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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]).
"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.
While the genetic findings will contribute to a more logical classification system of psychotropic disorders, the physiologic associations hold out a tantalizing promise for the future, Dr. Alessandro Serretti, lead author, wrote in an accompanying editorial.
"In addition to methodological issues, which are pertinent to researchers, genetic studies should provide translational value for clinicians," wrote Dr. Serretti of the University of Bologna, Italy. "With this perspective, the present study might contribute to future nosographic systems, which could be based not only on statistically determined clinical categories, but also on biological pathogenic factors that are pivotal to the identification of suitable treatments."
Calcium signaling is a critical regulator of neuronal growth and development, he said. Prior studies have confirmed the antidepressant effects of voltage-dependent calcium channel agonists in mice; a mutation that blocks such channels would be a logical underpinning for an inherited prediction toward depression and, perhaps, other disorders.
"[Single nucleotide polymorphisms] associated previously with different psychiatric disorders identified convergence of pathways in synaptogenesis, axonal guidance, and synaptic plasticity, and now calcium signaling, which is pivotal in the mechanisms of all these biological processes."
Not all patients with these genetic markers will develop one of the associated disorders. "We agree about the presence of some transdiagnostic risk factors, but many genes and polymorphisms are expected to confer a liability to individual psychiatric diseases." Prenatal and postnatal environments – both their negative and positive environmental conditions – modulate the expression of any genetic predilection.
But genetic predilections present an invaluable look into both the development and treatment of disease. "We therefore believe that genetics, possibly thanks to more comprehensive phenotype and endophenotype assessments, can contribute to prediction and prevention of psychiatric diseases, along with the identification of molecular targets for new generations of psychotropic drugs."
Dr. Serretti is a neuropsychiatrist at the University of Bologna, Italy. He had no financial disclosures.
While the genetic findings will contribute to a more logical classification system of psychotropic disorders, the physiologic associations hold out a tantalizing promise for the future, Dr. Alessandro Serretti, lead author, wrote in an accompanying editorial.
"In addition to methodological issues, which are pertinent to researchers, genetic studies should provide translational value for clinicians," wrote Dr. Serretti of the University of Bologna, Italy. "With this perspective, the present study might contribute to future nosographic systems, which could be based not only on statistically determined clinical categories, but also on biological pathogenic factors that are pivotal to the identification of suitable treatments."
Calcium signaling is a critical regulator of neuronal growth and development, he said. Prior studies have confirmed the antidepressant effects of voltage-dependent calcium channel agonists in mice; a mutation that blocks such channels would be a logical underpinning for an inherited prediction toward depression and, perhaps, other disorders.
"[Single nucleotide polymorphisms] associated previously with different psychiatric disorders identified convergence of pathways in synaptogenesis, axonal guidance, and synaptic plasticity, and now calcium signaling, which is pivotal in the mechanisms of all these biological processes."
Not all patients with these genetic markers will develop one of the associated disorders. "We agree about the presence of some transdiagnostic risk factors, but many genes and polymorphisms are expected to confer a liability to individual psychiatric diseases." Prenatal and postnatal environments – both their negative and positive environmental conditions – modulate the expression of any genetic predilection.
But genetic predilections present an invaluable look into both the development and treatment of disease. "We therefore believe that genetics, possibly thanks to more comprehensive phenotype and endophenotype assessments, can contribute to prediction and prevention of psychiatric diseases, along with the identification of molecular targets for new generations of psychotropic drugs."
Dr. Serretti is a neuropsychiatrist at the University of Bologna, Italy. He had no financial disclosures.
While the genetic findings will contribute to a more logical classification system of psychotropic disorders, the physiologic associations hold out a tantalizing promise for the future, Dr. Alessandro Serretti, lead author, wrote in an accompanying editorial.
"In addition to methodological issues, which are pertinent to researchers, genetic studies should provide translational value for clinicians," wrote Dr. Serretti of the University of Bologna, Italy. "With this perspective, the present study might contribute to future nosographic systems, which could be based not only on statistically determined clinical categories, but also on biological pathogenic factors that are pivotal to the identification of suitable treatments."
Calcium signaling is a critical regulator of neuronal growth and development, he said. Prior studies have confirmed the antidepressant effects of voltage-dependent calcium channel agonists in mice; a mutation that blocks such channels would be a logical underpinning for an inherited prediction toward depression and, perhaps, other disorders.
"[Single nucleotide polymorphisms] associated previously with different psychiatric disorders identified convergence of pathways in synaptogenesis, axonal guidance, and synaptic plasticity, and now calcium signaling, which is pivotal in the mechanisms of all these biological processes."
Not all patients with these genetic markers will develop one of the associated disorders. "We agree about the presence of some transdiagnostic risk factors, but many genes and polymorphisms are expected to confer a liability to individual psychiatric diseases." Prenatal and postnatal environments – both their negative and positive environmental conditions – modulate the expression of any genetic predilection.
But genetic predilections present an invaluable look into both the development and treatment of disease. "We therefore believe that genetics, possibly thanks to more comprehensive phenotype and endophenotype assessments, can contribute to prediction and prevention of psychiatric diseases, along with the identification of molecular targets for new generations of psychotropic drugs."
Dr. Serretti is a neuropsychiatrist at the University of Bologna, Italy. He had no financial disclosures.
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]).
"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.
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]).
"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.
FROM THE LANCET
Major Finding: Polymorphisms on four separate chromosomal locations are significantly associated with five separate psychiatric illnesses: schizophrenia, attention-deficit/hyperactivity disorder, major depressive disorder, autism spectrum disorders, and bipolar disorder.
Data Source: The genome-wide association study comprised 33,332 cases and 27,888 controls, all of European ancestry.
Disclosures: The work was sponsored by the National Institutes of Health; none of the authors had any financial disclosures.
