Genetic variants at four chromosomal positions have now been linked to five diverse childhood- and adult-onset psychiatric illnesses: schizophrenia, autism spectrum disorders, attention-deficit/hyperactivity disorder, bipolar disorder, and major depressive disorder.
Two of the four loci encode for transmembranal calcium ion transport, a physiologic finding that could become a treatment target, Dr. Jordan W. Smoller and his colleagues wrote in the Feb. 28 online issue of the Lancet (2013 Feb. 28 [http://dx.doi.org/10.1016/S0140-6736(12)62129-1]).
Dr. Jordan Smoller
"The finding that genetic variants have cross-disorder effects is an empirical step toward helping clinicians understand the common co-occurrence of clinical phenotypes in individual patients," wrote Dr. Smoller of the Massachusetts General Hospital, Boston, and his coauthors. "Our results implicate a specific biological pathway – voltage-gated calcium-channel signaling – as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease."
The findings also could further the goal of "moving beyond descriptive syndromes in psychiatry and towards a nosology informed by disease cause," the investigators noted.
The genome-wide association study – the largest yet of its kind – analyzed single nucleotide polymorphisms (SNPs) for the five disorders among 33,332 cases and 27,888 controls, all of European ancestry. Four independent regions contained SNPs that were significantly related to the disorders. Three were related to all five disorders, and one to only bipolar disorder and schizophrenia.
The analysis also identified additional cross-disorder associations with a number of loci previously identified only with schizophrenia, although these associations were not as strong as those seen with the four primary regions.
Two of the four loci are related to voltage-gated transmembranal calcium channels, the authors noted. One of these has been previously identified as a risk gene for schizophrenia, bipolar disorder, and major depressive disorder. The gene facilitates the passage of calcium ions into the plasma membrane.
"Thus, our results suggest that voltage-gated calcium signaling, and, more broadly, calcium channel activity, could be an important biological process in psychiatric disorders," Dr. Smoller and his colleagues wrote. "Alterations in calcium channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology."
The authors cited several possible limitations. For example, diagnostic misclassification in cases of schizophrenia and bipolar disorder could produce "spurious evidence of genetic overlap between disorders." In addition, because their analyses were restricted to people of European ancestry, it is unclear whether their findings would apply to other populations.
Nevertheless, they said these result could provide "insights into the shared causation of psychiatric disorders."
Dr. Smoller and his coauthors are members of the Cross-Disorder Group of the Psychiatric Genomics Consortium. Their work was sponsored by the National Institutes of Health; none of the authors had any financial disclosures.