By David N. Leff
¿April is the cruelest month,¿ wrote T.S. Eliot, in the ¿The Wasteland.¿
This year, April is also National Alcohol Awareness Month, co-proclaimed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the nonprofit National Mental Illness Screening Project.
All day yesterday, April 8, their program offered Americans free, anonymous, one-on-one consultations for alcohol problems at some 1,200 hospitals and health centers, plus 500 college campuses. More than half of all college drinkers say they imbibe alcoholic beverages ¿to get drunk.¿ And nearly one in 13 adult Americans are ethanol-dependant or abusers, at a social cost of more than $167 billion a year, said NIAAA director Enoch Gordis, marking the April day and month.
Alcoholics are not all created equal.
In fact, specialists studying ethanol abuse describe two separate behavioral types of alcoholism, I and II, encompassing four subtypes: antisocial personality disorder (ASPD); novelty-seeking; harm-avoidance; and reward dependence. But the leading risk factor for the disorder is gender: Male alcoholics outnumber females four to one.
And because the single inherited difference between the sexes is the X-linked, female-determining chromosome and the male-designating Y chromosome, genetic scrutiny focuses on the Y, for its putative share in tipping the preponderance of alcoholism toward men and boys.
¿There¿s something about the Y chromosome,¿ observed population geneticist Jeffrey Long at the NIAAA, ¿that would increase your risk for alcohol dependence. In fact,¿ he added, ¿there are even some forms of alcoholism that are nearly totally sex-limited. So, when we look at the type that is associated with very early-onset, antisocial behavior, you almost always see that only in men, whereas depression is more often diagnosed in alcoholic women.
¿Since we know that the Y chromosome increases this risk,¿ Long pointed out, ¿we asked, Do different Y chromosomes increase that risk differently?¿¿
The one and only genetic element that fathers, not mothers, bequeath to their sons, not daughters, is the Y chromosome. So, with this peculiar, sex-linked pattern of inheritance, it differs from the 44 other non-sex-linked chromosomes in the human karyotype.¿ And it¿s not really amenable to traditional types of genetic analysis,¿ Long pointed out, ¿where we would do linkage mapping, or something like that. The Y is one of the smallest chromosomes in the human genome, and has a very small amount of DNA, most of which is junk DNA. There¿s only a modest number of known genes on the Y. Some of them seem to encode formation of the testes, others, male infertility, and that men-only trait, male-pattern baldness ¿ androgenic alopecia.¿
How Guilty Of The A¿ Word Is Y¿?
¿We knew that Y chromosomes contribute to alcoholism vulnerability,¿ Long pointed out, ¿but we weren¿t sure whether there was any sort of real familial inheritance ¿ the actual features of a father passing down the risk in his sons ¿ other than the fact that his sons were male. So, that¿s what we set out to find out.¿
What he and his NIAAA colleagues found out appears in the current issue of The Proceedings of the National Academy of Sciences, dated Mar. 30, 1999. Their paper, of which he is joint senior author, bears the title: ¿Cladistic association analysis of Y chromosome effects on alcohol dependence and related personality traits.¿
¿Our basic motivation in doing this study,¿ Long told BioWorld Today, ¿was to link Y chromosomes back to a common genomic ancestor, according to their mutational history. What a cladistic diagram does is identify that mutational history and show how many mutations are part of these different evolved Y chromosomes. So, if there were any mutations that, say, changed a person¿s risk for any of the various alcoholism subtypes, then we would be able to find lineages of related Y chromosomes that carried these DNA sequences, and hopefully further our gene localization effort.¿
The types of gene mutations that Long and his co-authors saw on one typical locus of the Y chromosomes, he said, ¿were short tandem repeat trinucleotides. These repeats ranged from about 129 base pairs to 138. And they were not functional mutations; they didn¿t express any proteins. Rather, they served as genomic markers that mutated from one form to a slightly different form on the Y.
¿And because they are nonfunctional,¿ he said, ¿they¿re not likely to be causing the particular differences in alcoholism vulnerability. They do provide a framework for whatever functional genes may exist, embedded on the same set of chromosomal relationships.¿
To map these variant markers on the Y chromosomes of men possessing putative genetic traits for alcoholism called for a highly uniform human population. The team found it in Finland.
For 80 generations ¿ two millennia ¿ the inhabitants of that country have been relatively isolated and free from outside immigrants. Moreover, the living Finnish population of just over 5 million enjoys a high standard of medical and social care, with detailed records.
Finnish Criminals¿ DNA Gauged Alcoholism Risk
¿We know there¿s a common gene pool underlying the Finns,¿ Long said, ¿an identifiable population. For some years, the NIAAA had been studying impulsive criminals in Finland, because they all tended to have alcohol problems. Their offenses were mostly antisocial or violent crimes, some arson.
¿Our purpose was to identify subtypes of alcoholism that might allow us to work out better prevention strategies, or treatments,¿ he went on. ¿We collected DNA from 359 adult male Finnish criminals, their families, and control cohorts. Then, we did a structure analysis to see, if we combined all personality subtypes of alcoholics versus non-alcoholics, there was anything that would suggest that their Y chromosomes affected their vulnerability. The answer to that was yes.
¿Next,¿ Long said, ¿we looked at whether we could distinguish those alcoholism-defining personality subtypes on the basis of the variable Y chromosomes. And the answer to that was no.
¿We then determined that 5 to 10 percent of the variability in Finland, whether men were alcoholic or not, was accounted for by differences in their Y mutation patterns,¿ he said. ¿Some it would be a minor contributor to risk. Now, we can try to identify some of those contributors to that variability. We might predict that some of it is going to be genes, some of it specific or unidentifiable environmental factors, or whatever.
¿I think it was an unexpected discovery, because there hadn¿t been a lot of evidence before this for sex chromosomes as alcoholism risk factors,¿ Long said. ¿The fact that it accounts for minor component variants was a little bit comforting, because if we did a study that showed 100 percent of the variability accounted for by the Y chromosome, that would fly in the face of everything we already knew about alcoholism.¿
Long concluded: ¿This work is one step in a long research program. What we would like to do from here on is try to localize the specific Y genes that are involved, and look at the way their products affect development.¿