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2. Transcriptomics and the mechanisms of antidepressant efficacy

Author

Hodgson, Karen, Tansey, Katherine E., Powell, Timothy R., Coppola, Giovanni, Uher, Rudolf, Zvezdana Dernovšek, Mojca, Mors, Ole, Hauser, Joanna, Souery, Daniel, Maier, Wolfgang, Henigsberg, Neven, Rietschel, Marcella, Placentino, Anna, Aitchison, Katherine J., Craig, Ian W., Farmer, Anne E., Breen, Gerome, McGuffin, Peter, and Dobson, Richard

Published
2016
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4. Investigating the genetic variation underlying episodicity in major depressive disorder: Suggestive evidence for a bipolar contribution

Author

Ferentinos, Panagiotis, Rivera, Margarita, Ising, Marcus, Spain, Sarah L., Cohen-Woods, Sarah, Butler, Amy W., Craddock, Nicholas, Owen, Michael J., Korszun, Ania, Jones, Lisa, Jones, Ian, Gill, Michael, Rice, John P., Maier, Wolfgang, Mors, Ole, Rietschel, Marcella, Lucae, Susanne, Binder, Elisabeth B., Preisig, Martin, Tozzi, Federica, Muglia, Pierandrea, Breen, Gerome, Craig, Ian W., Farmer, Anne E., Müller-Myhsok, Bertram, McGuffin, Peter, and Lewis, Cathryn M.

Published
2014
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11. Dimensions of temperament and character as predictors of antidepressant discontinuation, response and adverse reactions during treatment with nortriptyline and escitalopram.

Author

Köhler-Forsberg, Ole, Keers, Robert, Uher, Rudolf, Hauser, Joanna, Maier, Wolfgang, Rietschel, Marcella, McGuffin, Peter, Farmer, Anne E., Aitchison, Katherine J., and Mors, Ole

Subjects
CITALOPRAM, PERSONALITY, NORTRIPTYLINE (Drug), COMBINATION drug therapy, SELF-perception, SELF-evaluation, REGRESSION analysis, TRANSCENDENCE (Philosophy), COOPERATIVENESS, TREATMENT effectiveness, AVOIDANCE (Psychology), RISK assessment, TEMPERAMENT, CHARACTER, MENTAL depression, RESEARCH funding, QUESTIONNAIRES, TERMINATION of treatment, LOGISTIC regression analysis, STATISTICAL models, DRUG side effects, PROPORTIONAL hazards models, DISEASE remission
Abstract

Background: Personality traits may predict antidepressant discontinuation and response. However, previous studies were rather small, only explored a few personality traits and did not include adverse drug effects nor the interdependency between antidepressant discontinuation patterns and response. Methods: GENDEP included 589 patients with unipolar moderate-severe depression treated with escitalopram or nortriptyline for 12 weeks. Seven personality dimensions were measured using the self-reported 240-item Temperament and Character Inventory-Revised (TCI-R). We applied Cox proportional models to study discontinuation patterns, logistic and linear regression to investigate response and remission after 8 and 12 weeks, and mixed-effects linear models regarding time-varying treatment response and adverse drug reactions. Results: Low harm avoidance, low cooperativeness, high self-transcendence and high novelty seeking were associated with higher risks for antidepressant discontinuation, independent of depressed mood, adverse drug reactions, drug, sex and age. Regression analyses showed that higher novelty seeking and cooperativeness scores were associated with a greater likelihood of response and remission after 8 and 12 weeks, respectively, but we found no correlations with response in the mixed-effects models. Only high harm avoidance was associated with more self-reported adverse effects. Conclusions: This study, representing the largest investigation between several personality traits and response to two different antidepressants, suggests that correlations between personality traits and antidepressant treatment response may be confounded by differential rates of discontinuation. Future trials on personality in the treatment of depression need to consider this interdependency and study whether interventions aiming at improving compliance for some personality types may improve response to antidepressants. [ABSTRACT FROM AUTHOR]

Published
2023
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13. Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders

Author

Ligthart, Lannie, Hottenga, Jouke-Jan, Lewis, Cathryn M., Farmer, Anne E., Craig, Ian W., Breen, Gerome, Willemsen, Gonneke, Vink, Jacqueline M., Middeldorp, Christel M., Byrne, Enda M., Heath, Andrew C., Madden, Pamela A. F., Pergadia, Michele L., Montgomery, Grant W., Martin, Nicholas G., Penninx, Brenda W. J. H., McGuffin, Peter, Boomsma, Dorret I., and Nyholt, Dale R.

