A Mutation that Lowers Risk for Schizophrenia?

Last month, Rees et al. (2014) reported that, in contrast to copy number variant (CNV) deletions at the genetic locus, 22q11, which increase schizophrenia risk, duplications in that same region appear to be linked with greater protection against the condition. Within the team’s discovery sample, which included 6,882 schizophrenics and 11,255 controls, no schizophrenics exhibited 22q11 duplication CNVs while 8% of controls did. Meanwhile, no controls harbored 22q11 deletions while 29% of schizophrenics displayed the CNV.

This follows quite quickly on the heels of a study published the same month in Neuron, reporting that two schizophrenic patients with the 22q11 deletion syndrome exhibited higher rates of insertion of the retrotransposon, LINE1, in neurons derived from their fibroblasts. The team suggested that hyperactive retrotransposition may somehow play an important role in genetic risk for schizophrenia. (I may have a commentary published on this in near future, however, so keep tuned. I have also covered some of these issues on SoaC previously.)

The newer study on the protective duplication is fascinating, in that it’s the first of its kind to report that a CNV may actually reduce risk of a given condition. Most genetics studies of this nature have focused on the protective roles of single nucleotide polymorphisms (SNP). It has generally been assumed that CNVs are usually either deleterious and disease-causing, or neutral. So the very idea that the duplication of a region could confer advantage (even if it also causes intellectual disability and other problems) is truly the romaticized, rare, yet very real stuff of Evolution.


This is a piece of artwork I found one day taped to a bus shelter in the midst of the medical campus. It reminded me of some of the Outsider Art produced by people with various mental health conditions. This one in particular I thought displayed a certain level of delusionality considering its reference to “physicians” and its location posted on the medical campus.

In addition to these novel findings, they may also help scientists further pin down which genes or groups of genes are key in the development of the 22q11 deletion syndrome, since the deletion typically spans about 3 million base pairs which contains about 30-40 genes. Thus far, the TBX1 and COMT genes seem to have strong association with certain symptoms of the condition, particularly the behavioral ones. But that fact that duplication of certain genes may confer protection against the development of schizophrenia, in contrast to increased risk with their deletion, may not only help to pinpoint specific genes as key players but it also tells us that a simple more/less relationship of a given gene or group of genes may dramatically affect schizophrenia risk. When these genes are knocked out, schizophrenia risk sky rockets; when they are even more abundant, risk is almost nonexistent.

Rarely is biology so simple and so elegant, but on occasion it does happen and this may be one of those instances.

4 responses to “A Mutation that Lowers Risk for Schizophrenia?

  1. Copy number variations can be associated with both increased risk and increased resistance to disease. Liu et all found that copy number varances in the CCL3L1 gene has both risk for and resistance to HIV-1 infection:


    ‘Our analyses indicate that CCL3L1 CNV is associated with susceptibility to HIV-1 infection. A lower copy number is associated with an increased risk of HIV-1 infection, while a higher copy number is associated with reduced risk for acquiring HIV-1’.

    • Thanks, Robert. Nice to see that there are other findings out there of CNVs which provide some sort of advantage. Funny how that was particularly played up in the media and within the article itself as the “first of its kind” to show that a particular CNV conferred advantage. Obviously, they didn’t bother to read. (And obviously, neither did I! LOL)

      • Interesting that both of these studies found that copy numbers greater than population norms confers some kind of advantage. Is it possible that having two X chromosomes may confer an advantage for females perhaps explaining the 4:1 male/female ratio in ASD?

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