Is being a cheap drunk genetic?

It seems most groups of friends have a term for that one friend who can’t handle their booze. For me, it was Cadbury (a glass and a half and I was done) or lightweight. We also used Two-can Sam, while Google tells me that two pot screamer and thimble guts are also used. Please put your own in the comments. But why are some people blasted after two drinks while others can keep going all night. There’s a lot of well-known contributing factors, things like body weight, whether they’ve eaten recently and how often people drink; another term we use is ‘mum drunk,’ when a new mum has that first night out after abstaining for 9 months and finds they’re now a total lightweight. But of course, I have to ask the question, is it genetic?

The question came to me when I came across the delightfully named cheapdate (there’s another term for it) mutation. In what sounds like an endlessly entertaining study, scientists got a bunch Drosophila (fruit flies) drunk on ethanol fumes and used the made-up sounding inebriometer to measure how quickly they got fall-down drunk.[1] Please enjoy this unrelated video of a drunk fly

They did a genetic screen of the flies and found that those flies with a mutation in the amnesiac gene, previously associated with memory defects, fell down the inebriometer quicker than those without.

They named this mutation cheapdrunk because that’s what fly scientists do; this same group later named mutations tipsy and barfly because they were associated with increased and decreased alcohol sensitivity respectively, though they didn’t appear to have investigated which genes may be affected by these mutations.[2]

Further experiments found cheapdate did not alter ethanol absorption or metabolism, and suggests that effects the brain’s response to alcohol, specifically by impairing cyclic AMP (cAMP) signalling. To see if a similar gene may play a role in lightweight humans, I conducted a BLAST (Basic Local Alignment Search Tool from NCBI) which searches for similar genes across species, indicating they most likely came from a common evolutionary ancestor. But this failed to find a human homolog to the amnesiac gene. However, cAMP has been found to increase in human cells following ethanol exposure,[3] while long-term alcohol exposure reduces cAMP signalling in these cells [4] and a study found alcoholics had reduced cAMP levels in their plasma.[5]

Another Drosophila study found flies with a mutation in another gene involved in cAMP signalling, pka-RII, to fall to the bottom of a tube in which they pumped in ethanol fumes quicker than control flies.[6] Unlike amnesiac, PKA-RII genes are found in humans and other mammals and removing the pka-RIIβ gene in mice actually made them less sensitive to ethanol.[7] By the way, they tested this by injecting mice with ethanol, waiting until they got sleepy then putting them on their back and seeing how long until they were able to right themselves reliably.

As with the cheapdate flies, these mice had normal ethanol consumption, but did have reduced cAMP protein kinase (PKA, of which pka-RIIβ is a regulatory subunit) activity in the brain, indicating impaired cAMP signalling. Similarly, mice with heterozygous deletion of the Gsα gene (meaning only one copy of the gene is active), which usually increases cAMP activity, took longer to right themselves when drunk than normal mice.[8] So it seems that cAMP signalling may play an important role in getting smashed, but why? cAMP signalling is complex and regulates many cellular functions so I won’t get into that much here. But one way that interfering with cAMP might increase drunkenness is by increasing GABA (γ-aminobutyric acid) activity. GABA is the main inhibitory neurotransmitter, meaning it decreases neuron activity, and increased GABA activity produces sedative effects, hence getting pass-out drunk.

These animal studies are all well and good, but what is the evidence in humans? Most of the studies on alcohol sensitivity in humans has focused on genes encoding enzymes involved in ethanol metabolism, namely alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). AHD helps converts ethanol to acetaldehyde, which is then converted to acetic acid with help from ALDH.

Mutations in these genes are responsible for the so-called ‘Asian flush,’ as they result in increased levels of the toxic alcohol metabolite acetaldehyde, which results in facial flushing and other unpleasant alcohol side effects, like headaches and feeling queasy (sidenote: much of the research on these genes was conducted in the 80s and 90s so has some rather, shall we say, outdated terminology). In particular, about 50% of people of eastern Asian descent (Chinese, Japanese and Korean) have a version of the ALDH2 gene (an allele) that is not found in people with European or African descent.[10] In a controlled experiment, people with two copies of this allele were sick, experiencing nausea, vomiting, high heartrate and low blood pressure after drinking “0.75 milliliters of alcohol per kilogram of body weight (mL/kg, equal to two to three alcoholic drinks),” nothing more than what many people will have over a dinner. Interestingly, people with one copy of this allele were more likely to describe themselves as feeling ‘high’ and ‘great overall’ than those without, so it seems this allele might make people more sensitive to both the positive and negative effects of booze.[11]

The ADH1B gene has 3 major alleles; ADH1B*1 which is the most common, ADH1B*2 which is found in 90% of people of eastern Asian descent and ADH1B*3 which is found in about a quarter of African Americans.[9] The mutations in this gene actually cause the enzyme to be more active, which means it converts ethanol to acetaldehyde more quickly. Interestingly, there is evidence that the ADH1B*2 is under positive selection pressure, that is, it spread quicker and occurs more commonly than expected by random chance.[12] So it seems this allele has some sort of evolutionary advantage. People carrying this allele are much less likely to become alcoholic,[13] if a small amount of booze makes you feel awful, you’re less likely to want it all the time. It has been suggested that the emergence of this allele coincides with the expansion of rice, and fermented rice beverages in Asia;[14] the prevalence of the allele may be for sakes sake. So, if your friends make fun of you for the Asian flush, you can say you are the product of thousands of years of human evolution, survival of the fittest!

