lederr

genes, genes…

In ADHD, ADHD Adult, ADHD child/adolescent, Autism Spectrum Disorders, General Psychology, Genes, Neuropsychology, Neuroscience, Personality Disorders, Psychiatry on Friday, 1 March 2013 at 06:15

i love gwas and really feel it will continue to broaden our understanding of psychiatric illnesses and, hopefully, lead to better treatment options.

Five Major Psychiatric Disorders Genetically Linked

By: Caroline Cassels

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 theCACNB2 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.”

The authors and editorialists have reported no relevant financial relationships.

Retrieved from: http://www.medscape.com/viewarticle/779979?src=nl_topic

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

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.

Retrieved from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)62129-1/abstract

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
Cross-Disorder Group of the Psychiatric Genomics Consortium
The Lancet – 28 February 2013
DOI: 10.1016/S0140-6736(12)62129-1

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