Published
2014
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14. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study

Author

Shatunov, Aleksey, Mok, Kin, Newhouse, Stephen, Weale, Michael E, Smith, Bradley, Vance, Caroline, Johnson, Lauren, Veldink, Jan H, van Es, Michael A, van den Berg, Leonard H, Robberecht, Wim, Van Damme, Philip, Hardiman, Orla, Farmer, Anne E, Lewis, Cathryn M, Butler, Amy W, Abel, Olubunmi, Andersen, Peter M, Fogh, Isabella, Silani, Vincenzo, Chiò, Adriano, Traynor, Bryan J, Melki, Judith, Meininger, Vincent, Landers, John E, McGuffin, Peter, Glass, Jonathan D, Pall, Hardev, Leigh, P Nigel, Hardy, John, Brown, Robert H, Jr, Powell, John F, Orrell, Richard W, Morrison, Karen E, Shaw, Pamela J, Shaw, Christopher E, and Al-Chalabi, Ammar

Published
2010
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16. Genome-wide association study of suicidal behaviour severity in mood disorders

Author

Zai, Clement C., primary, Fabbri, Chiara, additional, Hosang, Georgina M., additional, Zhang, Ruo Su, additional, Koyama, Emiko, additional, de Luca, Vincenzo, additional, Tiwari, Arun K., additional, King, Nicole, additional, Strauss, John, additional, Jones, Ian, additional, Jones, Lisa, additional, Breen, Gerome, additional, Farmer, Anne E., additional, McGuffin, Peter, additional, Vincent, John B., additional, Kennedy, James L., additional, and Lewis, Cathryn M., additional

Published
2021
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17. Rare copy number variants: a point of rarity in genetic risk for bipolar diosrder and schizophrenia

Author

Grozeva, Detelina, Kirov, George, Ivanov, Dobril, Jones, Ian R., Jones, Lisa, Green, Elaine K., St Clair, David M., Young, Allan H., Ferrier, Nicol, Farmer, Anne E., McGuffin, Peter, Holmans, Peter A., Owen, MIchael J., O'Donovan, Michael C., and Craddock, Nick

Subjects
Bipolar disorder -- Risk factors, Bipolar disorder -- Genetic aspects, Bipolar disorder -- Research, Schizophrenia -- Risk factors, Schizophrenia -- Genetic aspects, Schizophrenia -- Research, Genetic variation -- Research, Health, Psychology and mental health
Published
2010

18. Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: A genome-wide association and polygenic scoring study

Author

Mullins, Niamh, Perroud, Nader, Uher, Rudolf, Butler, Amy W., Cohen-Woods, Sarah, Rivera, Margarita, Malki, Karim, Euesden, Jack, Power, Robert A., Tansey, Katherine E., Jones, Lisa, Jones, Ian, Craddock, Nick, Owen, Michael J., Korszun, Ania, Gill, Michael, Mors, Ole, Preisig, Martin, Maier, Wolfgang, Rietschel, Marcella, Rice, John P., Müller-Myhsok, Bertram, Binder, Elisabeth B., Lucae, Susanne, Ising, Marcus, Craig, Ian W., Farmer, Anne E., McGuffin, Peter, Breen, Gerome, and Lewis, Cathryn M.

