***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Pharmacogenetics may allow for a personalized treatment , but a combination with clinical variables may further enhance prediction . In particular , in the present paper , we investigated early partial improvement ( EPI ) defined as 20 % or more improvement by rating scales 2 weeks after treatment , in combination with selected gene variants as a predictor of treatment outcome in patients with major depressive disorder . Two r and omized controlled trials with 168 Japanese depressed patients were used . A stepwise multiple linear regression model with HAM-D score change at week 6 as the dependent variable and genotypes , EPI , baseline HAM-D score , age and sex as independent variables was performed in paroxetine , fluvoxamine and milnacipran , respectively , to estimate the prediction of HAM-D change at week 6 . In the paroxetine sample , only EPI ( P<0.001 ) was significantly associated with HAM-D change ( n=81 , R2=0.25 , P<0.001 ) . In the fluvoxamine sample , 5-HTTLPR La/Lg , S ( P=0.029 ) , FGF2 rs1449683C/T ( P=0.013 ) and EPI ( P=0.003 ) were associated with HAM-D change ( n=42 , R2=0.43 , P<0.001 ) . In the milnacipran sample , HTR-1A-1019C/G ( P=0.001 ) , ADRA2A-1297C/G ( P=0.028 ) and EPI ( P<0.001 ) were associated with outcome ( n=45 , R2=0.71 , P<0.001 ) . EPI in combination with genetic variants could be a useful predictor of treatment outcome and could strengthen the practical use of pharmacogenetic data in clinical practice Childhood trauma is associated with the onset and recurrence of major depressive disorder ( MDD ) . The thermolabile T variant of the methylenetetrahydrofolate reductase ( MTHFR ) C677 T polymorphism ( rs1801133 ) is associated with a limited ( oxidative ) stress defense . Therefore , C677 T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life . We investigated the interaction between the C677 T MTHFR variant and exposure to traumatic childhood events ( TCEs ) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and , in an independent replication sample , on depressive symptomatology in 665 healthy individuals from the general population . In the discovery sample , Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence ( P=0.017 ) . Over the 5.5-year follow-up period , median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs ( T+ and TCE+ ) ; 461 days for T− and TCE+ patients ; 773 days for T+ and TCE− patients and 866 days for T− and TCE− patients . In the replication sample , a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology ( P=0.002 ) . Our results show that the effects of TCEs on the prospect ively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype . In conclusion , T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma Recent genome-wide association ( GWA ) studies of lipids have been conducted in sample s ascertained for other phenotypes , particularly diabetes . Here we report the first GWA analysis of loci affecting  total cholesterol ( TC ) , low-density lipoprotein ( LDL ) cholesterol , high-density lipoprotein ( HDL ) cholesterol and triglycerides sample d r and omly from 16 population -based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform . Our study included a total of 17,797–22,562 persons , aged 18–104 years and from geographic regions spanning from the Nordic countries to Southern Europe . We established 22 loci associated with serum lipid levels at a genome-wide significance level ( P < 5 × 10−8 ) , including 16 loci that were identified by previous GWA studies . The six newly identified loci in our cohort sample s are ABCG5 ( TC , P = 1.5 × 10−11 ; LDL , P = 2.6 × 10−10 ) , TMEM57 ( TC , P = 5.4 × 10−10 ) , CTCF-PRMT8 region ( HDL , P = 8.3 × 10−16 ) , DNAH11 ( LDL , P = 6.1 × 10−9 ) , FADS3-FADS2 ( TC , P = 1.5 × 10−10 ; LDL , P = 4.4 × 10−13 ) and MADD-FOLH1 region ( HDL , P = 6 × 10−11 ) . For three loci , effect sizes differed significantly by sex . Genetic risk scores based on lipid loci explain up to 4.8 % of variation in lipids and were also associated with increased intima media thickness ( P = 0.001 ) and coronary heart disease incidence ( P = 0.04 ) . The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors Several studies have demonstrated the involvement of 5-HT1A receptors in the pathogenesis of depression and in the antidepressant response to SSRIs . A functional new variant in the promoter region of the 5-HT1A gene was recently reported ( -1019 C > G ) . The aim of this study is to investigate a possible association between this 5-HT1A receptor variant and antidepressant response to fluvoxamine in a sample of 262 mood-disorder subjects ( 151 major depressed and 111 bipolars ) treated with fluvoxamine for 6 wk . The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression ( HAMD ) . 5-HT1A variants did not influence antidepressant response in the whole sample and in unipolar subjects . In bipolars , 5-HT1A*C/C genotype carriers showed a better response to fluvoxamine  ( p=0.036 ) , independently from clinical variables . The 5-HT1A polymorphism effect on antidepressant response was independent from the previously reported effect of the 5-HTTLPR polymorphism . In conclusion , 5-HT1A variants could influence the antidepressant efficacy in bipolar subjects , even if results must be verified on larger sample OBJECTIVE This study aim ed to clarify the relationship between the epsilon4 allele and late-life depression  , taking into account lipid profile , vascular diseases , and sociodemographics . METHODS Using a multilevel stratified r and om sampling strategy , a total of 500 subjects aged 65 to 74 years were recruited for this cross-sectional study from the official household records of an entire county in southern Taiwan .  