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Rs6265, also called Val66Met or G196A, is a gene variation, a single nucleotide polymorphism (SNP) in the BDNF gene that codes for brain-derived neurotrophic factor.

Well over a hundred research studies have examined the polymorphism.

Association with neuropsychiatric disorders

A number of studies have examined the role of this polymorphism in risk of neuropsychiatric disorders , including schizophrenia and depression. It is generally thought that some variants of the polymorphism lead to memory impairment and susceptibility to neuropsychiatric disorders, and a 2007 meta-analysis of case-control studies found a relationship between the SNP and substance-related disorders, eating disorders, and schizophrenia. Another 2007 meta-analysis could, however, find no association between the SNP and schizophrenia or bipolar disorder. Meta-analyses of Alzheimer's disease and Parkinson's disease also indicate that the SNP has little or no association with these diseases. Also inconsistencies in association studies with depression have been noted.

The reason for these inconsistent results have been suggested to stem from several sources, with one recent review arguing that statistical artefact, sampling bias, population stratification and uncontrolled gene-environment interactions are likely to underscore this effect . These same authors recently published a report which found that transgenic mice engineered to express human BDNF as well as carry the Val66Met permutation are selectively sensitive to the glucocorticoid stress hormone corticosterone (rodent equivalent of cortisol), which in turn primes the fear circuitry and hippocampus-dependent memory function of Met/Met homozygous mice . As hippocampal function is a core component of several psychiatric conditions, and stress is a non-specific but substantial risk factor for affective, anxiety, eating and psychotic disorders, Notaras et al. argue that "there is a long-term effect of glucocorticoids in 66Met carriers that potentiates the fear circuitry into adulthood, which may increase susceptibility to trauma, events with negative emotional valence and related psychopathology". This interpretation is consistent with a suggested role of BDNF and the Val66Met polymorphism in post-traumatic stress disorder, where it has been shown that 66Met variant perturbs extinction learning in both man and mouse. The Val66Met polymorphism alters vulnerability to stress in mice and humans, which likely contributes to PTSD risk.

In treatment response studies val/val homozygotes may respond better than met allele carriers with drug resistant depression treated with repetitive transcranial magnetic stimulation.

Subject variables in healthy humans

One study has reported that met/met carriers tends to have lower body mass index compared to the two other genotypes. Another study showed that subjects with the val/val genotype had higher mean intelligence. The same study found no association with personality traits as measured with the Tridimensional Personality Questionnaire. Also a Polish 2007 study observed no significant relationship between the polymorphism and personality in healthy females. A German 2005 study could though find an association with personality traits measured with NEO-Five Factor Inventory, with Val/Val subjects scoring higher on anxiety and neuroticism dimensions. Large studies and a meta-analysis inclusive of over 15,000 subjects, however, found no association between the Val66Met and Neuroticism.

Other studies

A study in transgenic mice has found that met/met mice exhibits increased anxiety-related behaviors.

