The HTR1B receptor gene has been linked to antisocial alcoholism in a Finnish population and an American Indian tribe [Lappalainen et al., Arch. Gen. Psychiatry, 55 (1998) 989]. Using a candidate gene approach, we genotyped 209 patients with alcoholism, 108 patients with major depression, 32 patients with panic disorder, 50 patients with generalized anxiety disorder, 58 patients with narcolepsy and 74 healthy volunteers for the HTR1B 861G>C polymorphism. There was a higher frequency of the HTR1B 861G alleles among the alcohol-dependent patients as compared to the control subjects (χ2=4.02, d.f.=2, P=0.04). However, the association resulted from higher frequencies of the opposite alleles (HTR1B 861G), as originally reported by Lappalainen et al. (1998). Although the association in our study might be due to a type I error, the higher degree of HTR1B allele sharing within both populations could also argue for another alcoholism-relevant gene within the proximity of the HTR1B gene on human chromosome 6.
Alterations of serotonergic neurotransmission have been described in a number of neuropsychiatric disorders, including alcoholism, anxiety disorders, major depressive disorder and narcolepsy (Benkert et al., 1993 and Murphy et al., 1998). Molecular cloning has revealed a number of polymorphisms within the genes encoding the different serotonergic receptors (e.g. Lappalainen et al., 1995, Peroutka, 1998 and Enoch and Goldman, 1999). The human hydroxytryptamine 1B receptor gene (HTR1B) has attracted special attention, because animals without a functional HTR1B receptor show a number of interesting behavioral features linked to neuropsychiatric disorders (see Scearce-Levie et al., 1999, for review). Mice lacking the gene encoding for the HTR1B receptor display heightened aggressive behavior against new intruders (Saudou et al., 1994), are less sensitive to ethanol-induced ataxia (Crabbe et al., 1996, Crabbe et al., 1999 and Phillips et al., 1999), and are more prone to the reinforcing effects of cocaine in a progressive ratio schedule (Rocha et al., 1998). The human HTR1B receptor is encoded by an intronless gene 1179 bp in length (Jin et al., 1992) located on human chromosome 6 (Lappalainen et al., 1995). A common HincII polymorphism (861G>C) in the human HTR1B gene was identified by Southern blotting–restriction digestion ( Sidenberg et al., 1993), and independently by SSCP and PCR-RFLP methods ( Lappalainen et al., 1995). The 861G>C polymorphism is in complete linkage equilibrium with another frequent nucleotide exchange at position 129 (129T>C) in this gene ( Huang et al., 1999). Both polymorphisms do not alter the amino acid sequence of the HTR1B protein ( Lappalainen et al., 1998 and Huang et al., 1999). Intriguingly, the HTR1B 861G>C receptor polymorphism was linked to antisocial alcoholism in a Finnish sample and a sample derived from an American Indian tribe ( Lappalainen et al., 1998).
In this study, we tested for association of the HTR1B 861G>C receptor polymorphism with the alcohol dependence phenotype in a clinical sample unselected for violent behavior. In addition, we assessed the association between the HTR1B gene and temperament dimensions among the alcohol-dependent patients and healthy control subjects using the dimensional personality model developed by Cloninger and colleagues (Cloninger, 1987 and Cloninger et al., 1995).
We expanded this investigation to other psychiatric disorders also linked to diminished serotonergic function, including major depression, generalized anxiety disorder, panic disorder and narcolepsy.
The gender distribution differed between the diagnostic groups. There was a higher proportion of females among the patients suffering from major depression, panic disorder, generalized anxiety disorder and narcolepsy as compared to alcohol-dependent patients and normal healthy control subjects (χ2=114.0, d.f.=6, P<0.0001, for details, see Section 2). Therefore, HTR1B 861G>C allele frequencies were separately analyzed for each sex. We found higher frequencies of the HTR1B 861G alleles among the male alcohol-dependent patients as compared to male healthy control subjects (χ2=6.31, d.f.=2, P=0.011, Table 1). In contrast to the males, the female alcohol-dependent patients and the female control subjects showed equal HTR1B 861G allele frequencies (χ2=0.07, d.f.=2, P=0.79, Table 1). In order to increase the power of our investigation, a sex-independent analysis on HTR1B 861G>C allele frequencies was carried out. There was a higher frequency of the HTR1B 861G alleles among the alcohol-dependent patients as compared to the control subjects (χ2=4.02, d.f.=2, P=0.04, Table 1). None of the other gender-dependent or -independent comparisons were statistically significant for differences in HTR1B 861G>C allele frequencies between patients suffering from major depression, panic disorder without agoraphobia, patients with generalized anxiety disorder or narcolepsy and the healthy control subjects ( Table 1).
