To our knowledge this is the first genome-wide study to detect genetic markers related to TESI. We found two novel markers that were associated with TESI in this sample. Although the marker on IL28RA did not achieve experiment-wise significance at the 0.05 level, we chose to make it a part of the predictive model because of the strength of the association, the consistency observed in the signal of neighboring markers, and biological plausibility. However, until functional alleles are demonstrated or replication is shown in an independent sample, these findings must be viewed as preliminary.
Due to the relatively low frequency of TESI, replication will require a very large prospectively ascertained treatment sample or a retrospective case-control design. It remains unclear whether our findings extend to other antidepressants. However, due to the extensive use in psychiatry and primary care of citalopram, and its low risk for pharmacokinetic interactions at the cytochorme P-450-2D6 level, these findings have relevance even if confined to citalopram and related compounds. Moreover, the effect size estimates reported herein are likely to be inflated (winner's curse) and only after replication in independent samples we would be able to estimate the “true” effect size. Until such experiments have been carried out it is impossible to make statements about any clinical utility of the reported markers.
This study has several limitations. Although consistent with prior reports [8
], TESI was defined on the basis of a single item on a depression rating scale. Neither the instrument, the item, nor the STAR*D study itself, were designed primarily to address TESI. Due to the lack of a placebo group it is impossible to determine what fraction of TESI in this study is directly attributable to antidepressant treatment. These limitations are characteristic of all existing large antidepressant treatment samples, suggesting the need for future large, placebo-controlled studies.
Although the present study took a genome-wide approach, covering over 100,000 markers, current genotyping technology now allows for the study of at least 5 times more potentially relevant polymorphisms. Moreover, as described above, the design of the Illumina Infinium I chip is exon-centric. Therefore, the markers used did not sample potential regulatory regions between genes. Of course, factors other than sequence polymorphisms may be of relevance in TESI, such as copy number variation, methylation and acetylation patterns, and environmental influences.
As in all case-control genetic association studies, hidden population stratification is always a risk. When the trait of interest and marker allele frequencies differ among ancestral groups, spurious associations (and inflated test statistics) may arise. We have previously shown that there is no relationship between race and TESI in this sample. [8
] We further adjusted the results for any differences in allele frequencies, using covariates. The final distribution of p-values was consistent with expectations under the null hypothesis (), and the genomic inflation factor (lambdaGC
), based on the median of all the observed chi-square values, was 1.00. Thus, our findings are unlikely to be the result of population stratification.
PAPLN is a 37kb, 26 exon gene on chromosome 14 that encodes a proteoglycan-like sulfated glycoprotein called papilin. There is a paucity of information about papilin in humans.
The other gene implicated in this study, IL28RA, is a 33kb, 6 exon gene on chromosome 1 that encodes for a protein in the class II cytokine receptor family. Viral infection can induce the expression of interleukin 29 (IL29) (or interferon lambda 1), interleukin 28A (IL28A) (or interferon lambda 2) and interleukin 28B (IL28B) (or interferon lambda 3) [27
]. While little is known about the role of this receptor or interleukin 28 (interferon lambda 2), or their relevance to mood disorders and suicidality, it is notable that the therapeutic use of interferon alpha is associated with a significant incidence of depression and suicidality [28
In summary, we have identified markers in two novel genes that together with previous reports may shed light on the biological basis of suicidal ideation that emerges during antidepressant treatment. If replicated, these findings may take us a step closer toward developing markers with clinically meaningful predictive value for this potentially serious adverse event. Further work is needed to replicate these findings and uncover the functional variation that underlies the association signals we observe.