Does This Acetylcholine Receptor Gene Influence Overall Cognitive Ability? (CHRNA5)

The CHRNA5 gene codes for alpha-5 nicotinic acetylcholine receptors (“α5 nAChRs”). These acetylcholine receptors allow calcium to flow into neurons, which is one of the main triggers of synaptic plasticity [R, R, R].

Because it is responsible for creating acetylcholine receptors, this gene plays a key role in determining the overall activity of this neurotransmitter throughout the brain.

Or, another way to think about it would be that it partially determines how “sensitive” a person’s brain is to acetylcholine — because the more of these receptors someone has, the more of an influence this neurotransmitter will be able to have on the many different cognitive processes happening throughout the brain.

The CHRNA5 gene is responsible for creating alpha-5 nicotinic acetylcholine receptors. Therefore, this gene plays a wide-ranging role in determining how “sensitive” a person’s brain is to the effects of the major neurotransmitter acetylcholine.

Acetylcholine receptors are located throughout the brain, and are especially plentiful in key areas involved in cognitive processing, such as the prefrontal cortex (PFC) and the hippocampus [R, R].

The specific type of receptors created by this gene have also been implicated in triggering  synaptic plasticity, which is one of the main mechanisms the brain uses to adjust the connections between neurons. In general, this is what allows us to store new information and memories [R, R, R].

For this reason, the acetylcholine system has been widely associated with cognitive processes related to learning and memory.

However, as with all major brain systems, the acetylcholine system is highly complex, and it has also been reported to interact with other neurotransmitter systems, such as dopamine and serotonin. Therefore, acetylcholine activity can also influence the levels and activity of other major neurotransmitters as well [R, R].

Acetylcholine has been linked to a variety of cognitive processes — most often those related to learning and memory. In part, this stems from the role that acetylcholine receptors play in triggering synaptic plasticity. Acetylcholine can also have “indirect” influences on the levels and activity of other major neurotransmitters, such as dopamine and serotonin.

According to some recent genetics studies, variants in the CHRNA5 gene have been linked to differences in how much this gene is actively expressed throughout the body and brain [R, R].

In general, higher activity of this gene (higher mRNA transcription levels) is believed to lead to an increased number of αlpha-5 nicotinic acetylcholine receptors (α5 nAChRs) in many different important areas of the brain [R].

Having more of these specific acetylcholine receptors, in turn, makes neurons more responsive to calcium signaling, which is one of the main mechanisms that cells use to trigger synaptic plasticity [R].

Having more of these receptors may also be associated with increased levels of other important neurotransmitters, such as dopamine [R, R].

Conversely, low activity in these receptors has been associated with reduced neural plasticity and relatively lower levels of dopamine release in the PFC. These mechanisms, in turn, have been reported to result in impaired attention and working memory [R, R, R, R].

All together, the influence that CHRNA5 has on several important brain mechanisms is most likely why variants in this gene have been associated with differences in many aspects of overall cognitive ability.

Certain genetic variants in CHRNA5 have been linked to differences in the overall expression of this gene, which influences the number of acetylcholine receptors a person has. The important roles that acetylcholine plays in synaptic plasticity, learning, and memory is most likely why these variants have also been associated with cognitive differences.

CHRNA5 and Smoking

As a sidenote, one other interesting thing about the CHRNA5 gene is that it creates the specific types of acetylcholine receptors that are primarily targeted by the drug nicotine (α5-nAChRs) [R, R].

Because of the wide-ranging role of alpha-5 acetylcholine receptors in cognitive processing, nicotine’s ability to target and stimulate these receptors could potentially explain why this drug is sometimes reported to have “positive effects” on cognition [R, R, R].

In fact, some recent studies have reported that carriers of certain variants that increase CHRNA5 activity — such as the ‘T’ allele of the SNP rs588765 and the ‘A’ allele of rs637137 — may be at relatively lower risk of being habitual cigarette smokers [R, R, R, R, R].

