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Potential Effects of rs6265 (BDNF): Stress, Weight, Cognition + More

Written by Puya Yazdi, MD | Last updated:
Matt Carland
Medically reviewed by
Matt Carland, PhD (Neuroscience) | Written by Puya Yazdi, MD | Last updated:

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One of the most well-studied genetic variants in the BDNF gene is the SNP rs6265. The variant that a person carries for this SNP has been reported to affect how much BDNF their brain produces. Because BDNF is believed to be critical for many important processes – such as neurogenesis and synaptic plasticity – this genetic variation could potentially have a variety of significant effects on various aspects of physical health and mental well-being. In this post, we’ll discuss what some of the latest science has to say about some of the effects that may be associated with certain genotypes for this SNP. Read on to learn more!

What Is The rs6265 Variant?

In our previous post on the BDNF gene SNP rs6265, we discussed how certain variants in this gene may influence the amount of BDNF a person produces, as well as some of the potential mechanisms that might be responsible for these differences.

If you missed that post, we highly recommend starting there first – you can find it by clicking here.

Additionally, if you want a more detailed breakdown of exactly what BDNF is and why it’s important, we recommend checking out our comprehensive post on BDNF here.

In this post, we’ll turn to discussing some of the scientific findings that have associated each of the different rs6265 genotypes with more complex effects, which may, in turn, affect various aspects of physiological and psychological health!

You can use SelfDecode to find out what your genotype is.

However, once again keep in mind the limitations and caveats we discussed in the previous post! These findings are all just associations, and these links have not been demonstrated to be directly causative yet. Therefore, just because you have a certain genotype does not automatically mean that you will have any of the traits or conditions that have been associated with that genotype.

With that in mind, let’s see what the science has to say about what the different genotypes for the BDNF SNP rs6265 could potentially mean!

BDNF (rs6265) and Weight

A number of studies have investigated the relationship between this BDNF variant and body weight/obesity.

For example, in men, carriers of the ‘CC’ genotype for rs6265 have been reported to have roughly twice the risk of being overweight compared to people with one or more ‘T’ alleles. However, this same study reported the opposite association in women, where carriers of the ‘CC’ genotype were reported to be up to 50% less likely to be overweight, compared to carriers of one or more ‘T’ alleles [1]. The results of this study may, therefore, suggest that some of this BDNF variant’s effects may be sex-specific, and more research will be needed to fully tease these nuances out.

Relatedly, some early evidence suggests that rs6265 may influence the effects of certain diets on overall body weight. For example, one study reported that among men with the ‘CC’ genotype, those who consumed diets rich in poly-unsaturated fatty acids (PUFAs) tended to weigh significantly less than ‘CC’ carriers with other diets [1]. This may suggest that people who carry the ‘CC’ genotype may be more likely to benefit from a high-PUFA diet.

This same study also reported a similar trend among women with the ‘CC’ genotype, although this effect was smaller, and ultimately failed to reach statistical significance [1]. This may suggest that this association, too, is sex-specific.

While these early findings are promising, much more research will still be needed before any firm conclusions can be made about the effect of this particular BDNF variant on overall body weight.

BDNF (rs6265) and the Stress Response

Preliminary findings from some early studies may suggest that BDNF variants – such as rs6265 – may also play a key role in how the body and brain respond to stress.

For example, one study has reported that men with the ‘CC’ genotype showed a larger increase in salivary levels of the “stress hormone” cortisol compared to men with one or more ‘T’ alleles [2].

Relatedly, another study has also reported that carriers of the ‘T’ allele for rs6265 showed significantly less stress-related activity in the HPA axis compared to people with the ‘CC’ genotype [2].

While these initial findings might seem to suggest that carriers of the ‘CC’ genotype might be relatively more sensitive to stress in general, at least one additional study has actually reported the opposite effect! According to this study, ‘CC’ carriers were reported to actually show less stress-induced anxiety-like behaviors compared to people with the ‘TT’ genotype [3].

Overall, while some early evidence suggests a potential relationship between rs6265 genotype and the stress response, the complicated and sometimes-contradictory nature of the findings so far indicates that this relationship may be quite complex, and will most likely need a lot more intensive research before we can fully understand the nuances behind it.

BDNF and Stress: Potential Mechanisms

If there is a potential link between BDNF and stress, what might the nature of this relationship be, and what mechanisms might be responsible?

Some clues come from animal studies. For example, injections of BDNF into the hypothalamus of animals led to increased production of the stress-related hormone CRH, and activated the brain’s HPA axis [4].

