More than Meets the Eye: Eye Color and Alcoholism

Studies found a statistically significant association between blue eye color and alcohol dependency among Americans of European ancestry. Here, I discuss the basis for light eye color and the evidence for a genetic contribution to risk for alcohol dependency.

Introduction

Upon first encountering a new patient, a good physician notes physical features that suggest increased risk of pathology. For example, an obese patient should probably be tested for diabetes. A patient with clubbed fingernails or toenails should be evaluated for pulmonary insufficiency. A patient with extensive tattoos may be a candidate for hepatitis testing.

Inferring behavioral pathology from casual inspection is much more challenging. However, a recent paper suggests that blue-eyed Americans of European ancestry are at higher risk for alcohol dependency than brown-eyed Americans. Is this finding a basis for special scrutiny of blue-eyed patients?

Genetics of Eye Color

Eye color in humans is the result of variation in the number and size of melanin-containing organelles called melanosomes that are themselves contained in cells called melanocytes that are distributed within the outer iris stroma (See Figure 1). The number of melanocytes is similar among the different iridial colors. Blue eye color results from having few melanosomes, causing short wavelength visible light (the blue end of the spectrum) to be reflected. People with more melanosomes have hazel/green eyes; those with the most melanosomes in their iris stromal melanocytes reflect the least blue light and have brown eyes

Figure 1.

Eye color is determined by the number and melanin content of melanosomes within the melanocytes of the anterior iris stroma. Left : representations of the pupil (black) and surrounding iris color in (top) blue eyes, (middle) hazel eyes and (bottom) brown eyes. Right: melanosomes (colored ovals) increase in number and melanin content in (top) blue eye melanocytes, (middle) hazel eye melanocytes and (bottom) brown melanocytes. N = melanocyte cell nucleus. Adapted from http://www.bioscience-explained.org/ENvol4_1/pdf/eyecoloureng.pdf.

Most Americans are taught that eye color is a single-gene trait - that a brown-eye gene variant is dominant over the blue-eye variant. The reality is somewhat more complex. The OCA2 gene on human chromosome 15 has a major impact on eye color by producing a protein that controls melanin formation and processing.¹ The more OCA2 activity in the iris melanocytes, the darker the eye color. However, as many as seven other genes can impact melanin deposition, resulting in shades of blue and green and explaining why two blue-eyed parents can have green-eyed children.

Eye colors other than brown only occur in individuals of European descent. The current genetic evidence suggests that the first humans had brown eyes. As our ancestors migrated out of Africa, some found their way into Europe. About 6,000–10,000 years ago, probably in the area of the Black Sea, a single individual was born with a mutation that programs reduced OCA2 gene expression and blue eyes.¹ The evidence suggests that all people with blue eyes carry this same variant. So the parts of the world where descendants of that founder individual are most common have the highest frequency of blue eyes; where those descendants are rare, darker eye colors are the dominant eye color.

Genetics of Alcohol Dependency

The 4^th edition of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric association classifies behavior as alcohol dependency if it meets three of the following seven criteria in a twelve month period:

• tolerance;

• withdrawal symptoms or clinically-defined alcohol withdrawal syndrome;

• use in larger amounts or for longer periods than intended;

• persistent desire or unsuccessful efforts to cut down on use;

• significant time spent obtaining alcohol or recovering from its effects;

• social, occupational and/or recreational pursuits are reduced or abandoned because of use;

• continued use despite knowledge of alcohol-related physical or psychological harm.

In 2013, alcohol dependency was formally reclassified together with alcohol abuse as “alcohol use disorder (AUD).”

Excessive alcohol use is the third leading modifiable cause of death in the United States.² In 2012, approximately 11.2 million adult men, 5.7 million adult women and 855,000 persons aged 12– 17 had AUD in the U.S. (http://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-use-disorders). Excessive alcohol consumption kills about 88,000 people in the U.S. each year. A 2006 Centers of Disease Control study estimated the cost of excessive alcohol consumption to be $223.5 billion, reflecting a toll on workplace productivity, health care expense, criminal justice expenses and from motor vehicle crashes (http://www.cdc.gov/features/alcoholconsumption/).

Alcohol use disorder has an estimated heritability of 40–60%,^3–6 with complex underlying genetics. Genome-wide association studies and candidate gene analyses have identified many gene variants significantly associated with alcohol dependency. Many of these genes encode proteins important for neurotransmitter signaling, receptors activated by drugs and enzymes required for alcohol metabolism (See Table 1). The individual association of each of these genes with the risk of alcohol dependency is relatively weak. Rather, as with other complex traits such as BMI or cancer risk, risk is the result of the cumulative effect of multiple variants with modest individual impact.

Table I.

