Electronic Letters to:
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eLetters: Electronic letters published:
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The BDNF Val66Met polymorphism and the affective component – another false positive?
- Timothy J Crow (13 May 2009)
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Response to Dr. Crow
- Todd Lencz, Robert H. Lipsky, Pamela DeRosse, Katherine E. Burdick, David Goldman, Colin Hodgkinson, John M. Kane, Anil K. Malhotra (27 May 2009)
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Val66Met and Bipolar Disorder: suggestions from previous studies
- Alvaro M. Dias (3 June 2009)
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Response to Mr. Dias
- Todd Lencz, Anil K Malhotra (15 June 2009)
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Timothy J Crow, Hon Director SANE POWIC Warneford Hospital
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tim.crow{at}psych.ox.ac.uk Timothy J Crow
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Dear Sir I read the paper by Lencz et al. 1 with concern for the future of psychosis genetics. These authors claim that their candidate gene study of BDNF is "the first… to demonstrate association with schizo-affective disorder but not schizophrenia” and therefore that “BDNF variation is associated with psychiatric disorders with a primary affective component”. To reach this conclusion they argue on the basis of a sample size of 596 individuals against two meta-analyses and two cohort studies with sample sizes between six and 26 times larger (table). Each of these studies examined the Val66Met polymorphism the subject of Lencz et al’s report and reached the conclusion that BDNF genotype does not exert an influence on the development of affective illness whether or not associated with psychosis. Table. Sample sizes and P-values of the main findings of two recent studies of the Val66Met variation in BDNF in relation to psychiatric diagnosis compared to Lencz et al.1 BWHHS - British Women's Heart & Health Study; ALSPAC - Avon Longitudinal Study of Parents and Children. A literature survey indicates between 2004 and 2009 these authors between them published 25 papers relating to associations of 19 genes with aspects of psychiatric disease. Concerning one gene (FEZ1) they drew negative conclusions, but concerning each of the other 18 they claim a relationship was established. Such a rate of gene discovery would be a remarkable achievement. My review of the linkage literature 4, as represented by the four largest (each >300 sibpairs) studies suggests that none of Lencz et al’s candidate genes were replicated in these systematic searches, and the association study of Sanders et al 5 that investigated six of them (DISC1, DAOA, HTTLPR, DTNBP1, COMT, DRD2 receptor) in 1870 cases and 2002 controls concluded these genes were unrelated to psychosis. When large numbers of variables are examined simultaneously alluring relationships can often be discerned that evaporate in the wider context of large and systematic studies. It appears that by ignoring this context Lencz et al are operating an algorithm for generating positive associations in selected data sets. Reference List (1) Lencz T, Lipsky RH, DeRosse P, Burdick KE, Kane JM, Malhotra AK. Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes. Brit J Psychiatry 2009; 194: 313-8. (2) Kanazawa T, Glatt SJ, Kia-Keating B, Yoneda H, Tsuang MT. Meta- analysis reveals no association of the Val66Met polymorphism of brain- derived neurotrophic factor with either schizophrenia or bipolar disorder. Psychiatric Genet 2007; 17: 165-70. (3) Chen L, Lawlor DA, Lewis SJ, Yuan W, Abdollahi MR, Timpson NJ, et al. Genetic association study of BDNF in depression: Finding from two cohort studies and a meta-analysis. Am J Med Genet (Neuropsychiatric Genet ) 2008; 147B(6): 814-21. (4) Crow TJ. How and why genetic linkage has not solved the problem of psychosis: review and hypothesis. Am J Psychiatry 2007; 164: 13-21. (5) Sanders AR, Duan J, Levinson DF, Shi J, He D, Hou C, et al. No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry 2008; 165(4): 497-506. |
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Todd Lencz, Associate Director of Research The Zucker Hillside Hospital, Robert H. Lipsky, Pamela DeRosse, Katherine E. Burdick, David Goldman, Colin Hodgkinson, John M. Kane, Anil K. Malhotra
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lencz{at}lij.edu Todd Lencz, et al.
