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Linkage of Antisocial Alcoholism to the Serotonin 5-HT1B Receptor Gene in 2 Populations
Jaakko Lappalainen, MD, PhD;
Jeffrey C. Long, PhD;
Monica Eggert, MD;
Norio Ozaki, MD;
Robert W. Robin, PhD;
Gerald L. Brown, MD;
Hannu Naukkarinen, MD;
Matti Virkkunen, MD;
Markku Linnoila, MD, PhD;
David Goldman, MD
Arch Gen Psychiatry. 1998;55:989-994.
Background In mice, quantitative trait locus studies and behavioral evaluation of animals deleted for 5-HT1B have implicated this serotonin autoreceptor in alcohol consumption and aggressive behavior. We therefore investigated whether the 5-HT1B gene (HTR1B) is linked to alcoholism with aggressive and impulsive behavior in the human, as represented by 2 psychiatric diagnoses: antisocial personality disorder and intermittent explosive disorder comorbid with alcoholism.
Methods Linkage was first tested in 640 Finnish subjects, including 166 alcoholic criminal offenders, 261 relatives, and 213 healthy controls. This was followed by a study in a large multigenerational family derived from a Southwestern American Indian tribe (n=418) with a high rate of alcoholism. All subjects were psychiatrically interviewed, blind-rated for psychiatric diagnoses, and typed for a HTR1B G861C polymorphism and for a closely linked short-tandem repeat locus, D6S284. Linkage was evaluated in sib pairs, and by using an association approach in which pedigree randomization corrects for nonindependence of observations on related subjects.
Results In Finnish sib pairs, antisocial alcoholism showed significant evidence of linkage to HTR1B G861C (P=.04) and weak evidence with D6S284 (P=.06). By association analysis, the 183 Finnish antisocial alcoholics had a significantly higher HTR1B-86IC allele frequency than the other 457 Finns we studied (P=.005). In the Southwestern American Indian tribe, significant sib pair linkage of antisocial alcoholism to HTR1B G861C (P=.01) was again observed, and there was also significant linkage to D6S284 (P=.01).
Conclusion These results suggest that a locus predisposing to antisocial alcoholism may be linked to HTR1B at 6q13-15.
From the Section of Population Genetics and Linkage (Drs Lappalainen and Long), Laboratory of Neurogenetics (Drs Ozaki, Robin, and Goldman), and Laboratory of Clinical Studies (Drs Brown and Linnoila), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Md; and Department of Psychiatry, University of Helsinki, Helsinki, Finland (Drs Eggert, Naukkarinen, and Virkkunen).
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