How Might This Gene Influence Cognitive Function? (BCL2)

As you go about your daily life, the cells in your body are continually being exposed to sources of potential stress and damage. One well-known example is oxidative stress. While a certain amount of oxidative stress is perfectly normal, too much of it can cause damage to your cells, or the DNA inside them.

Usually, when your cells detect damage of some kind, one of two things will happen:

When the damage isn’t too severe, a damaged cell will activate mechanisms that come in and repair it, bringing the cell back to normal. For example, the PARP1 gene is one of the mechanisms that your body uses to repair damaged DNA, which helps cells to recover from oxidative stress and other common causes of DNA damage. (You can learn more about this gene —and your genotype for it— in our SelfDecode Blog post on PARP1.)

However, sometimes the damage is more serious. In this case, the cell might instead decide to undergo a process called apoptosis: a kind of “self-destruct” mechanism that causes the cell to kill itself! This ultimately helps your body out by allowing a newer, healthier cell to take its place instead.

Your cells have two main ways of responding to damage. When the damage isn’t too bad, they will get fixed up by the body’s natural repair mechanisms. However, when the damage is more severe, they will actually “self-destruct” through a process called apoptosis, making way for a healthy new cell to take its place!

Why Is Apoptosis Important?

Although it might seem odd that your cells come with a built-in “self-destruct” trigger, there’s actually a very good reason for this! This is because cell damage can occasionally lead to mutations in its DNA that will cause it to reproduce uncontrollably.

In fact, this is how tumors often start — and tumorous cells can go on to develop into full-blown cancer unless your body finds a way to stop these tumorous cells from reproducing further.

Therefore, telling cells to “self-destruct” when their DNA gets damaged is one of the key mechanisms that your body uses to protect itself against cancer — it’s basically playing it safe by simply killing off the cell before it has a chance to turn into an even greater problem!

In this post, we’ll be looking at BCL2, a gene that plays a role in deciding when damaged cells get repaired, versus when they “self-destruct”. As we will see, keeping these two processes in careful balance can be important for many different aspects of your health.

Apoptosis is important because it is one of the key ways that your body actively prevents damaged cells from potentially turning into cancers.

The BCL2 gene is activated whenever cells experience stress or damage. When activated, this gene basically acts as a signal that tells the damaged cell not to self-destruct, so that it keeps itself alive while it waits to get repaired by other mechanisms [R].

In other words, this gene protects cells from dying off too quickly due to oxidative stress, inflammation, or even strokes and other serious physical injuries to the brain [R, R].

For example, in patients who suffered from brain damage, higher levels of BCL2 activity were associated with better chances of survival and better overall cognitive function after recovery: most likely because their brain was able to keep more of its neurons alive so that they could be repaired [R].

In general, you might think that higher levels of BCL2 would be better, since this helps keep cells alive. However, recall that part of the reason our cells come with pre-programmed “death switches” is to ensure that damaged or mutated cells can be disposed of safely without turning cancerous [R]. Therefore, because BCL2 suppresses cell death, elevated levels of BCL2 could also potentially increase long-term risk of tumor formation (tumorigenesis) [R, R, R].

For example, one study observed higher levels of BCL2 in healthy breast tissue from women who had previously survived a diagnosis of breast cancer compared to women who never had cancer [R]. Although it’s still not known to what degree BCL2 levels might be directly involved in cancer development, this early finding provides suggestive evidence for a link that will have to be followed up by future studies [R, R, R].

Because of its dual role, at the end of the day what you really want is to have this gene in balance! Having too little of it could make your brain more vulnerable to oxidative stress and other sources of cell damage; but too much of it could make you more susceptible to cancer in the long run.

Keeping the BCL2 gene well-balanced can be important for making sure cells stay healthy, while also keeping your long-term chances of cancer at a minimum.

Just like any other cell in your body, your brain’s neurons are also vulnerable to stress, and have to be either repaired or disposed of when they’re damaged. Because BCL2 plays a key role in the repair processes that keep your neurons healthy, variants that affect how this gene works may influence how well your brain is able to carry out complex cognitive processes.

For example, SNPs in BCL2 have been associated with overall cognitive function, fluid intelligence, learning and memory, processing speed, and cognitive flexibility [R, R, R].

This gene has also been associated with increased brain size (grey matter volume) in several key brain areas involved in higher cognitive processes, such as the striatum and the hippocampus. This increase in brain size probably reflects the role of BCL2 in keeping neurons alive when they are damaged, which over time would result in having more neurons overall (and therefore a relatively larger brain). This association between BCL2 and brain size probably explains some of the relationships between this gene and various different aspects of cognition [R, R, R].

The BCL2 gene helps keep brain cells healthy and more likely to recover from damage, which leads to lower rates of cell death. Losing fewer neurons over time leads to increases in overall brain size — which is probably why certain variants in this gene have been associated with differences in cognitive abilities.

You can see your genotype for the BCL2 SNP rs956572 in the table below. However, keep in mind that this is only one gene that is related to cognitive ability, which can be influenced by hundreds of different genes! In other words, your genotype for this SNP doesn’t necessarily reflect your “overall” level of intelligence — just one of many genetic factors potentially related to it.

The two possible alleles for this SNP are ‘A’ (major) and ‘G’ (minor). When it comes to cognitive function, it’s probably better to have the ‘AA’ genotype (which ~13% of the population carries).

For example, one targeted gene study in ~100 healthy older Taiwanese males reported that carriers of the ‘GG’ (homozygous minor) genotype tended to perform worse (by about 7%) on a test of general cognitive function compared to carriers of one or more ‘A’ alleles. In this study, the ‘GG’ genotype appeared to affect language-based abilities especially — and the authors suggest that this might be due to BCL2’s influence on the relative size of certain language-related brain areas (such as the middle temporal gyrus, or MTG) [R].

Similarly, another gene-targeted study in 220 postmenopausal women (predominantly Caucasian) found that SNPs in the BCL2 gene — including rs956572 — were related to a wide variety of cognitive functions including processing speed, concentration, cognitive flexibility, and several types of memory [R, R].

Nonetheless, there are some important limitations to note about these studies. One is that their sample sizes were relatively small, and studies with greater numbers of participants will be needed to confirm these effects. Secondly, these findings have so far only been reported in a Taiwanese and a predominantly Caucasian sample — so similar studies in other ethnic groups will be needed to know if these effects apply to other populations as well.