Genetic Variation in PCLO Is Associated with Prefrontal Cortex Expression and Bipolar Disorder

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1 T here is no shortage of findings in studies of postmortem brains of patients with psychiatric disorders (1). Evidence that these findings are related to the pathophysiology and/or etilogy of major mental illnesses has been far less common. Conounds of treatment, substance abuse, and postmortem artifacts hat affect RNA and protein degradation are unfortunately the ule rather than the exception (2). The advent of agnostic, hyothesis-blind approaches, such as microchip array expression echnology, have the potential to exacerbate this problem insoar as these studies generate data on thousands of genes in a ingle experiment. An alternative approach in postmortem brain studies is to use ene expression and/or protein levels or activity as an intermediate henotype for the genetic variation that is thought to increase risk or brain diseases such as schizophrenia ([3–5]; for a review, see [6]). his approach has been applied to bipolar disorder in the Choi et al. 7) manuscript in this issue of Biological Psychiatry. Choi et al. (7) identify 367 genes that are differentially expressed n prefrontal cortex (PFC) of patients with bipolar disorder that are ot thought to be the result of the usual postmortem confounds. xpression data from these genes were then examined for associaion with single nucleotide polymorphisms (SNPs) within 100 kiloases of the gene, yielding 45 SNP-gene expression associations. astly, one of those SNPs, an intronic SNP in piccolo (PCLO), s13438494, is associated with bipolar disorder in a meta-analysis of enome-wide association studies (GWAS). This study is to be applauded for at least two reasons. First, it einforces once again the idea that postmortem confounds, such as rior treatment, substance abuse, and the like, can be mitigated by he use of genotyping in the analysis of expression data. Second, it hows the value of postmortem brain in helping to elucidate the enetic underpinnings of a major mental illness, bipolar disorder. It does not, however, explain why bipolar disorder patients as a roup have decreased expression of PCLO in PFC relative to control ubjects. The difference in frequency for the risk allele in patients elative to control subjects is clearly too small to account for the ifferences in expression between the patients and the control ubjects. The possibility that allelic variation in other genes may