Response to Li and Su Letter

To the Editor: We thank Drs. Li and Su for the positive comments and the interest shown in our work, and indeed, we hope that our study will encourage future research on molecular mechanisms of NOTCH4 in bipolar disorder and related disorders.

We appreciate the opportunity to comment on the issues raised by Drs. Li and Su. First, as noted in the article, this is a case-control study and we cannot offer any certain explanation as to why we observed an increase in NOTCH4 expression in patients with bipolar disorder. Although we controlled for a range of potential environmental factors, other environmental factors or even epigenetic mechanisms that we have not taken into account might be influencing NOTCH4 expression. As stated in the article, we call for longitudinal studies investigating NOTCH4 activity in relation to disease state and trait.

Second, Drs. Li and Su claim that we observed significant effects of the SNPs on NOTCH4 expression in comparison subjects only. This is not correct. The effects presented in Table 3 in the article are for the sample as a whole and not just for the healthy comparison subjects. Drs. Li and Su correctly point out that none of the SNPs associated with NOTCH4 expression have been reported to show significant associations with bipolar disorder in other large-scale samples. In fact, we also reported that we did not find any association between SNPs and diagnosis, nor did we find any significant interaction effect of SNP by diagnosis on NOTCH4 expression levels. We would like to repeat that our primary aim was to investigate NOTCH4 mRNA levels and that our sample was probably too small to detect any true genetic effects on diagnosis.

Finally, we agree with Drs. Li and Su that the NOTCH4 gene might harbor unidentified SNPs that might influence the expression of NOTCH4 in patients, and one possible direction for future studies might be deep sequencing of the NOTCH4 gene.

In light of evidence provided by our group as well as by others, the NOTCH4 gene has emerged as an interesting area for further research concerning disease mechanisms in bipolar disorder.