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Shared Genes May Link ADHD, Autism and Depression
Health.com
February 27, 2013


WEDNESDAY, Feb. 27 (HealthDay News) ? Autism, attention-deficit/hyperactivity disorder (ADHD), major depression, bipolar disorder and schizophrenia may all share common genetic risk factors, a new study says.

In this largest study of its kind, researchers spotted gene variations governing brain function that may raise the risk for these often devastating mental woes. In the future, these gene variants might become key targets for prevention or treatment, the scientists said.

?This study, for the first time, shows that there are specific genetic variants that influence a range of childhood and adult-onset psychiatric disorders that we think of as clinically different,? said lead researcher Dr. Jordan Smoller, a professor of psychiatry at Harvard Medical School in Boston.

?We also found that there was significant overlap in the genetic components of several disorders, especially schizophrenia with bipolar disorder and depression, and to a lesser extent autism with schizophrenia and bipolar disorder,? he said.

The researchers don?t yet understand exactly how these variants are involved in the disorders, he noted. ?This is the first clue that specific genes and pathways may cause a broader susceptibility to a number of disorders. Now the important work will be to figure out how this actually happens,? said Smoller, who is also associate vice chair of the department of psychiatry at Massachusetts General Hospital.

Dr. Alessandro Serretti, from the Psychiatry Institute at the University of Bologna in Italy, wrote an accompanying journal editorial on the study. He believes that ?we are not able to understand what are the pathways to [these] psychiatric disorders.?

There are potential clinical applications, both in the classification of disorders, predicting who?s most at risk, and perhaps new and better drug therapies, Serretti said. However, there?s no immediate clinical application for these findings, he added.

The report was published Feb. 28 in the online edition of The Lancet.

To look for common genetic markers, called nucleotide polymorphisms, that might be risk factors for the five disorders, the Psychiatric Genomics Consortium scanned the genes of more than 33,000 people suffering from these disorders and nearly 28,000 people without such issues. This is the largest study of the genetics of psychiatric illness yet conducted, the researchers said.

Smoller?s group found four gene areas that all overlapped with the five disorders, two of which regulate calcium balance in the brain.

These overlapping gene variants appear to increase the risk for bipolar disorder, major depressive disorder and schizophrenia in adults, the researchers said.

Further analysis found that genes governing calcium channel activity in the brain might also be important in the development of all five disorders, autism and ADHD included.

Smoller noted these genetic risk factors may only account for a very small part of the risk driving these disorders, and just how big a share they account for isn?t yet known.

So, looking for these genes in an individual now would not be considered a diagnostic tool. ?They are not enough to predict any individual?s risk. And you might carry all of these variants and never develop a psychiatric disorder,? Smoller said.

However, the new findings add to the understanding of these conditions and may help in developing new treatments, he explained.

?It could also change the way we define and diagnose these disorders, based on the biological causes,? Smoller said. ?Some of the disorders we think of as clinically distinct actually have more of a relationship than we might have thought.?

Two experts not connected to the study agreed.

?This is the first genome-wide evidence showing that neuropsychiatric diseases share genetic risk factors,? said Eva Redei, professor of psychiatry at the Feinberg School of Medicine at Northwestern University in Chicago.

She noted that all five of the conditions tackled in the study can share certain clinical features and symptoms, including variation in mood, mental impairments, and even psychosis.

?Therefore, the question is whether the identified shared genetic risk factors are related to the diseases or to the shared clinical symptoms,? Redei said. ?Shared genetic contribution can identify some key regulators in the brain, and can also help to find new drug targets,? she said.

Simon Rego, director of psychology training at Montefiore Medical Center at the Albert Einstein College of Medicine in New York City, agreed that the findings are ?an important next step? in understanding mental illness.

As more gene studies are conducted and analyzed, scientists will ?be in a better place to identify shared cause of psychiatric disorders at a molecular level,? he said. ?Ultimately, [this could] generate new models for drug interventions and possibly even prevention.?
 

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Five Major Psychiatric Disorders Genetically Linked
Medscape Psychiatry and mental Health News
February 27, 2013

In the largest genetic study of psychiatric illness to date, scientists have discovered genetic links between 5 major psychiatric disorders.

Investigators from the Cross-Disorder Group of the Psychiatric Genomics Consortium have found that autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share common genetic risk factors.

Specifically, the results of the genome-wide association study (GWAS) reveal single-nucleotide polymorphisms (SNPs) in 2 genes — CACNA1C and CACNB2 — both of which are involved in the balance of calcium in brain cells, are implicated in several of these disorders, and could provide a potential target for new treatments.

"This analysis provides the first genome-wide evidence that individual and aggregate molecular genetic risk factors are shared between 5 childhood-onset or adult-onset psychiatric disorders that are treated as distinct categories in clinical practice," study investigator Jordan Smoller, MD, Massachusetts General Hospital, Boston, said in a release.

The study was published online February 28 in the Lancet.

Potential Therapeutic Target
The researchers note that findings from family and twin studies suggest that genetic risks for psychiatric disorders do not always map to current diagnostic categories and that "doubt remains about the boundaries between the syndromes and the disorders that have overlapping foundations or different variants of one underlying disease."

"The pathogenic mechanisms of psychiatric disorders are largely unknown, so diagnostic boundaries are difficult to define. Genetic risk factors are important in the causation of all major psychiatric disorders, and genetic strategies are widely used to assess potential overlaps," the investigators write.

The aim of the study was to identify specific variants underlying genetic effects shared between 5 major psychiatric disorders: ASD, ADHD, BD, MDD, and schizophrenia.

The researchers analyzed genome-wide SNP data for the 5 disorders in 33,332 cases and 27,888 control participants of European ancestry. They identified 4 risk loci that have significant and overlapping links with all 5 diseases. These included regions on chromosomes 3p21 and 10q24, and SNPs in the gene CACNA1C, which has previously been linked to bipolar disorder and schizophrenia, and in the CACNB2 gene.

Polygenic risk scores confirmed cross-disorder effects, most strongly between adult-onset disorders BD and MDD and schizophrenia. Further pathway analysis corroborated that calcium channel activity could play an important role in the development of all 5 disorders.

"Significant progress has been made in understanding the genetic risk factors underlying psychiatric disorders. Our results provide new evidence that may inform a move beyond descriptive syndromes in psychiatry and towards classification based on underlying causes.

"These findings are particularly relevant in view of the imminent revision of classifications in the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases," said Dr. Smoller.

The investigators add that the study results "implicate a specific biological pathway — voltage-gated calcium-channel signalling — as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease."

In an accompanying editorial, Alessandro Serretti, MD, PhD, and Chiara Fabbri, MD, from the University of Bologna, Italy, assert that "the main innovative contribution of the present study is the combination of qualitative and quantitative analyses of the shared genetic features associated with vulnerability of these 5 disorders."

They add, "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."
 

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Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
The Lancet, Early Online Publication, 28 February 2013

Cross-Disorder Group of the Psychiatric Genomics Consortium?

Summary


Background
Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

Methods
We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.

Findings
SNPs at four loci surpassed the cutoff for genome-wide significance (p<5?10−8) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.

Interpretation
Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.

Funding: National Institute of Mental Health.
 

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