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Dear Sir, Dr. Crow is concerned that the publication of our recent study on BDNF endangers the field of psychiatric genetics. We would suggest that this concern may be overstated for the following reasons: 1) Dr. Crow claims that the two meta-analyses and two cohort studies invalidate our results. We find this conclusion to be puzzling, given that none of these studies assessed the phenotype of schizoaffective disorder. Notably, the cohort studies relied on a single self-report item as the primary assessment of psychopathology. We addressed limitations of the meta-analyses in our original paper. We suggest that careful and comprehensive examination of the diverse phenotypes associated with neuropsychiatric illness may be a more fruitful approach. 2) Dr. Crow cites his own review of the linkage literature to suggest that most of the candidate genes reported by our group, and many others, are not supported by linkage studies, and thus should be discounted. This reasoning is based on a flawed understanding of the role of linkage in complex disorders and is inconsistent with a large body of recent empirical evidence in complex genetics. In other complex disorders, a majority of susceptibility loci that have been unambiguously replicated in association studies fall outside of previously identified areas of even suggestive linkage (e.g., reference 1). Therefore, an argument utilizing nonsignificant linkage data to invalidate a subsequent candidate gene association is erroneous. 3) Dr. Crow notes the productivity of our lab over the last several years as a source of concern for him. In so doing he mischaracterizes our papers. First, Dr. Crow is simply incorrect in stating that only one paper reports strictly negative results (references 2,3). Moreover, many of our papers report complex relationships that are not so simplistically reduced to “positive” vs. “negative”. More importantly, Dr. Crow fails to mention that most our papers are not simply analyses of association to schizophrenia diagnosis, but instead examine alternative phenotypes. For example, our study of DRD2 (ref. 4) assessed the relationship between a functional promoter region polymorphism and clinical response to olanzapine and risperidone in the context of a randomized controlled clinical trial in first episode schizophrenia. Therefore, it is not surprising that our DRD2 results were not “replicated” in either linkage studies or the association study of Sanders et al. (5), as these papers were restricted to mere association to diagnosis. Finally, we reluctantly note that Dr. Crow has made similarly erroneous assertions about various research groups across a number of venues (letters to the editor, theoretical articles, and public remarks), despite repeated correction. His criticisms invariably reflect a failure to understand the implications of the pathophysiologic complexity of psychiatric disorders and the heterogeneity of the underlying genetics. While Dr. Crow is entitled to his opinions, the field of psychiatric genetics may be better served by more constructive discussion leading towards a better understanding of the complexities of these devastating disorders. References: (1)JC Barrett et al. (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nature Genetics, 40: 955-962. (2)Funke BH, Lencz T, Finn CT, DeRosse P, Poznik GD, Plocik AM, Kane J, Gregersen PK, Rogus J, Malhotra AK, Kucherlapati R. (2007) Analysis Of TBX1 variation in patients with psychotic and affective disorders. Molecular Medicine,13: 407-14. (3)Hodgkinson CA, Goldman D, Ducci F, DeRosse P, Caycedo DA, Newman ER, Kane JM, Roy A, Malhotra AK. (2007) The FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations. Neuropsychopharmacology, 32: 190-6. (4) Lencz T, Robinson DG, Xu K, Ekholm J, Sevy S, Gunduz-Bruce H, Woerner MG, Kane JM, Goldman D, Malhotra AK. (2006) DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first- episode schizophrenia patients. American Journal of Psychiatry, 163: 529-531. (5) Sanders AR, Duan J, Levinson DF, Shi J, He D, Hou C, et al. (2008) No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry, 165: 497-506. |
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Alvaro M. Dias, Doctorial Candidate University of Săo Paulo
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alvaromd{at}usp.br Alvaro M. Dias
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Dear Sir I read the paper by Lencz et al with great enthusiasm (1). Schizoaffective disorders are not only genetically puzzling, but are clinically challenging. New genetic findings may contribute to the development of new ad hoc treatment in the near future, as much as they warn clinicians of the importance of interventions to increase BDNF levels in the proper circumstances. Despite the enthusiasm, I must admit that I was puzzled with the statement “Most prior case-control association studies of BDNFVal66Met in bipolar disorder have been negative (except for one)”, so I searched Pubmed to find out whether it is true or not. “BDNF and Bipolar disorder” retrieves 166 results, among which 22 are BDNF Val66Met case-control association studies. 