Published
2014
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20. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

Author

Fogh, Isabella, Ratti, Antonia, Gellera, Cinzia, Lin, Kuang, Tiloca, Cinzia, Moskvina, Valentina, Corrado, Lucia, Sorarù, Gianni, Cereda, Cristina, Corti, Stefania, Gentilini, Davide, Calini, Daniela, Castellotti, Barbara, Mazzini, Letizia, Querin, Giorgia, Gagliardi, Stella, Del Bo, Roberto, Conforti, Francesca L., Siciliano, Gabriele, Inghilleri, Maurizio, Saccà, Francesco, Bongioanni, Paolo, Penco, Silvana, Corbo, Massimo, Sorbi, Sandro, Filosto, Massimiliano, Ferlini, Alessandra, Di Blasio, Anna M., Signorini, Stefano, Shatunov, Aleksey, Jones, Ashley, Shaw, Pamela J., Morrison, Karen E., Farmer, Anne E., Van Damme, Philip, Robberecht, Wim, Chiò, Adriano, Traynor, Bryan J., Sendtner, Michael, Melki, Judith, Meininger, Vincent, Hardiman, Orla, Andersen, Peter M., Leigh, Nigel P., Glass, Jonathan D., Overste, Daniel, Diekstra, Frank P., Veldink, Jan H., van Es, Michael A., Shaw, Christopher E., Weale, Michael E., Lewis, Cathryn M., Williams, Julie, Brown, Robert H., Landers, John E., Ticozzi, Nicola, Ceroni, Mauro, Pegoraro, Elena, Comi, Giacomo P., DʼAlfonso, Sandra, van den Berg, Leonard H., Taroni, Franco, Al-Chalabi, Ammar, Powell, John, Silani, Vincenzo, Brescia Morra, Vincenzo, Filla, Alessandro, Massimo, Filosto, Marsili, Angela, Viviana, Pensato, Puorro, Giorgia, La Bella, Vincenzo, Logroscino, Giancarlo, Monsurrò, Maria Rosaria, Quattrone, Aldo, Simone, Isabella Laura, Ahmeti, Kreshnik B., Ajroud-Driss, Senda, Armstrong, Jennifer, Birve, Anne, Blauw, Hylke M., Bruijn, Lucie, Chen, Wenjie, Comeau, Mary C., Cronin, Simon, Soraya, Gkazi Athina, Grab, Josh D., Groen, Ewout J., Haines, Jonathan L., Heller, Scott, Huang, Jie, Hung, Wu-Yen, Jaworski, James M., Khan, Humaira, Langefeld, Carl D., Marion, Miranda C., McLaughlin, Russell L., Miller, Jack W., Mora, Gabriele, Pericak-Vance, Margaret A., Rampersaud, Evadnie, Siddique, Nailah, Siddique, Teepu, Smith, Bradley N., Sufit, Robert, Topp, Simon, Vance, Caroline, van Vught, Paul, Yang, Yi, and Zheng, J.G.

Published
2014
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21. Genome-wide association analysis accounting for environmental factors through propensity-score matching: Application to stressful live events in major depressive disorder

Author

Power, Robert A., Cohen-Woods, Sarah, Ng, Mandy Y., Butler, Amy W., Craddock, Nick, Korszun, Ania, Jones, Lisa, Jones, Ian, Gill, Michael, Rice, John P., Maier, Wolfgang, Zobel, Astrid, Mors, Ole, Placentino, Anna, Rietschel, Marcella, Aitchison, Katherine J., Tozzi, Federica, Muglia, Pierandrea, Breen, Gerome, Farmer, Anne E., McGuffin, Peter, Lewis, Cathryn M., and Uher, Rudolf

Published
2013
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24. Dissecting the Genetic Heterogeneity of Depression Through Age at Onset

Author

Power, Robert A., Keers, Robert, Ng, Mandy Y., Butler, Amy W., Uher, Rudolf, Cohen-Woods, Sarah, Ising, Marcus, Craddock, Nick, Owen, Michael J., Korszun, Ania, Jones, Lisa, Jones, Ian, Gill, Michael, Rice, John P., Hauser, Joanna, Henigsberg, Neven, Maier, Wolfgang, Zobel, Astrid, Mors, Ole, Placentino, Anna S., Rietschel, Marcella, Souery, Daniel, Kozel, Dejan, Preisig, Martin, Lucae, Susanne, Binder, Elisabeth B., Aitchison, Katherine J., Tozzi, Federica, Muglia, Pierandrea, Breen, Gerome, Craig, Ian W., Farmer, Anne E., Müller-Myhsok, Bertram, McGuffin, Peter, and Lewis, Cathryn M.