Candidate genes for alcohol dependence (modified from ref. 6)

Pathway	Gene	Gene product function
GABA	GABRA221	GABA receptor subunit
	GABRG316	GABA receptor subunit
	GABRA622	GABA receptor subunit
	GABRB122	GABA receptor subunit
	GABRB223	GABA receptor subunit
	GABRB324	GABA receptor subunit
Muscarinic receptor	CHRM225	muscarinic acetylcholine receptor
Taste receptors	TAS2R1626	gustducin-coupled receptor
Nicotinic receptors	CHRNA527	neuronal nicotinic acetylcholine receptor
Opioid	OPRK128	G-protein coupled κ opioid receptor
	PDYN28	ligands for κ-type opioid receptors
	OPRM129	G-protein coupled μ opioid receptor
	OPRD130	G-protein coupled δ opioid receptor
Alcohol metabolism	ADH417	alcohol dehydrogenase
	ADH1C31	alcohol dehydrogenase
	ADH532,33	alcohol dehydrogenase
	ADH733	alcohol dehydrogenase
	ALDH1A133	aldehyde dehydrogenase
	ALDH227,33	aldehyde dehydrogenase
	CYP2E133,34	cytochrome P450
	ADH1A17	alcohol dehydrogenase
Other	TACR335	G-protein coupled tachykinin receptor
	ACN936,37	succinate dehydrogenase complex assembly factor
	NPY29,33	neuropeptide Y
	NFKB138	NFκ-B transcription factor
	AKAP939	protein phosphatase 1 regulatory subunit
Stomach/gastrointestine	CCK33	cholecystokinin
	CCKAR33	cholecystokinin A receptor
	CCKBR33	cholecystokinin B receptor
Dopamine	DRD236,37,40	dopamine D2 receptor
	DRD341	dopamine D2 receptor
Glutamate	GAD142,43	glutamate decarboxylase
	GRM844	G-protein coupled metabotropic glutamate receptor
	GRIN139,45	N-methyl-D-aspartate receptor
	GRIN2B32,39,45	N-methyl-D-aspartate receptor
Serotonin	HTR1A30,46	G protein-coupled serotonin receptor
	HTR1B25,47	G protein-coupled serotonin receptor
	HTR2A43	G protein-coupled serotonin receptor
	TPH133	tryptophan 5-monooxygenase
	TPH233	tryptophan 5-monooxygenase
	SLC6A443	serotonin transporter

It is important to appreciate that variants of genes that decrease alcohol dependency have also been described. For example, a variant of the ALDH2 gene is associated with low-dose alcohol-induced facial flushing reaction in persons of East Asian descent, leading to alcohol aversion and a lower frequency of alcoholism in this cohort.⁷ Types and frequencies of alcohol tolerance and alcohol sensitivity variants differ in different populations, and are unlinked from the major eye color-determining variants.

Is Pale Eye Color Associated with Elevated Risk of Alcoholism?

A recently published study looked at over 1,200 people who were either diagnosed alcoholics or were similar in age, sex, and ethnic background (European descent) but were not alcoholics although they did occasionally consume alcohol.⁸ What the study found was a higher statistical correlation between lighter eye color and alcoholism than between brown eye color and alcoholism, and the correlation was markedly higher for blue eyes.

This is not the first association to be made between eye color and alcohol use. A study of 10,860 Caucasian adult male inmates in the Georgia state prison system found that 42% of light-eyed inmates had alcohol abuse problems while the fraction of dark-eyed inmates with alcohol abuse problems was 38%.⁹ The same report also examined data from 1,862 Caucasian American women, and found that light-eyed women reported significantly more alcohol than dark-eyed women. In both cases, the effect sizes were small, but the samples were not corrected for population stratification. The more recent study did statistical tests to demonstrate that the samples were moderately homogeneous. That said, the strength of the association they found was modest: the odds of a blue-eyed person being alcohol dependent is 1.8 fold higher than an American of European descent with brown eyes. This is comparable to the association between type II diabetes and hypertension, which was examined in the Nationwide Inpatient Sample (NIS) database (~7.8 million cases). The study found that the odds of having hypertension were 2.2 times higher among patients with type II diabetes versus patients without type II diabetes.¹⁰ In contrast, the risk of non-cardia gastric cancer is six to eight times higher for people infected with Helicobacter pylori than for uninfected people,^11,12 and smokers are 25 times more likely to develop lung cancer than people who never smoked.¹³

Why might having blue eyes put one at higher risk for alcohol dependency than having brown eyes? One possible explanation is that a gene lying near the OCA2 gene on chromosome 15 carries a mutation that leads to increased alcohol tolerance, and thus a tendency to drink too much. Indeed, the authors noted a tight genetic linkage between the OCA2 gene and a nearby gene encoding a cluster of γ-amino butyric acid (GABA) receptor genes, including the GABRG3 gene (See Figure 2). GABA receptors have been implicated in alcohol tolerance and alcohol dependency,^14,15 and surveys for genes associated with alcoholism identified GABRG3.^16,17 GABA is a major inhibitory neurotransmitter, so a mutation in a brain GABA receptor that reduced its ability to respond to GABA might impair an inhibitory response to alcohol. This would explain why people with such a mutation might continue drinking when others stop. One hypothesis is that the OCA2 blue-eye mutation resulting in blue eyes occurred on a chromosome that already carried a GABRG3 mutation. Since the OCA2 and GABRG3 genes are separated by only about 0.2% of the length of chromosome 15, the chromosomal coupling of a blue-eyed variant of OCA2 and an alcohol tolerant GABRG3 variant has been maintained in most descendents of the first blue-eyed human.