So, is being a lightweight genetic? Well, if you’re of eastern Asian descent, you can probably blame it on your genes. For the rest of us, evidence is limited in humans. It may very well be a factor, but things like body weight and how often you drink probably play a bigger role. In general, if you don’t want your night to finish early, line your stomach, pace yourself and remember that water is your friend!

References
1. Moore MS, DeZazzo J, Luk AY, et al. Ethanol Intoxication in Drosophila: Genetic and Pharmacological Evidence for Regulation by the cAMP Signaling Pathway. Cell 1998;93(6):997-1007. doi: https://doi.org/10.1016/S0092-8674(00)81205-2
2. Singh CM, Heberlein U. Genetic Control of Acute Ethanol-Induced Behaviors in Drosophila. Alcoholism: Clinical and Experimental Research 2000;24(8):1127-36. doi: https://doi.org/10.1111/j.1530-0277.2000.tb02075.x
3. Atkinson JP, Sullivan TJ, Kelly JP, et al. Stimulation by Alcohols of Cyclic AMP Metabolism in Human Leukocytes: POSSIBLE ROLE OF CYCLIC AMP IN THE ANTI-INFLAMMATORY EFFECTS OF ETHANOL. J Clin Invest 1977;60(2):284-94. doi: 10.1172/JCI108776
4. Mochly-Rosen D, Chang FH, Cheever L, et al. Chronic ethanol causes heterologous desensitization of receptors by reducing alpha s messenger RNA. Nature 1988;333(6176):848-50. doi: 10.1038/333848a0 [published Online First: 1988/06/30]
5. Lykouras L, Markianos M, Moussas G. Plasma cyclic AMP in non-abstinent chronic alcoholics. Relation to clinical parameters. Drug Alcohol Depend 1988;21(1):7-9. doi: 10.1016/0376-8716(88)90003-8 [published Online First: 1988/02/01]
6. Park SK, Sedore SA, Cronmiller C, et al. Type II cAMP-dependent protein kinase-deficient Drosophila are viable but show developmental, circadian, and drug response phenotypes. J Biol Chem 2000;275(27):20588-96. doi: 10.1074/jbc.M002460200 [published Online First: 2000/04/27]
7. Thiele TE, Willis B, Stadler J, et al. High ethanol consumption and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice. J Neurosci 2000;20(10):RC75-RC75. doi: 10.1523/JNEUROSCI.20-10-j0003.2000
8. Wand G, Levine M, Zweifel L, et al. The cAMP-protein kinase A signal transduction pathway modulates ethanol consumption and sedative effects of ethanol. J Neurosci 2001;21(14):5297-303. doi: 10.1523/JNEUROSCI.21-14-05297.2001
9. Lee H, Kim SS, You KS, et al. Asian Flushing: Genetic and Sociocultural Factors of Alcoholism Among East Asians. Gastroenterology Nursing 2014;37(5):327-36. doi: 10.1097/sga.0000000000000062
10. Wall TL, Ehlers CL. Genetic Influences Affecting Alcohol Use Among Asians. Alcohol Health Res World 1995;19(3):184-89.
11. Wall TL, Thomasson HR, Schuckit MA, et al. Subjective feelings of alcohol intoxication in Asians with genetic variations of ALDH2 alleles. Alcohol Clin Exp Res 1992;16(5):991-5. doi: 10.1111/j.1530-0277.1992.tb01907.x [published Online First: 1992/10/01]
12. Evsyukov A, Ivanov D. Selection variability for Arg48His in alcohol dehydrogenase ADH1B among Asian populations. Hum Biol 2013;85(4):569-77. doi: 10.3378/027.085.0404 [published Online First: 2014/07/16]
13. Li D, Zhao H, Gelernter J. Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases. Biol Psychiatry 2011;70(6):504-12. doi: 10.1016/j.biopsych.2011.02.024 [published Online First: 2011/04/19]
14. Peng Y, Shi H, Qi X-b, et al. The ADH1B Arg47His polymorphism in east Asian populations and expansion of rice domestication in history. BMC Evol Biol 2010;10:15-15. doi: 10.1186/1471-2148-10-1