Depressive symptoms were assessed by the Taiwanese Depression Question naire ( TDQ ) . Cognitive function was assessed by the Short Portable Mental Status Question naire . Blood sample s were collected for the determination of the apolipoprotein E ( ApoE ) polymorphism and the lipid profile . RESULTS A total of 283 subjects ( 58.7 % male , with a mean age of 69.2 + /- 2.7 years ) completed all question naires and collection of blood sample s. Using the chi(2 ) test , the overall difference for frequency of the presence of the epsilon4 allele was significant among the severe group ( TDQ score > 18 ) , moderate group ( TDQ score 9 - 18 ) , and mild group ( TDQ score < 9 ) . The proportion of history of heart disease was significantly higher in the severe group than in the mild or moderate group . Kruskal-Wallis statistics revealed that the mean total and low-density lipoprotein cholesterol levels were significantly higher in the severe group than in the moderate or mild group . With our two-level four-class latent class regression model , the presence of the epsilon4 allele was significantly associated with the severely depressed group as compared to the nondepressed group , adjusting for vascular diseases and lipid profile . CONCLUSION The ApoE epsilon4 allele may be correlated with  severe depression in the elderly through ways other than the " vascular depression " hypothesis Objective : The alpha 2A-adrenergic receptor ( ADRA2A ) plays a central role in the regulation of systemic sympathetic activity . Recently , the functional defect of ADRA2A has been implicated as a cause of depression , attention deficit hyperactivity disorder , and Tourette syndrome . In this study , the effect of genetic variants of the ADRA2A gene on the response to selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors ( SNRIs ) was examined in depressed patients . Method : Ninety-three Japanese depressed patients were recruited in the present study , assigned r and omly to paroxetine or milnacipran , and assessed by the Hamilton Rating Scale for Depression ( HAM-D ) scoring every 2 weeks before and after drug administration . The ADRA2A C-1297 G polymorphism was considered in the association analysis with the efficacy of antidepressants . Results : There were significant differences in the HAM-D percent score change over time ( P = 0.019 ) among C/C , C/G , and G/G of the ADRA2A C-1297 G polymorphism in the total subjects . The C allele carriers of the ADRA2A C-1297 G polymorphism showed a significantly better improvement than G/G subjects at weeks 2 , 4 , and over time ( P = 0.037 ) in the milnacipran group . Discussion : Our findings suggest that ADRA2A plays an important role in depression therapy . The level of ADRA2A expression could be associated with the efficacy of SSRIs/SNRIs , especially milnacipran , although the functional change brought about by C-1297 G polymorphism has not yet been fully identified in vivo and in vitro . Conclusions : The ADRA2A polymorphism could be a reasonable c and i date to predict the response to milnacipran . Our results are still preliminary , and a large sample size will be required to confirm our findings . However , to the best of our knowledge , this study is the first to suggest a possible association of ADRA2A variants with the SNRI response Aim Brain-derived neurotrophic factor ( BDNF ) is associated with antidepressant response on the cellular level , in animal models , and in clinical studies . A common variant in the BDNF gene results in a substitution of a methionine ( Met ) for a valine at the amino acid position 66 . Previous studies reported that the Met variant results in enhanced response to antidepressant medications . These findings may be at odds with studies indicating that on a cellular level the Met variant impairs the secretion of BDNF . Material s and methods We examined the effects of BDNF single nucleotide polymorphisms ( SNPs ) in response to the antidepressants paroxetine and mirtazapine in a sample of 246 geriatric patients with major depression , treated in a double-blind , r and omized , 8-week clinical trial . We also examined the effects of genetic variation at the BDNF-related loci neurotrophic tyrosine kinase receptor 2 , cyclic AMP responsive element binding protein 1 ( CREB1 ) , and CREB binding protein . A total of 53 SNPs were genotyped . Results BDNF genetic variation had a significant effect on the efficacy of paroxetine , with patients carrying the Met allele showing impaired response . SNPs at the CREB1 locus , which encodes a transcription factor important in BDNF signaling , also predicted response to paroxetine . Furthermore , we found a significant gene – gene interaction between BDNF and CREB1 that affected response to paroxetine . Because BDNF has been associated with cognitive function , we tested the effects of BDNF SNPs on change in a wide variety of cognitive tests over the 8-week trial , but there were no significant effects of genotype on cognition . Conclusion These results provide new evidence for the importance of the BDNF pathway in antidepressant response in geriatric patients . The negative effect of the Met66 allele on antidepressant outcomes is consistent with basic science findings indicating a negative effect of this variant on BDNF activity in the brain . Further , the effect of BDNF genetic variation on antidepressant treatment is modified by variation in the gene encoding the downstream effector CREB1 
    Output:
    
A pathway analysis of these genes revealed significant pathways : corticotrophin-releasing hormone signaling , AMPK signaling , cAMP-mediated or G-protein coupled receptor signaling , axonal guidance signaling , serotonin or dopamine receptors signaling , dopamine-DARPP32 feedback in cAMP signaling , circadian rhythm signaling and leptin signaling .
Our review provides insights into the shared biological mechanisms of mood disorders and cardiometabolic diseases