded, one implication of the study is that genetics "can contribute to prediction and prevention of psychiatric diseases, along with the identification of molecular targets for new generations of psychotropic drugs."
But that is not likely to happen soon, according to Randy Ross, MD, of the University of Colorado School of Medicine in Aurora, Colo.
The study is a "beginning step to give us ideas that will eventually lead to new treatments," he toldMedPage Today.
In the long run, however, this study and subsequent research will change both diagnosis and treatment, Ross said, as psychiatric diseases are put on a biological footing.
The researchers found that SNPs (single-letter changes in the genetic code) in four regions were associated with all five disorders: two on chromosome 10, including the L-type voltage-gated calcium-channel subunit CACNB2, one on chromosome 3, and another calcium-channel subunit,CACNA1C, on chromosome 12.
The statistical significance of all four surpassed the cutoff for genome-wide significance ofP<5x10-8 and="" br="" colleagues="" reported.="" smoller="">
The calcium-channel gene CACNA1C has been previously linked to bipolar disorder, schizophrenia, and major depressive disorder, they wrote, as well as to Timothy syndrome, a developmental disorder that can include autism.
The other calcium-channel gene has been linked to bipolar disorder in people of Han Chinese ethnicity, they added.
"Our results suggest that voltage-gated calcium signaling, and, more broadly, calcium-channel activity, could be an important biological process in psychiatric disorders," they argued.
The region on chromosome 3 includes more than 30 genes, Smoller and colleagues noted, but previous research has linked SNPs in the area to bipolar disorder, schizophrenia, and depression.
They cautioned that they compared models of cross-disorder effects with widely used goodness-of-fit measures, but different criteria might yield other results.
They also noted that diagnostic misclassification in the study cohort might produce "spurious evidence of genetic overlap between disorders," although such errors would have to be widespread to affect the results.
Another limitation: the members of the study cohort were of European ancestry, so it's not known if the findings apply to other populations.
The study was supported by the National Institute of Mental Health, as well as grants from the NIH, government grants from other countries, and private and foundation support.
The authors declared they had no conflicts.
The comment authors declared they had no conflicts.
Primary source: Lancet
Source reference:
Smoller JW, et al "Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis" Lancet 2013; DOI: 10.1016/S0140-6736(12)62129-1.
Additional source: Lancet
Source reference:
Alessandro Serretti, Chiara Fabbri "Shared genetics among major psychiatric disorders" Lancet 2013; DOI: 10.1016/S0140-6736(13)60223-8.
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