Published
2012
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31. Genetic basis of schizophrenia

Author

McGuffin, Peter, Owen, Michael J., and Farmer, Anne E.

Subjects
Schizophrenia -- Genetic aspects, Mental illness -- Genetic aspects
Published
1995

34. Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder

Author

Rucker, James J.H., Tansey, Katherine E., Rivera, Margarita, Pinto, Dalila, Cohen-Woods, Sarah, Uher, Rudolf, Aitchison, Katherine J., Craddock, Nick, Owen, Michael J., Jones, Lisa, Jones, Ian, Korszun, Ania, Barnes, Michael R., Preisig, Martin, Mors, Ole, Maier, Wolfgang, Rice, John, Rietschel, Marcella, Holsboer, Florian, Farmer, Anne E., Craig, Ian W., Scherer, Stephen W., McGuffin, Peter, and Breen, Gerome

Subjects
Adult, Male, Adolescent, DNA Copy Number Variations, MOSAICISM, VARIANTS, UNIPARENTAL DISOMY, HIDDEN-MARKOV MODEL, Young Adult, DUPLICATIONS, SCHIZOPHRENIA, Databases, Genetic, SEX-CHROMOSOME ABNORMALITIES, Genetics, Humans, Genetic Predisposition to Disease, SNP GENOTYPING DATA, Biological Psychiatry, Chromosome Aberrations, Depressive Disorder, Copy number variation, Depression, BIPOLAR DISORDER, MAJOR DEPRESSION, Middle Aged, Case-Control Studies, Chromosome Aberrations/statistics & numerical data, DNA Copy Number Variations/genetics, Depressive Disorder/genetics, Female, Genome-Wide Association Study, Linear Models, Affective disorders, Archival Report, Phenotypes
Abstract

BackgroundDefining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD. MethodsIn this reanalysis of our RDD dataset(N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. ResultsWe found an enrichment of Turner's syndrome among cases of depression compared with the frequency observed in a large population sample(N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79-33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002). ConclusionsAfter statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.

Published
2016

37. Utility of the pooling approach as applied to whole genome association scans with high-density Affymetrix microarrays

Author

Gray Joanna, Gunasinghe Cerisse, Korszun Ania, Elkin Amanda, Schalkwyk Leonard C, Cohen-Woods Sarah, Gaysina Darya, Pirlo Katrina, Schosser Alexandra, Jones Lisa, Meaburn Emma, Farmer Anne E, Craig Ian W, and McGuffin Peter

Subjects
Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract

Abstract Background We report an attempt to extend the previously successful approach of combining SNP (single nucleotide polymorphism) microarrays and DNA pooling (SNP-MaP) employing high-density microarrays. Whereas earlier studies employed a range of Affymetrix SNP microarrays comprising from 10 K to 500 K SNPs, this most recent investigation used the 6.0 chip which displays 906,600 SNP probes and 946,000 probes for the interrogation of CNVs (copy number variations). The genotyping assay using the Affymetrix SNP 6.0 array is highly demanding on sample quality due to the small feature size, low redundancy, and lack of mismatch probes. Findings In the first study published so far using this microarray on pooled DNA, we found that pooled cheek swab DNA could not accurately predict real allele frequencies of the samples that comprised the pools. In contrast, the allele frequency estimates using blood DNA pools were reasonable, although inferior compared to those obtained with previously employed Affymetrix microarrays. However, it might be possible to improve performance by developing improved analysis methods. Conclusions Despite the decreasing costs of genome-wide individual genotyping, the pooling approach may have applications in very large-scale case-control association studies. In such cases, our study suggests that high-quality DNA preparations and lower density platforms should be preferred.