Figure 2.

Cartoon map of human chromosome 15, showing the positions of the tight linkage of the OCA2 and GABRG3 genes. bp = base pairs.

Genetics, Risk, and Destiny

It is common to refer to “the gene for sickle cell disease” or “the gene for muscular dystrophy.” In reality, there are no genes for diseases. The “gene for sickle cell disease” is actually the adult beta hemoglobin gene, which we all have. Sickle cell disease patients inherited a particular form, or “allele” of the beta hemoglobin gene that causes their red blood cells to sickle under low oxygen tension.

Similarly, there is no “gene for blue eye color” or “gene for alcoholism.” The OCA2 gene plays a major role in eye color, and a genetic variant that reduces OCA2 gene expression accounts for most cases of blue eye color. The GABA receptor gene family encodes a family of proteins required for nerve cell function. There may be variants of one or more GABA receptor genes that make their carriers less sensitive to alcohol and thus raise risk for excessive alcohol consumption leading to dependency. Of course, there are also variants of genes implicated in alcohol sensitivity that result in increased alcohol sensitivity or intolerance. These could balance the effects of the blue-eye-color- associated alcohol tolerance variants. So in any given blue-eyed person, the statistical tendency towards alcohol dependency observed in the blue-eyed population may be amplified or offset by combinations of variants at other genes.

It is also important to appreciate that culture plays a large role in patterns of alcohol use. In the extreme case, most observant Muslims, Seventh Day Adventists and Southern Baptists abstain for religious reasons. In many cultures that do condone alcohol consumption, it is considered as a food, and alcohol abuse is subject to disapprobation. Regional cultural variations probably help explain why the rather uniform North-South cline in eye color across Europe is not mirrored by a similar cline in per capita annual alcohol consumption patterns (See Figure 3). Seasonal Affective Disorder (SAD) is a form of depression associated with a change in seasons—usually with the shorter daylight of winter—that is comorbid with alcohol dependency.¹⁸ However, there appears to be no significant difference in the prevalence of SAD in Italy and Norway,¹⁹ suggesting that latitude alone should not contribute significantly to alcohol dependency in areas where light eye color is most common. Further complicating things, light eye color appears to be protective for SAD.²⁰

Figure 3.

Distribution of blue eye color does not explain per capita annual alcohol consumption across Europe. Left : percent light eye color across Europe (modified from: http://1.bp.blogspot.com/-eqhQhrOT-Ck/UAAA-9E-BOI/AAAAAAAAABc/o-4yE8Ou6i4/s1600/europe-eyes-general--lig.png). Right: per capita annual alcohol consumption by nation across Europe (modified from: http://jakubmarian.com/wp-content/uploads/2015/05/alcohol.jpg).

The author of this article has blue eyes and pale skin. Throughout adult life, he has been careful to wear long pants, long-sleeve shirts and a hat whenever practical, and to use sunscreen to avoid skin cancer. To have pale skin is not to have the gene for basal cell carcinoma or melanoma. But a person with pale skin is at higher risk for skin cancer and should be more vigilant to mitigate that risk through responsible behavior. Similarly, having blue eyes may mean that a person should be more vigilant about alcohol consumption to avoid the risk of becoming alcohol dependant.

Any routine patient history should include questions about alcohol consumption. There is also an online self-assessment tool to evaluate personal alcohol intake levels: http://www.alcoholscreening.org/Screening/Page04.aspx. Excessive alcohol consumption is a risk factor for heart disease, liver cirrhosis, and cancer. The evidence that blue-eyed Americans may be more susceptible to alcohol dependency shouldn’t change that standard practice. Should evidence for alcohol dependency emerge through the history, counseling or other intervention may be appropriate, but eye color alone is not a sufficient guide to action.

Identifying and treating alcohol dependency is a worthy clinical and public health challenge. Alcoholics can be secretive about their addiction and frequently deny it long after it takes a toll on their families, friends and employers. While eye color per se is not a strong predictor of risk for alcohol dependency, the advent of personalized medicine and the thousand dollar genome will soon allow comprehensively assessing patients for all known genetic risk factors, and counseling them accordingly.

Biography

Joel C. Eissenberg, PhD, is a Professor and Associate Dean for Research, Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine.

Contact: eissenjc@slu.edu