Some researchers have suggested that this may be because since these peoples’ acetylcholine levels are already relatively high, they may on average feel less of a need to stimulate their acetylcholine system further by ingesting nicotine [R, R].

Conversely, this idea could also explain the opposite association, according to which people with lower-activity CHRNA5 variants — such as the ‘C’ allele for rs588765 and the ‘T’ allele of rs637137 — are relatively more likely to become chronic smokers. In other words, smoking could be these peoples’ (rather unhealthy) way of trying to “counteract” their relatively lower natural levels of acetylcholine activity [R, R, R].

Nonetheless, it probably goes without saying that we are definitely not “recommending” smoking or other forms of nicotine use, no matter what your genes say! After all, the negative effects of nicotine use are very severe and well-known, and would definitely cancel out any other so-called “positive” effects of this drug. But it’s an interesting example of how genetic factors can be subtle influences on peoples’ behavior — especially when it comes to harmful health-related factors like smoking [R, R].

Interestingly, the CHRNA5 gene makes the specific type of acetylcholine receptors that are targeted by nicotine — and the variants that people carry for this gene could be a potential factor explaining why some people are relatively more or less likely to develop harmful health habits such as cigarette-smoking.

You can see your genotypes for several different CHRNA5 SNPs in the table below. However, keep in mind that these results are based purely on association studies, and much more research will be needed to know what role (if any) these variants play in actually directly causing differences in cognitive ability.

Also, many different genetic, lifestyle, and environmental factors can affect cognitive function. Therefore, just having a few “bad” CHRNA5 genotypes does not necessarily reflect your entire cognitive ability as a whole — just one particular genetic factor potentially related to it!

With that in mind, the following table summarizes your results for several different CHRNA5 SNPs that have been linked to differences in cognitive function:

Primary SNP: rs588765 [R, R]

Other Important SNPs:

• rs16969968 [R]
• rs1051730 [R]
• rs637137 [R]

The two possible alleles for the “main” CHRNA5 SNP rs588765 are ‘C’ (major) and ‘T’ (minor). When it comes to cognitive function, some evidence suggests that it is probably better to have the less common ‘TT’ genotype (which ~9% of the population carries).

For example, a targeted gene study in 403 adults reported that carriers of the ‘TT’ genotype tended to achieve significantly higher scores on verbal sections of an IQ test, compared to carriers of one or more ‘C’ allele [R].

Relatedly, other CHRNA gene studies suggest that it is probably relatively better to carry the major ‘G’ allele for rs16969968, the major ‘G’ allele for rs1051730, and the minor ‘A’ allele of rs637137.

For example, based on a sample of 2,186 study participants, carriers of the minor ‘A’ allele of rs16969968 were reported to show relatively lower scores on the WAIS (a common type of IQ test) compared to carriers of the ‘G’ allele, whose performance was better [R].

Similarly, according to a sample of 485 adult subjects, carriers of the minor ‘A’ allele for rs1051730 were reported to show relatively reduced performance on the n-back test (a cognitive test of working memory function), relative to carriers of the major ‘G’ allele [R].

CHRNA5 SNP Mechanisms

The exact mechanisms responsible for these cognitive effects are not yet fully understood. However, several teams of researchers have noted that carriers of some of the “beneficial” CHRNA5 genotypes — such as ‘TT’ for rs588765 and the ‘A’ allele for rs637137 — show levels of CHRNA5 activity (mRNA transcription levels) that are up to twice as high as carriers of other genotypes [R, R].

This suggests that the cognitive effects associated with these CHRNA5 variants may be due to differences in the number of α5-acetylcholine receptors that people have [R, R].

Carriers of certain “beneficial” CHRNA5 variants have been reported to show enhanced performance on IQ tests and other common measures of cognitive ability. These effects may be due to increased numbers of α5-acetylcholine receptors, which would imply that these peoples’ brains are more sensitive to the overall effects of acetylcholine.