Published
2010
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38. Suicidal ideation during treatment of depression with escitalopram and nortriptyline in Genome-Based Therapeutic Drugs for Depression (GENDEP): a clinical trial

Author

Giovannini Caterina, Zobel Astrid, Strohmaier Jana, Jorgensen Lisbeth, Szczepankiewicz Aleksandra, Placentino Anna, Souery Daniel, Maier Wolfgang, Hauser Joanna, Henigsberg Neven, Mors Ole, Rietschel Marcella, Marusic Andrej, Uher Rudolf, Perroud Nader, Elkin Amanda, Gunasinghe Cerisse, Gray Joanna, Campbell Desmond, Gupta Bhanu, Farmer Anne E, McGuffin Peter, and Aitchison Katherine J

Subjects
Medicine
Abstract

Abstract Background Suicidal thoughts and behaviours during antidepressant treatment, especially during the first weeks of treatment, have prompted warnings by regulatory bodies. The aim of the present study is to investigate the course and predictors of emergence and worsening of suicidal ideation during tricyclic antidepressant and serotonin reuptake inhibitor treatment. Methods In a multicentre part-randomised open-label study, 811 adult patients with moderate to severe unipolar depression were allocated to flexible dosage of escitalopram or nortriptyline for 12 weeks. The suicidality items of three standard measures were integrated in a suicidal ideation score. Increases in this score were classified as treatment emergent suicidal ideation (TESI) or treatment worsening suicidal ideation (TWOSI) according to the absence or presence of suicidal ideation at baseline. Results Suicidal ideation decreased during antidepressant treatment. Rates of TESI and TWOSI peaked in the fifth week. Severity of depression predicted TESI and TWOSI. In men, nortriptyline was associated with a 9.8-fold and 2.4-fold increase in TESI and TWOSI compared to escitalopram, respectively. Retirement and history of suicide attempts predicted TWOSI. Conclusion Increases in suicidal ideation were associated with depression severity and decreased during antidepressant treatment. In men, treatment with escitalopram is associated with lower risk of suicidal ideation compared to nortriptyline. Clinicians should remain alert to suicidal ideation beyond the initial weeks of antidepressant treatment. Trial registration EudraCT (No.2004-001723-38) and ISRCTN (No. 03693000).

Published
2009
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42. Stressful life events and Catechol-O-methyl-transferase (COMT) gene in bipolar disorder

Author

Hosang, Georgina M., Fisher, Helen L., Cohen-Woods, Sarah, McGuffin, Peter, and Farmer, Anne E.

Subjects
mental disorders
Abstract

Background: A small body of research suggests that gene-environment interactions play an important role in the development of bipolar disorder. The aim of the present study is to contribute to this work by exploring the relationship between stressful life events and the COMT Val158Met polymorphism in bipolar disorder. Methods: A total of 482 bipolar cases and 205 psychiatrically healthy controls completed the List of Threatening Experiences Questionnaire. Bipolar cases reported the events experienced 6 months before their worst depressive and manic episodes; controls reported those events experienced 6 months prior to their interview. The genotypic information for the COMT Val158Met variant (rs4680) was extracted from GWAS analysis of the sample. Results: The impact of stressful life events was moderated by the COMT genotype for the worst depressive episode using a Val dominant model (adjusted Risk Difference = 0.09, 95% confidence intervals 0.003-0.18, p=0.04). For the worst manic episodes no significant interactions between COMT and stressful life events were detected. Conclusions: This is the first study to explore the relationship between stressful life events and the COMT Val158Met polymorphism focusing solely on bipolar disorder. The results of this study highlight the importance of the interplay between genetic and environmental factors for bipolar depression.

Published
2016

44. Whole genome linkage scan of recurrent depressive disorder from the depression network study

Author

McGuffin, Peter, Knight, Jo, Breen, Gerome, Brewster, Shyama, Boyd, Peter R., Craddock, Nick, Gill, Mike, Korszun, Ania, Maier, Wolfgang, Middleton, Lefkos, Mors, Ole, Owen, Michael J., Perry, Julia, Preisig, Martin, Reich, Theodore, Rice, John, Rietschel, Marcella, Jones, Lisa, Sham, Pak, Farmer, Anne E., McGuffin, Peter, Knight, Jo, Breen, Gerome, Brewster, Shyama, Boyd, Peter R., Craddock, Nick, Gill, Mike, Korszun, Ania, Maier, Wolfgang, Middleton, Lefkos, Mors, Ole, Owen, Michael J., Perry, Julia, Preisig, Martin, Reich, Theodore, Rice, John, Rietschel, Marcella, Jones, Lisa, Sham, Pak, and Farmer, Anne E.