In other words, increased BDNF in the hypothalamus may stimulate the stress response (via CRH), whereas reduced expression of BDNF, in general, has been associated with a somewhat suppressed stress response (again via CRH).

However, research from other stress-related mechanisms suggests that the main “stress hormone” cortisol sometimes “shuts off” the stress response by decreasing BDNF levels in the hypothalamus. When cortisol levels are not regulated properly – which can sometimes occur in response to both chronic or severe acute stress – CRH levels can also become dysregulated (elevated), which causes the stress response to be chronically activated [4].

If BDNF also acts on the stress response by increasing CRH levels, this may potentially explain why people who produce more BDNF (i.e. the ‘CC’ genotype) might tend to be more sensitive to stress.

Additionally, some research suggests that BDNF increases neural activity in certain brain regions that produce and secrete CRH – such as the paraventricular nucleus, or PVN – by suppressing GABA, the brain’s main “inhibitory” neurotransmitter. This means that increased BDNF levels in these regions would actually increase CRH levels (i.e. by “inhibiting the inhibitor,” or double-inhibition) These elevated CRH levels would in turn chronically stimulate the HPA axis, thereby potentially leading to symptoms resembling chronic stress [5].

In any case, this is just an “educated guess” about some of the possible mechanisms involved in the relationship between BDNF levels and stress – and much more research will still be needed in order to explore this relationship in greater detail.

BDNF (rs6265) and Depression

Some links have also been suggested between this particular BDNF variant and depression.

For example, one of the other significant biological factors that have been linked to depression is the levels of cortisol that a person has in their body and brain in the morning after waking up. However, this link between morning (“AM”) cortisol may depend on a person’s genotype for rs6265 [6]:

  • ‘CC’: higher AM cortisol levels = relatively increased risk of depression
  • ‘CT’/’TT’: lower AM cortisol levels = relatively increased risk of depression

Screenshot 2015-01-17 12.10.41

In other words, people with different specific BDNF genotypes may experience a greater risk of mood disorders in different scenarios.

BDNF and Depression: Potential Mechanisms

While the links between rs6265 genotype and depression risk will still have to be followed-up on and confirmed by extensive additional research, if there is in fact a link here, why might this be?

As we discussed in the previous section, high cortisol levels often go hand-in-hand with high CRH levels. Therefore, if a person has a “high-producing” BDNF genotype (i.e. ‘CC’), their brain could have more difficulty in shutting down the HPA axis’ stress response (since that elevated BDNF will also be stimulating high CRH levels) [4].

This could contribute to stress – but where does the link to depression come in?

Well, CRH has also been reported to have a variety of negative effects on a wide range of different hormones involved in regulating the circadian rhythm. This is the body’s “master clock” that is important for controlling many important behaviors, such as appetite and sleep. Moreover, circadian rhythm disruptions are very common in mood disorders, and are widely believed to play some sort of causal (albeit highly complex) role in the development of depression.

Therefore, one possibility is that the links between BDNF and depression might be at least partially explained by the complex interactions of these compounds with the circadian rhythm. However, much more research will still be needed to verify this potential explanation for sure.

BDNF (rs6265) and Cognitive Function

Possibly due to the key role that BDNF plays in important brain functions such as neurogenesis and synaptic plasticity [7, 8, 9], SNPs in the BDNF gene have been associated with a number of different cognitive functions, including overall cognitive ability [10, 11], fluid intelligence (“performance IQ”) [12], learning and memory [13, 14, 15, 16], cognitive flexibility (executive function) [17], and even total brain volume [18, 19].

Moreover, low levels of BDNF may also be associated with reduced synaptic plasticity in several key brain areas (such as the hippocampus) – at least according to a few early studies [15, 20, 21, 22].

For these reasons, some researchers have looked at the possibility that the rs6265 BDNF variant may affect overall intelligence. For example, one early study reported that carriers of the ‘CC’ genotype for this SNP may have slightly higher intelligence (IQ) compared to ‘T’ allele carriers [23].

However, some follow-up studies have failed to find this association. In fact, a meta-analysis from 2012 combined data from a large number of individual studies, and concluded that there was not yet any strong evidence for an effect of rs6265 genotype on a person’s overall intelligence [24].

Nonetheless, there is still some evidence that this SNP may affect some specific cognitive functions, at least in certain specific brain regions. Many of these studies have focused on the hippocampus in particular, which is a brain region that is widely believed to play a critical role in many forms of learning and memory.

According to one early study, human ‘T’ allele carriers were reported to show slightly reduced overall hippocampal activity. The authors of this study also proposed that this allele may slightly reduce synaptic plasticity in this brain area, although the evidence is not fully conclusive yet [25, 26].

