Speaking of copies, rare copy number variants (CNVs) have been found to be associated with schizophrenia and other neurodevelopmental disorders including autism. The operative word here being 'rare'. Copy number variants are generally large (1000 basepair or greater) genomic insertions or deletions, that, by definition, vary widely among individuals. They're either inherited from a parent who carries the CNV, or arise anew. When CNVs were first recognized, it was thought that they would be found to be associated with many diseases, but the most common CNVs seem to not be disease-related at all. After all, genomes evolve largely by segment duplication.
So given how Nature touts this result, we thought we must have misread, surely. But, no, the paper confirms:
Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample.That's 0.35%, as in 3 schizophrenics per thousand. That's a signal so weak that even a smoke alarm couldn't detect it. So, what's the real import of this finding? Nothing new at all -- schizophrenia is a complex disorder, or suite of disorders, that is multigenic, and/or has multiple different causes. Like most other complex diseases, as has been shown over and over.
But the authors go on to discuss the gene (VIPR2) at the identified chromosomal locus that they think might be causative, and conclude, in what may be the Oversell of the Century to date:
The link between VIPR2 duplications and schizophrenia may have significant implications for the development of molecular diagnostics and treatments for this disorder. Genetic testing for duplications of the 7q36 region could enable the early detection of a subtype of patients characterized by overexpression of VIPR2. Significant potential also exists for the development of therapeutics targeting this receptor. For instance, a selective antagonist of the VPAC2 receptor could have therapeutic potential in patients who carry duplications of the VIPR2 region. Peptide derivatives and small molecules have been identified that are selective VPAC2 inhibitors, and these pharmacological studies offer potential leads in the development of new drugs. Although duplications of VIPR2 account for a small percentage of patients, the rapidly growing list of rare CNVs that are implicated in schizophrenia indicates that this psychiatric disorder is, in part, a constellation of multiple rare diseases. This knowledge, along with a growing interest in the development of drugs targeting rare disorders, provides an avenue for the development of new treatments for schizophrenia.You may not have heard of this infamous gene, so for your edification, it's name is Vasoactive intestinal peptide receptor 2 (hence VIPR2). The ultra high plausibility of this Major Gene for--what was it? schizophrenia--is made clear by the sites in which it is expressed: the uterus, prostate, smooth muscle of the GI tract, seminal vescicles, blood vessels, and thymus. Wiki adds as an afterthought that VIPR2 is also expressed in the cerebellum (whew! A narrow escape chance for relevance?).
In fact, here's a section from GenePaint showing VIPR2 expression in a 14.5 day mouse embryo. The gene is expressed where you see the darker blue -- the snout, the vertebrae, the ribs and lungs.... Not in the brain, but then this is only one stage in development, so it's relevance to brain function can't be ruled out.
But from the evidence, targeting this for therapy might ease digestion and calm the nerves.....including those in the genitals. (So maybe schizophrenia is a sex problem, after all.)
We thought and thought what would be the right way to characterize this stunning discovery. A supernova of genetics? Darwin redux? The sting of the VIPR2? No, those images are too pedestrian. We needed to go much deeper, to something with much more profound imagery, to capture what has just been announced.
Of course, it's possible that we've missed something in the story that is far more important than our impression has been. It's always possible since we're no less fallible than the next person.
Nonetheless, based on our understanding of the story, we thought, well, Zen Buddhism is about as profound as it gets, in human thought and experience. So we decided that the clamour of this new finding, the glory of GWAS, was the roaring sound of one hand clapping. Listen very, very (very) carefully, and you, too, may be able to hear it!