Abstract

Genome-wide linkage analysis was carried out in a sample of 497 sib pairs concordant for recurrent major depressive disorder (MDD). There was suggestive evidence for linkage on chromosome 1p36 where the LOD score for female-female pairs exceeded 3 (but reduced to 2.73 when corrected for multiple testing). The region includes a gene, MTHFR, that in previous studies has been associated with depressive symptoms. Two other regions, on chromosomes 12q23.3-q24.11 and 13q31.1-q31.3, showed evidence for linkage with a nominal P<0.01. The 12q peak overlaps with a region previously implicated by linkage studies of unipolar and bipolar disorders and contains a gene, DAO, that has been associated with both bipolar disorder and schizophrenia. The 13q peak lies within a region previously linked strongly to panic disorder. A fourth modest peak with an LOD of greater than 1 on chromosome 15q lies within a region that showed genome-wide significant evidence of a recurrent depression locus in a previous sib-pair study. Both the 12q and the 15q findings remained significant at genome-wide level when the data from the present study and the previous reports were combined

Published
2017

46. Interaction between the FTO gene, body mass index and depression: meta-analysis of 13701 individuals

Author

Rivera, Margarita, primary, Locke, Adam E., additional, Corre, Tanguy, additional, Czamara, Darina, additional, Wolf, Christiane, additional, Ching-Lopez, Ana, additional, Milaneschi, Yuri, additional, Kloiber, Stefan, additional, Cohen-Woods, Sara, additional, Rucker, James, additional, Aitchison, Katherine J., additional, Bergmann, Sven, additional, Boomsma, Dorret I., additional, Craddock, Nick, additional, Gill, Michael, additional, Holsboer, Florian, additional, Hottenga, Jouke-Jan, additional, Korszun, Ania, additional, Kutalik, Zoltan, additional, Lucae, Susanne, additional, Maier, Wolfgang, additional, Mors, Ole, additional, Müller-Myhsok, Bertram, additional, Owen, Michael J., additional, Penninx, Brenda W. J. H., additional, Preisig, Martin, additional, Rice, John, additional, Rietschel, Marcella, additional, Tozzi, Federica, additional, Uher, Rudolf, additional, Vollenweider, Peter, additional, Waeber, Gerard, additional, Willemsen, Gonneke, additional, Craig, Ian W., additional, Farmer, Anne E., additional, Lewis, Cathryn M., additional, Breen, Gerome, additional, and McGuffin, Peter, additional

Published
2017
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48. Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