References

1. ^ Notaras, M.; Hill, R.; van den Buuse, M. (2015-08-01). "The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy". Molecular Psychiatry. 20 (8): 916–930. doi:10.1038/mp.2015.27. ISSN 1359-4184. PMID 25824305.
2. Notaras, Michael; Hill, Rachel; van den Buuse, Maarten (2015-04-01). "A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review". Neuroscience & Biobehavioral Reviews. 51: 15–30. doi:10.1016/j.neubiorev.2014.12.016. PMID 25562189. S2CID 25716989.
3. Ribeiro L, Busnello JV, Cantor RM, Whelan F, Whittaker P, Deloukas P, Wong ML, Licinio J (August 2007). "The brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism and depression in Mexican-Americans". NeuroReport. 18 (12): 1291–1293. doi:10.1097/WNR.0b013e328273bcb0. PMC 2686836. PMID 17632285.
4. Kevin G. Bath & Francis S. Lee (March 2006). "Variant BDNF (Val66Met) impact on brain structure and function". Cognitive, Affective, & Behavioral Neuroscience. 6 (1): 79–85. doi:10.3758/CABN.6.1.79. PMID 16869232.
5. Mònica Gratacòs, Juan R. González, Josep M. Mercader, Rafael de Cid, Mikel Urretavizcaya & Xavier Estivill (April 2007). "Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia". Biological Psychiatry. 61 (7): 911–912. doi:10.1016/j.biopsych.2006.08.025. PMID 17217930. S2CID 34873602.{{cite journal}}: CS1 maint: multiple names: authors list (link)
6. Kanazawa, Tetsufumi; Glatt, Stephen J.; Kia-Keating, Brett; Yoneda, Hiroshi; Tsuang, Ming T (June 2007). "Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder". Psychiatric Genetics. 17 (3): 165–170. doi:10.1097/YPG.0b013e32801da2e2. PMID 17417060. S2CID 25579523.
7. "META-ANALYSIS OF ALL PUBLISHED AD ASSOCIATION STUDIES (CASE-CONTROL ONLY) rs6265". Alzheimer Research Forum. Archived from the original on 2013-02-23. Retrieved 2008-06-20.
8. E. Zintzaras E; G. M. Hadjigeorgiou (2005). "The role of G196A polymorphism in the brain-derived neurotrophic factor gene in the cause of Parkinson's disease: a meta-analysis". J. Hum. Genet. 50 (11): 560–566. doi:10.1007/s10038-005-0295-z. PMID 16172806.
9. J. O. Groves (December 2007). "Is it time to reassess the BDNF hypothesis of depression?". Molecular Psychiatry. 12 (12): 1079–88. doi:10.1038/sj.mp.4002075. PMID 17700574.
10. ^ Notaras, M.; Hill, R.; Gogos, J. A.; van den Buuse, M. (2015-10-06). "BDNF Val66Met genotype determines hippocampus-dependent behavior via sensitivity to glucocorticoid signaling". Molecular Psychiatry. 21 (6): 730–2. doi:10.1038/mp.2015.152. ISSN 1476-5578. PMC 4879187. PMID 26821977.
11. Zhang, L.; Benedek, D. M.; Fullerton, C. S.; Forsten, R. D.; Naifeh, J. A.; Li, X. X.; Hu, X. Z.; Li, H.; Jia, M. (2014-01-01). "PTSD risk is associated with BDNF Val66Met and BDNF overexpression". Molecular Psychiatry. 19 (1): 8–10. doi:10.1038/mp.2012.180. ISSN 1359-4184. PMID 23319005.
12. Soliman, Fatima; Glatt, Charles E.; Bath, Kevin G.; Levita, Liat; Jones, Rebecca M.; Pattwell, Siobhan S.; Jing, Deqiang; Tottenham, Nim; Amso, Dima (2010-02-12). "A Genetic Variant BDNF Polymorphism Alters Extinction Learning in Both Mouse and Human". Science. 327 (5967): 863–866. Bibcode:2010Sci...327..863S. doi:10.1126/science.1181886. ISSN 0036-8075. PMC 2829261. PMID 20075215.
13. Notaras, Michael; van den Buuse, Maarten (2020-01-03). "Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders". Molecular Psychiatry. 25 (10): 2251–2274. doi:10.1038/s41380-019-0639-2. ISSN 1476-5578. PMID 31900428. S2CID 209540967.
14. Luisella Bocchio-Chiavetto, Carlo Miniussi, Roberta Zanardini, Anna Gazzoli, Stefano Bignotti, Claudia Specchia & Massimo Gennarelli (May 2008). "5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression" (PDF). Neuroscience Letters. 437 (2): 130–134. doi:10.1016/j.neulet.2008.04.005. hdl:11572/145667. PMID 18450378. S2CID 36187651.{{cite journal}}: CS1 maint: multiple names: authors list (link)
15. John Gunstad; Peter Schofield; Robert H. Paul; Mary Beth Spitznagel; Ronald A. Cohen; Leanne M. Williams; Michael Kohn; Evian Gordon (2006). "BDNF Val66Met Polymorphism Is Associated with Body Mass Index in Healthy Adults". Neuropsychobiology. 53 (3): 153–156. doi:10.1159/000093341. PMID 16707914. S2CID 45218374.
16. Shih-Jen Tsaia; Chen-Jee Hong; Younger W.-Y. Yuc; Tai-Jui Chen (2004). "Association Study of a Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism and Personality Trait and Intelligence in Healthy Young Females". Biological Psychiatry. 49 (1): 13–16. doi:10.1159/000075333. PMID 14730195. S2CID 45591436.
17. Rybakowski F, Dmitrzak-Weglarz M, Szczepankiewicz A, Skibinska M, Slopien A, Rajewski A, Hauser J (April 2007). "Brain derived neurotrophic factor gene Val66Met and -270C/T polymorphisms and personality traits predisposing to anorexia nervosa". Neuro Endocrinol. Lett. 28 (2): 153–158. PMID 17435670.
18. Undine E. Lang; Rainer Hellweg; Peter Kalus; Malek Bajbouj; Kirsten P. Lenzen; Thomas Sander; Dieter Kunz; Jürgen Gallinat (June 2005). "Association of a functional BDNF polymorphism and anxiety-related personality traits". Psychopharmacology. 180 (1): 95–99. doi:10.1007/s00213-004-2137-7. PMID 15918078. S2CID 32939759.
19. Terracciano, Antonio; Tanaka, T.; Sutin, A.R.; Deiana, B.; Balaci, L.; Sanna, S.; Olla, N.; Maschio, A.; Uda, M.; Ferrucci, L.; Schlessinger, D.; Costa, P.T. Jr (2010). "BDNF Val66Met is associated with introversion and interacts with 5-HTTLPR to influence neuroticism". Neuropsychopharmacology. 35 (5): 1083–1089. doi:10.1038/npp.2009.213. PMC 2840212. PMID 20042999.
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