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Modulatory effects of brain-derived neurotrophic factor Val66Met polymorphism on prefrontal regions in major depressive disorder

  • Rebecca MacGregor Legge (a1), Shahbaz Sendi (a1), James H. Cole (a2), Sarah Cohen-Woods (a3), Sergi G. Costafreda (a4), Andrew Simmons (a5), Anne E. Farmer (a6), Katherine J. Aitchison (a7), Peter McGuffin (a8) and Cynthia H. Y. Fu (a9)...

Abstract

Background

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism contributes to the development of depression (major depressive disorder, MDD), but it is unclear whether neural effects observed in healthy individuals are sustained in MDD.

Aims

To investigate BDNF Val66Met effects on key regions in MDD neurocircuitry: amygdala, anterior cingulate, middle frontal and orbitofrontal regions.

Method

Magnetic resonance imaging scans were acquired in 79 persons with MDD (mean age 49 years) and 74 healthy volunteers (mean age 50 years). Effects on surface area and cortical thickness were examined with multiple comparison correction.

Results

People who were Met allele carriers showed reduced caudal middle frontal thickness in both study groups. Significant interaction effects were found in the anterior cingulate and rostral middle frontal regions, in which participants in the MDD group who were Met carriers showed the greatest reduction in surface area.

Conclusions

Modulatory effects of the BDNF Val66Met polymorphism on distinct subregions in the prefrontal cortex in MDD support the neurotrophin model of depression.

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Copyright

Corresponding author

Dr C. H. Y. Fu, School of Psychology, University of East London, Stratford Campus, Water Lane, London E15 4LZ, UK. Email: c.fu@uel.ac.uk.

Footnotes

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These authors contributed equally to the paper.

Declaration of interest

None.

Footnotes

References

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Modulatory effects of brain-derived neurotrophic factor Val66Met polymorphism on prefrontal regions in major depressive disorder

  • Rebecca MacGregor Legge (a1), Shahbaz Sendi (a1), James H. Cole (a2), Sarah Cohen-Woods (a3), Sergi G. Costafreda (a4), Andrew Simmons (a5), Anne E. Farmer (a6), Katherine J. Aitchison (a7), Peter McGuffin (a8) and Cynthia H. Y. Fu (a9)...
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Ethnic differences in BDNF Val66Met polymorphism

I read with great interest the article 'Modulatory effects of brain-derived neurotrophic factor Val66Met polymorphism on prefrontal regions in major depressive disorder' in May’s issue [of the British Journal of Psychiatry]. I would like to thank the authors for their hard work investigating such an interesting topic.

The article focused on brain derived neurotrophic factor’s (BDNF's) Val66Met polymorphism contribution to major depressive disorder (MDD) and the authors’ quest to determine if the same neural effects would be observed in healthy individuals. There was a specific focus on cortical thickness in the amygdala, prefrontal regions of the anterior cingulate cortex and middle frontal and orbitofrontal cortices. The study focused on 79 patients with diagnosed major depressive disorder and 74 control subjects, all of white European ancestry. The main effects were of Met- carrier status on cortical thinning in the caudal middle frontal cortex in MDD and controls. The polymorphism in the caudate middle frontal was greater and no significant interaction was found in the amygdala.

One limitation not covered by the authors was the lack of ethnic diversity amongst the sample population. One previous study (Ribero et al. ,2007) investigated the BDNF polymorphism in an exclusively Mexican

-American experimental and control population and found it also to be associated with MDD. However, previous studies have displayed the polymorphism has allele frequencies dependent on ethnic background. In Caucasian populations, The Val- allele is found to be the most common and the frequency of the Met- allele is 25-32% (Cargill et al., 1999 and Shimizu, Hashimoto, Iyo, 2004). In Asian populations the Met allele is more frequent, being around 40-50% (Choi et al. 2006, Itoh, Hashimoto, Kumakiri, Shimizu, Iyo, 2004, & Tsai et al. 2003). As Legge et al. found the Met- allele had the greatest effect on MDD one would assume it would be paramount importance to examine how differing frequencies affect the occurrence of MDD. Pivac et al. (2009) in their study on ethnic differences in BDNF val66met polymorphism in a Croatian and Korean non-clinical sample found polymorphisms and mood disorders may be dependent on ethnicity.

Searches for studies of the BDNF polymorphism in African-Carribbean and other ethnicities obtained no results. As generalisable conclusions cannot be drawn on the varying effects of the BDNF polymorphism on MDD or any major psychiatric illness on different ethnic groups, further examination into this topic would be significant.

References

Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw, N., Lane, C.R., Lim, E.P., Kalyanaraman, N., Nemesh, J., Ziaugra, L., Friedland, L., Rolfe, A., Warrington, J., Lipshutz, R., Daley, G.Q., Lander, E.S. (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature Genetics, 22: 231–238.

Choi M.J., Kang R.H., Lim S.W., Oh K.S., Lee M.S (2006) Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Research. 1118, 176–182.

Itoh K., Hashimoto K., Kumakiri C., Shimizu E., Iyo M. (2004) Association between brain-derived neurotrophic factor 196 G/A polymorphism and personality traits in healthy subjects. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 124, 61–63.

Legge, R.M., Sendi, S., Cole, J.H., Cohen-Woods, S., Costafreda, S.G., Simmons, A., Farmer, A.E., Aitchison, K.J., McGuffin, P., Fu, C.H.Y. (2015) Modulatory effects of brain-derived neurotrophic factor Val66Met polymorphism on prefrontal regions in major depressive disorder. The British Journal of Psychiatry, 206, 5, 379-384.

Pivac N., Kim B., Nedić G., Joo Y.H., Kozarić-Kovacić D., Hong J.P., Muck-Seler D. (2009) Ethnic differences in brain-derived neurotrophic factor Val66Met polymorphism in Croatian and Korean healthy participants. Crotian medical journal, 50, 1, 43-48.

Shimizu E., Hashimoto K., Iyo M. (2004). Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 126, 122–123.

Tsai S.J., Cheng C.Y., Yu Y.W., Chen T.J., Hong C.J. (2003) Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 123, 19–22.

Verhagen M,. van der Meij A., van Deurzen P.A., Janzing J.G., Arias-Vasquez A., Buitelaar J.K., Franke B. (2010). Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Molecular Psychiatry, 15, 260–71.

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