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, Smoller JW, Craddock N, Kendler K, Lee PH, Neale BM, Nurnberger JI, Ripke S, Santangelo S, Sullivan PF. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013 Apr 20 ; 381(9875):1371-9. Pubmed Abstract

Comments on News and Primary Papers


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

Comment by:  Laura Almasy
Submitted 5 March 2013
Posted 5 March 2013

This is a very important paper. Just a few years ago, the idea of shared genetic effects across psychiatric disorders was virtual heresy. This study provides empirical evidence to help us move past our biases and consider new hypotheses. These results also support the importance of identifying and studying phenotypes that tap into the layers of function between genes and diagnoses, and may help us to understand what is shared across disorders and what may be unique.

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

Comment by:  Francis McMahon, SRF Advisor
Submitted 5 March 2013
Posted 5 March 2013

This very important study provides a broader context for the 2009 finding from the International Schizophrenia Consortium (ISC) that schizophrenia and bipolar disorder overlap substantially in terms of common risk allele burden. Now we see that this overlap extends not only to depression (as shown previously by Schulze et al., 2012), but also to autism and ADHD. This study could only have been accomplished with strong cooperation among many groups, and its success is a testament to the cooperative approach of the Psychiatric Genomics Consortium (PGC).

What does it all mean? Perhaps common alleles are not really the seeds of psychiatric disorders, but rather the soil in which those seeds take root? Could the expression of particular symptoms depend largely on non-genetic factors? Or are common alleles—which account for only about 5 percent of the observed phenotypic variance—too blunt an instrument for parsing the numerous combinations of genetic risk factors that underlie mental illnesses? We need to understand more about the role of less common alleles and specific environmental risk factors before we can really answer these questions. Meanwhile, this study shows that we still have more to learn from GWAS.

References:

Schulze TG, Akula N, Breuer R, Steele J, Nalls MA, Singleton AB, Degenhardt FA, Nöthen MM, Cichon S, Rietschel M; The Bipolar Genome Study, McMahon FJ. Molecular genetic overlap in bipolar disorder, schizophrenia, and major depressive disorder. World J Biol Psychiatry. 2012 Mar 9. Abstract

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

Comment by:  Ben Pickard
Submitted 6 March 2013
Posted 6 March 2013

Smoller et al., comprising the Cross-Disorder group of the Psychiatric Genomics Consortium, present clear evidence to support a small, but statistically significant, component of genetic susceptibility that is shared among the major neuropsychiatric disorders.

The authors discuss the disconnect between the discrete diagnostic boundaries currently used to partition individuals in a healthcare setting and these new findings that indicate a blurring of such distinctions. This is not a unique observation. The overlap of genes in inflammatory disorders is described by Smoller, and MAPT, the tau protein gene, may also be a useful reference point. It is involved in tangles of Alzheimer’s pathology, Parkinson’s disorder risk, as well as participating in a number of other degenerative disorders such as progressive supranuclear palsy, Pick’s disease, and frontotemporal lobar degeneration.

The implicit assumption in the current study is that there must be universal biological processes driven by these common risk genes that impact on disorders ranging from ADHD to schizophrenia. Necessarily, there must be other factors—both genetic and environmental—that act, in addition, to resolve this general liability into more specific and recognizable phenotypes. Understanding the nature of these interactions is important, as it may provide a clearer understanding of the specific pathological processes that result in each of the disorders. I can think of three hypothetical ways that interactions might occur.

Firstly, there is the traditional neurodevelopmental view that shared risk factors might act by causing abnormal patterning or connectivity of the brain during embryogenesis. Secondary factors would then act in the presence of this weakness to define entry into one of the phenotypically defined endpoints at the appropriate age of onset.

A second hypothesis is that there is some shared impairment in adult brain activity (equivalent to an "endophenotype"). The identification of several calcium channels and their ancillary proteins in the shared gene group might suggest that these are responsible for some generalized disruption of baseline neuronal excitability or the propensity to activate secondary messenger signaling. This mechanism is reminiscent of altered Mendelian phenotype ratios brought about by synthetic pathway mutants, in that both the shared and disorder-specific risk factors would have to be present simultaneously to give rise to full phenotypic expression.

The final model would be one in which the shared genes represent a general homeostatic response to disorder-specific genetic/environmental disruption of brain function. For example, the shared genes could all participate in the productive/harmful resolution of inflammatory processes previously triggered in the CNS. Alternatively, they might mediate the compensatory actions of particular interneurons or astrocytes in the face of glutamatergic or dopaminergic dysfunction.

We may get further clues to the true nature of these genes, and the pathologies they promote, from a still broader scan of disease genetics. For example, it is intriguing to note that the chromosome 10 region identified in the paper has been additionally linked with coronary artery disease, intracranial aneurysm, and Parkinson’s disease by GWAS.

Perhaps most importantly, the identification of these shared genetic risks opens up new opportunities for drug development—one can imagine the potential market for calcium channel modulators with broadly inclusive "labels."

View all comments by Ben Pickard