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. 2009 Sep;19(9):666-74.
doi: 10.1097/FPC.0b013e32832e4bcd.

Genome-wide association study of suicidal ideation emerging during citalopram treatment of depressed outpatients

Gonzalo Laje  1 , Andrew S Allen, Nirmala Akula, Husseini Manji, A John Rush, Francis J McMahon
Affiliations

Genome-wide association study of suicidal ideation emerging during citalopram treatment of depressed outpatients

Gonzalo Laje et al. Pharmacogenet Genomics. 2009 Sep.

Abstract

Objectives: Suicidal ideation is an uncommon but worrisome symptom than can emerge during antidepressant treatment. We have described earlier the association between treatment-emergent suicidal ideation (TESI) and markers in genes encoding glutamate receptor subunits GRIK2 and GRIA3. The present genome-wide association study was conducted to identify additional genetic markers associated with TESI that may help identify individuals at high risk who may benefit from closer monitoring, alternative treatments, and/or specialty care.

Methods: A clinically representative cohort of outpatients with nonpsychotic major depressive disorder enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were treated with citalopram under a standard protocol for up to 14 weeks. DNA samples from 90 White participants who developed TESI and a sex-matched and race-matched equal number of treated participants who denied any suicidal ideas were genotyped with 109 365 single nucleotide polymorphisms on the Illumina's Human-1 BeadChip.

Results: One marker was found to be associated with TESI in this sample at the experiment-wide adjusted P less than 0.05 level (marker rs11628713, allelic P = 6.2x10, odds ratio = 4.7, permutation P = 0.01). A second marker was associated at the experiment-wide adjusted P = 0.06 level (rs10903034, allelic P = 3.02x10, odds ratio = 2.7, permutation P = 0.06). These markers reside within the genes PAPLN and IL28RA, respectively. PAPLN encodes papilin, a protoglycan-like sulfated glycoprotein. IL28RA encodes an interleukin receptor.

Conclusion: Together with our earlier report, these findings may shed light on the biological basis of TESI and may help identify patients at increased risk of this potentially serious adverse event.

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Conflict of interest statement

Disclosures and Acknowledgements: Dr. Allen and Ms Akula report no competing interests. Drs. Laje, Manji, Rush and McMahon are listed as co-inventors on a patent application the NIH has filed based in part on the diagnostic technology described in this paper. NeuroMark of Boulder, CO, executed a non-exclusive license with the NIH to develop this technology commercially. The authors were not involved in the negotiation and execution of this license, but under federal law the NIH is required to pay them a portion of any royalties the NIH receives under the license. The authors do not endorse any commercial use of the patent. Dr. Rush has served as an advisor, consultant, or speaker for or received research support from Advanced Neuromodulation Systems, Inc.; AstraZeneca; Best Practice Project Management, Inc.; Bristol-Myers Squibb Company; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals, Inc.; Gerson Lehman Group; GlaxoSmithKline; Healthcare Technology Systems, Inc.; Jazz Pharmaceuticals; Magellan Health Services; Merck & Co., Inc.; the National Institute of Mental Health; Neuronetics; Ono Pharmaceutical; Organon USA Inc.; Pamlab; Personality Disorder Research Corp.; Pfizer Inc.; the Robert Wood Johnson Foundation; the Stanley Medical Research Institute; the Urban Institute; and Wyeth-Ayerst Laboratories Inc. He has equity holdings in Pfizer Inc and receives royalty/patent income from Guilford Publications and Healthcare Technology Systems, Inc.

Figures

Figure 1
Figure 1
Q-Q plot used for residual bias detection shows the observed –log10 p-values against the–log10 p-values expected under the null hypothesis.
Figure 2
Figure 2
Allelic comparisons for each of the 109,365 markers, ordered by physical position. The dashed lines represent permutation-corrected values.
Figure 3
Figure 3
Risk estimates derived from a multiple logistic regression model which includes additive effects of four genotypes (rs11628713, rs10903034, rs4825476 and rs2518224) by gender (males above). Figures are separated by gender (A: females, B: males) since one of the markers resides on a chromosome X and thus males are hemizygous for this variant. The x-axis represents PAPLN and IL28RA genotypes, the y-axis represents the risk estimate, and the z-axis represents GRIA3 and GRIK2 genotypes
See this image and copyright information in PMC

References

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