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Identification of Genetic Loci For Treatment Response of Selective Serotonin Reuptake Inhibitors on Empirically Defined Depression Syndromal Factors
S390
Abstracts of the XXIV World Congress of Psychiatric Genetics (WCPG) 2016
and CACNA1C polymorphisms were extracted from imputed genome-wide data. In the prospective samples changes in ECG intervals (QTc, PR, QRS, RR, and QR) between baseline and follow-up were analyzed in relation to the number of psychotropic drugs stratified according to their cardiovascular risk (from moderate-high to none). In the crosssectional sample ECG parameters were compared among groups taking psychotropic drugs with different cardiovascular risk. The effect of genotypes on these associations was tested. Results: There was no evidence of mean QTc prolongation or increased risk of QTc prolongation Z 20 ms in association with risk drugs. The prescription of drugs with cardiovascular risk was less common in older subjects (p = 0.04) or with cardiovascular comorbidities (p = 0.02). Other factors (gender, ethnicity, baseline QTc, kidney function) affected QTc. rs1006737 modulated QTc duration/changes in the original prospective sample (p= 0.04) and in crosssectional sample (p =0.002) and four polymorphisms in linkage disequilibrium with it modulated QTc changes in the CATIE. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples. Discussion: A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not found. A number of other factors may influence QTc. CACNA1C rs1006737 may modulate the risk of QTc prolongation in patients treated with risk drugs. Finally, high resting heart rate, even within the accepted normal range, should not be overlooked in patients treated with psychotropic drugs since it was independently associated with increased risk of all-causes mortality.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.425
M35. IDENTIFICATION OF GENETIC LOCI FOR TREATMENT RESPONSE OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS ON EMPIRICALLY DEFINED DEPRESSION SYNDROMAL FACTORS
Po-Hsiu Kuo1, Yi-Ting Chen2, Chung-Feng Kao2, Albert C. Yang3, Shih-Jen Tsai3, Yu-Li Liu4 1
Institute of Epidemiology and Preventive Medicine, NTU 2 Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan 3 Division of Psychiatry, National Yang-Ming University, Taipei, Taiwan
4
Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan
Background: Major depressive disorder (MDD) is a complex and multifactorial disorder with heterogeneous syndromal presentations. Patients’ response to commonly prescribed selective serotonin reuptake inhibitors (SSRIs) varies across individuals and symptoms. Certain genetic variants may modify the effects of SSRIs treatment on different symptoms. Methods: We recruited patients with a diagnosis of MDD from two central hospitals in Taiwan, who were treated with escitalopram (38.5 %), paroxetine (38.5%), fluoxetine (18.3%), and citalopram (4.8%). Depression severity was rated using the 21-item Hamilton Rating Scale for Depression (HRSD) in all participants, with a minimum score of 14 at baseline for inclusion. Patients were assessed repeatedly at week 2, 4, and 8. All participants were genotyped using Illumina HumanOmniExpressExome BeadChips in the International SSRI Pharmacogenomics Consortium. After quality controls, 421 patients (mean age of 43.7 years and 71% of females) with 4,241,701 genotyped and well-imputed SNPs were retained for analysis. We first performed exploratory factor analysis to identify latent syndromal factors for baseline HRSD. Treatment response was defined for two variables: score change (score difference between baseline and week-4, divided by the total score in each factor – scaling to range between 0-1), and binary response (⩾50% score reduction from baseline to week-4). Linear and logistic regression models were used for association testing while adjusted for age and sex. Results: We obtained six empirically derived factors for HRSD, namely sleep, core, anxiety, somatization, psychomotor, and energy. The degree of improvement in syndromal severity at week-4 was ranged from 33% (energy) to 70% (psychomotor). No markers reached genome-wide significance level. Nevertheless, several loci showed suggestive signals with p-valueo5 10-6, 43 for score change and 12 for response. The most significant marker was rs2938029 (P =6.4 10-7) in NRXN3 for anxiety score change. A number of known genes were mapped for their associations with syndrome improvement in different factors, such as IL7R and MORN3 (core), RARB and SLC5A8 (psychomotor), KCNIP4 (energy) for score change, and SUCLG2 (anxiety), C8A and POC1B (psychomotor) for binary response. Interestingly, loci in or near (15kb away) an enhancer (ENSR00002058236) were associated with sleep factor in both score change and response outcome variables. Discussion: We found several genes that might affect treatment response of different empirically defined syndromal factors among SSRIs treated depression patients. Further replication studies are needed to confirm our findings in other populations.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.426