Author

Arloth, Janine, Bogdan, Ryan, Altmann, Andre, Lawson, William B, Lewis, Glyn, MacIntyre, Donald, Maier, Wolfgang, Mattheisen, Manuel, McGrath, Patrick J, McIntosh, Andrew, McLean, Alan, Middeldorp, Christel M, Middleton, Lefkos, Trümbach, Dietrich, Montgomery, Grant M, Murphy, Shawn N, Nauck, Matthias, Nolen, Willem A, Nyholt, Dale R, O'Donovan, Michael, Oskarsson, Högni, Pedersen, Nancy, Scheftner, William A, Schulz, Andrea, Wurst, Wolfgang, Schulze, Thomas G, Shyn, Stanley I, Sigurdsson, Engilbert, Slager, Susan L, Smit, Johannes H, Stefansson, Hreinn, Steffens, Michael, Thorgeirsson, Thorgeir, Tozzi, Federica, Treutlein, Jens, Mehta, Divya, Uhr, Manfred, van den Oord, Edwin J C G, Van Grootheest, Gerard, Völzke, Henry, Weilburg, Jeffrey B, Willemsen, Gonneke, Zitman, Frans G, Neale, Benjamin, Daly, Mark, Levinson, Douglas F, Sullivan, Patrick F, Klengel, Torsten, Erhardt, Angelika, Carey, Caitlin E, Conley, Emily Drabant, Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics, Weber, Peter, Ruepp, Andreas, Müller-Myhsok, Bertram, Hariri, Ahmad R, Binder, Elisabeth B, PGC, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Ripke, Stephan, Wray, Naomi R, Lewis, Cathryn M, Hamilton, Steven P, Weissman, Myrna M, Frishman, Goar, Breen, Gerome, Byrne, Enda M, Blackwood, Douglas H R, Boomsma, Dorret I, Cichon, Sven, Heath, Andrew C, Holsboer, Florian, Lucae, Susanne, Madden, Pamela A F, Martin, Nicholas G, Menke, Andreas, McGuffin, Peter, Muglia, Pierandrea, Noethen, Markus M, Penninx, Brenda P, Pergadia, Michele L, Potash, James B, Rietschel, Marcella, Lin, Danyu, Shi, Jianxin, Wagner, Klaus V, Steinberg, Stacy, Grabe, Hans J, Lichtenstein, Paul, Magnusson, Patrik, Perlis, Roy H, Preisig, Martin, Smoller, Jordan W, Stefansson, Kari, Uher, Rudolf, Kutalik, Zoltan, Balsevich, Georgia, Tansey, Katherine E, Teumer, Alexander, Viktorin, Alexander, Barnes, Michael R, Bettecken, Thomas, Breuer, René, Castro, Victor M, Churchill, Susanne E, Coryell, William H, Schmidt, Mathias V, Craddock, Nick, Craig, Ian W, Czamara, Darina, De Geus, Eco J, Degenhardt, Franziska, Farmer, Anne E, Fava, Maurizio, Frank, Josef, Gainer, Vivian S, Gallagher, Patience J, Karbalai, Nazanin, Gordon, Scott D, Goryachev, Sergey, Gross, Magdalena, Guipponi, Michel, Henders, Anjali K, Herms, Stefan, Hickie, Ian B, Hoefels, Susanne, Hoogendijk, Witte, Hottenga, Jouke Jan, Iosifescu, Dan V, Ising, Marcus, Jones, Ian, Jones, Lisa, Jung-Ying, Tzeng, Knowles, James A, Kohane, Isaac S, Kohli, Martin A, Korszun, Ania, Landen, Mikael, Psychiatry, NCA - Neurobiology of mental health, Molecular Microbiology, Biological Psychology, and Neuroscience Campus Amsterdam - Neurobiology of Mental Health

Subjects
Male, Netherlands Twin Register (NTR), genetics [Transcriptome], Genome-wide association study, genetics [Stress, Psychological], Disease, genetics [Mental Disorders], Transcriptome, Cohort Studies, Mice, 0302 clinical medicine, Glucocorticoid receptor, Risk Factors, Gene Regulatory Networks, 0303 health sciences, General Neuroscience, Mental Disorders, Brain, genetics [Genetic Variation], Schizophrenia, genetics [Gene Regulatory Networks], genetics [Polymorphism, Single Nucleotide], medicine.medical_specialty, Neuroscience(all), BF, diagnosis [Mental Disorders], Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, physiology [Brain], SDG 3 - Good Health and Well-being, Genetic variation, medicine, Animals, Humans, ddc:610, Psychiatry, 030304 developmental biology, Mechanism (biology), Genetic Variation, medicine.disease, diagnosis [Stress, Psychological], Mice, Inbred C57BL, Endophenotype, RC0321, 030217 neurology & neurosurgery, Stress, Psychological, Forecasting
Abstract

Summary Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain. Video Abstract, Highlights • SNPs in long-range enhancers alter the transcriptional response of GR target genes • These functional SNPs predict risk for psychiatric but not other medical disorders • These variants are associated with differential neural circuit responses to threat • GR transcripts are strongly co-expressed and regulated in the brain of animal models, Using a stimulated eQTL approach, Arloth et al. show that common genetic variants that alter the initial transcriptome response to stress hormone receptor activation also cumulatively increase the risk for stress-related psychiatric disorders and predict a threat response from the amygdala.

Published
2015

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