14 of these studies endorse an association between bipolar disorder and Val66Met, while only 8 deny it. For some examples: (2-4). There are also 7 indirect findings (e.g. post-mortem studies, studies based on BDNF serum level, and associations between BDNF and brain morphology). One interesting fact is that, proportionally the Val66Met polymorphism is less associated with the Asiatic BD population then to Caucasians; e.g. considering the above 14 studies, only 3 were based on Asiatic samples. If we only take into account the Caucasian BD population (that is, if we focus on the cohort of the present study), we may say that Val66Met is a well established SNP risk factor. Unfortunately, I cannot cite all these papers here but I will be glad to provide this review to anyone who asks. Moreover, despite the fact that the authors have no obligation to know all the previous studies in the field, their statement that “(to our knowledge) this is the first candidate gene study to demonstrate association with schizoaffective disorder but not schizophrenia”, contrasts with the recent publication of a molecular-genetic study addressing nosological differences between schizoaffective disorder and schizophrenia based on the following genetic polymorphisms: 5-HTR2A, 5-HTTLPR and BDNF (5). This study included 563 patients with schizophrenia, 171 with schizoaffective disorder and 536 normal controls. Interestingly, one of the main findings was that schizoaffective disorder indeed has some genetic specificities, among which the authors point to a higher frequency of genotypes with BDNF Met alleles, as much as SS genotype of the 5-HTTLPR (short arm of the serotonin receptor gene), which is known to be associated with major depression. In conclusion to this point, we may consider that it is not the case to say that Lencz et al main findings are not new, but that the idea as a whole indeed was tested before and that the results could be found in Pubmed and many other databases. References 1. Lencz T, Lipsky RH, DeRosse P, Burdick KE, Kane JM, Malhotra AK. Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes. Br J Psychiatry. 2009 Apr;194(4):313-8. 2. Liu L, Foroud T, Xuei X, Berrettini W, Byerley W, Coryell W, et al. Evidence of association between brain- derived neurotrophic factor gene and bipolar disorder. Psychiatr Genet. 2008 Dec;18(6):267-74. 3. Lohoff FW, Sander T, Ferraro TN, Dahl JP, Gallinat J, Berrettini WH. Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet. 2005 Nov 5;139B(1):51-3. 4. Tramontina J, Frey BN, Andreazza AC, Zandona M, Santin A, Kapczinski F. Val66met polymorphism and serum brain-derived neurotrophic factor levels in bipolar disorder. Mol Psychiatry. 2007 Mar;12(3):230-1. 5. Golimbet VE, Abramova LI, Kaleda VG, Alfimova MV, Korovaitseva GI, Lavrushina OM, et al. [The molecular- genetic aspects of differentiation of schizoaffective psychosis and attack-like progressive schizophrenia]. Vestn Ross Akad Med Nauk. 2007(3):3-8. |
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Todd Lencz, Associate Director of Research The Zucker Hillside Hospital, Anil K Malhotra
Send letter to journal:
lencz{at}lij.edu Todd Lencz, et al.
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Dear Sir, We appreciate the interest of Mr. Dias, a student at University of Sao Paolo, in our recent paper (1), and we agree that the relationship between BDNF and affective disorders is an important and rapidly advancing area of investigation. As noted by Mr. Dias, our study presented evidence for an association between BDNF polymorphisms and bipolar disorder. We must respectfully disagree, however, with his suggestion that prior literature demonstrates that BDNF Val66Met was already “a well established SNP risk factor” for bipolar disorder in Caucasian populations. As noted in our paper, it is more accurate to characterize the published record as of the time of our writing as mixed. Mr. Dias cites three articles supporting his conclusion (2- 4); however, these citations are inapposite to his point. The first article (2) was published after our manuscript was accepted for publication, and therefore was not included in our literature review. The second article (3) was cited in our manuscript as a notable example of association, contrary to the impression left by Mr. Dias. The third article (4) is erroneously cited by Mr. Dias as supporting an association between BDNF Val66Met and bipolar disorder. In fact, the article reports negative results: no significant association of BDNF Val66Met to illness or to serum BDNF levels. Finally, Mr. Dias calls our attention to a recent paper in a Russian-language journal (5) investigating genetic associations to schizoaffective disorder. While we are intrigued that other groups are studying similar questions, we are unable to evaluate this Russian-language article. To our knowledge, our report remains the only study in the English-language literature to demonstrate a molecular differentiation between schizophrenia and schizoaffective disorder. References 1. Lencz T, Lipsky RH, DeRosse P, Burdick KE, Kane JM, Malhotra AK. Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes. Br J Psychiatry. 2009 Apr;194(4):313-8. 2. Liu L, Foroud T, Xuei X, Berrettini W, Byerley W, Coryell W, et al. Evidence of association between brain- derived neurotrophic factor gene and bipolar disorder. Psychiatr Genet. 2008 Dec;18(6):267-74. 3. Lohoff FW, Sander T, Ferraro TN, Dahl JP, Gallinat J, Berrettini WH. Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet. 2005 Nov 5;139B(1):51-3. 4. Tramontina J, Frey BN, Andreazza AC, Zandona M, Santin A, Kapczinski F. Val66met polymorphism and serum brain-derived neurotrophic factor levels in bipolar disorder. Mol Psychiatry. 2007 Mar;12(3):230-1. 5. Golimbet VE, Abramova LI, Kaleda VG, Alfimova MV, Korovaitseva GI, Lavrushina OM, et al. [The molecular- genetic aspects of differentiation of schizoaffective psychosis and attack-like progressive schizophrenia]. Vestn Ross Akad Med Nauk. 2007(3):3-8. |
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