Abstracts of the XXIV World Congress of Psychiatric Genetics (WCPG) 2016
and CACNA1C polymorphisms were extracted from imputed genome-wide data. In the prospective samples changes in ECG intervals (QTc, PR, QRS, RR, and QR) between baseline and follow-up were analyzed in relation to the number of psychotropic drugs stratified according to their cardiovascular risk (from moderate-high to none). In the crosssectional sample ECG parameters were compared among groups taking psychotropic drugs with different cardiovascular risk. The effect of genotypes on these associations was tested. Results: There was no evidence of mean QTc prolongation or increased risk of QTc prolongation Z 20 ms in association with risk drugs. The prescription of drugs with cardiovascular risk was less common in older subjects (p = 0.04) or with cardiovascular comorbidities (p = 0.02). Other factors (gender, ethnicity, baseline QTc, kidney function) affected QTc. rs1006737 modulated QTc duration/changes in the original prospective sample (p= 0.04) and in crosssectional sample (p =0.002) and four polymorphisms in linkage disequilibrium with it modulated QTc changes in the CATIE. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples. Discussion: A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not found. A number of other factors may influence QTc. CACNA1C rs1006737 may modulate the risk of QTc prolongation in patients treated with risk drugs. Finally, high resting heart rate, even within the accepted normal range, should not be overlooked in patients treated with psychotropic drugs since it was independently associated with increased risk of all-causes mortality.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.425
M35. IDENTIFICATION OF GENETIC LOCI FOR TREATMENT RESPONSE OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS ON EMPIRICALLY DEFINED DEPRESSION SYNDROMAL FACTORS
Po-Hsiu Kuo1, Yi-Ting Chen2, Chung-Feng Kao2, Albert C. Yang3, Shih-Jen Tsai3, Yu-Li Liu4 1
Institute of Epidemiology and Preventive Medicine, NTU 2 Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan 3 Division of Psychiatry, National Yang-Ming University, Taipei, Taiwan
4
Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan
Background: Major depressive disorder (MDD) is a complex and multifactorial disorder with heterogeneous syndromal presentations. Patients’ response to commonly prescribed selective serotonin reuptake inhibitors (SSRIs) varies across individuals and symptoms. Certain genetic variants may modify the effects of SSRIs treatment on different symptoms. Methods: We recruited patients with a diagnosis of MDD from two central hospitals in Taiwan, who were treated with escitalopram (38.5 %), paroxetine (38.5%), fluoxetine (18.3%), and citalopram (4.8%). Depression severity was rated using the 21-item Hamilton Rating Scale for Depression (HRSD) in all participants, with a minimum score of 14 at baseline for inclusion. Patients were assessed repeatedly at week 2, 4, and 8. All participants were genotyped using Illumina HumanOmniExpressExome BeadChips in the International SSRI Pharmacogenomics Consortium. After quality controls, 421 patients (mean age of 43.7 years and 71% of females) with 4,241,701 genotyped and well-imputed SNPs were retained for analysis. We first performed exploratory factor analysis to identify latent syndromal factors for baseline HRSD. Treatment response was defined for two variables: score change (score difference between baseline and week-4, divided by the total score in each factor – scaling to range between 0-1), and binary response (⩾50% score reduction from baseline to week-4). Linear and logistic regression models were used for association testing while adjusted for age and sex. Results: We obtained six empirically derived factors for HRSD, namely sleep, core, anxiety, somatization, psychomotor, and energy. The degree of improvement in syndromal severity at week-4 was ranged from 33% (energy) to 70% (psychomotor). No markers reached genome-wide significance level. Nevertheless, several loci showed suggestive signals with p-valueo5 10-6, 43 for score change and 12 for response. The most significant marker was rs2938029 (P =6.4 10-7) in NRXN3 for anxiety score change. A number of known genes were mapped for their associations with syndrome improvement in different factors, such as IL7R and MORN3 (core), RARB and SLC5A8 (psychomotor), KCNIP4 (energy) for score change, and SUCLG2 (anxiety), C8A and POC1B (psychomotor) for binary response. Interestingly, loci in or near (15kb away) an enhancer (ENSR00002058236) were associated with sleep factor in both score change and response outcome variables. Discussion: We found several genes that might affect treatment response of different empirically defined syndromal factors among SSRIs treated depression patients. Further replication studies are needed to confirm our findings in other populations.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.426