Relatedly, another similar study reported a slight association of the ‘T’ allele with reduced hippocampal volume. However, this same study also reported that there was no effect of this allele on the actual structure of the hippocampus, nor did it appear to impact memory performance in any noticeable or significant manner [27].

Overall, while some preliminary evidence suggests that a person’s genotype for this SNP may have some effect on certain specific forms of cognitive function, much more research will still be needed to determine exactly what these effects might be, as well as if they actually play a significant role in cognitive function across people with different rs6265 genotypes.

Other Reported Associations of rs6265

In addition to some of the purported effects we’ve discussed so far, there is also much research that has been done on a wide variety of other possible influences that this BDNF variant may have.

We’ll briefly describe some of these very diverse findings below: but as we can see, many of the results are quite mixed, and paint a picture that is rather complex and difficult to boil down into a single or simple summary!

Once again, keep in mind that all of the associations described below are just that – associations – and that the science behind these potential effects are still in a very early stage. As such, these reported findings should be taken with a healthy grain of salt until much more additional research is done to fully confirm and extend these preliminary findings. Until then, none of these findings should be taken to mean that a person with these genotypes or alleles will necessarily have (or develop) any of the following traits or conditions.

Potential Associations with the ‘CC’ Genotype

According to preliminary research, the ‘CC’ (homozygous major) genotype for rs6265 may be associated with:

  • Approximately 20 minutes more “slow-wave” sleep (stage-3 and stage-4 sleep) per night, along with somewhat shorter phases of “superficial” (stage-2 sleep) and increased overall “sleep intensity” (compared to ‘CT’) [25]
  • More alpha brainwave activity during wakefulness, and more alpha-, theta-, and sigma brainwave activity during REM (“deep”) sleep (compared to ‘CT’) [25]
  • Better response accuracy on a verbal 2-back working memory task (compared to ‘T’ allele carriers) [28]
  • Better performance on a spatial working memory task (compared to ‘TT’; study in Chinese population only) [29]
  • Better antidepressant response to treatment with transcranial magnetic stimulation (TMS) in treatment-resistant depression (compared to ‘CT’) [23]
  • More responsive to positive and negative emotional cues (e.g. happy- or sad-face stimuli (compared to ‘CT’) [30]
  • Slightly higher risk of allergies (compared to ‘T’ allele carriers) – especially among patients with allergic rhinitis, asthma, and atopic eczema [31]
  • Possibly slightly higher scores on self-reported measures of trait anxiety and neuroticism (compared to ‘T’ allele carriers) [32]: however, this result was only a trend in the data, and did not reach full statistical significance; also, other similar studies were unable to replicate this association [32]

Potential Associations with the ‘T’ Allele

Compared against people with the ‘CC’ genotype, some preliminary research suggests that carrying one or more ‘T’ alleles for rs6265 (i.e. having the ‘CT’ or ‘TT’ genotypes) may be associated with:

  • Lower overall average body mass index (BMI) [23]
  • Lower systolic blood pressure [33]
  • Higher levels of introversion [34, 32] (Interestingly, because the ‘T’ allele for this SNP is significantly more prevalent among Asian populations, some researchers have suggested that this genetic difference may account for the relatively higher levels of anxiety often reported in Asian populations [35])
  • Possibly reduced risk of certain neurodegenerative disorders, such as Parkinson’s and Huntington’s disease, Lupus, and multiple sclerosis (MS) [36]
  • Somewhat lower risk of depression induced by stress from repeated social defeat [37]
  • Significantly lower rates of symptoms related to reduced sexual drive/desire (OR=0.32; p<0.01) [38]
  • Reduced decrease in brain size (grey matter volume) caused by MS [39]
  • May be slower to recover from certain brain injuries (such as strokes) [36]
  • Increased tendency to binge-eat after a prolonged period of dietary restriction [40]
  • Increased rates of eating disorders (+33%) and schizophrenia (+19%), but decreased rates of substance-abuse disorders (-21%) [41]
  • Somewhat poorer executive functioning in OCD [42]
  • Possibly increased rates of Alzheimer’s disease (in non-APOE4 risk allele carriers) [43]
  • A weaker memory bias for positive-emotion words during early development/childhood [44]

Other BDNF Genes

Because rs6265 is one of the most well-studied SNPs in the BDNF gene, we have focused on the wealth of preliminary scientific data available for this particular variant in this post.

Nonetheless, this SNP is far from the only important BDNF variant! There are many other SNPs that have been associated with BDNF production, levels, and potential health-related traits or effects.

All of the SNPs listed below are also a part of the BDNF gene – and you can use SelfDecode to explore your genetic variants even further:

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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