ANALYSIS OF 5-HYDROXYTRYPTAMINE 2C RECEPTOR GENE PROMOTER VARIANTS AS ALCOHOL-DEPENDENCE RISK FACTORS

Salim Mottagui-Tabar1, Shane McCarthy1, Jana Reinemund1, Björn Andersson1, Claes Wahlestedt1 and Markus Heilig2,*

1 Center for Genomics and Bioinformatics and 2 Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Stockholm, Sweden

* Author to whom correspondence should be addressed at: Karolinska Institutet, Neurotec Department, Division of Psychiatry, Huddinge University Hospital, M57, SE-141 86 Stockholm, Sweden. Tel.: +46 8 58 58 6666; Fax: +46 8 58 58 5785; E-mail: markus.heilig{at}neurotec.ki.se

(Received 24 May 2004; first review notified 28 May 2004; in revised form 24 June 2004; accepted 29 June 2004)


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims: To examine whether polymorphic variants of the HTR2C gene are associated with diagnosis of alcohol dependence. Methods: We compared allele frequencies of five HTR2C promoter polymorphisms in a Nordic population of alcohol dependent individuals (Males: n = 309; Females: n = 127) and ethnically matched controls (Males: n = 83; Females: n = 190) in whom alcohol dependence was established, or any diagnosis of substance disorder was excluded, respectively. Patients were further subtyped into Type I (late onset) and Type II (early onset) alcoholics. Results: None of the individual polymorphisms indicated significant association with alcohol dependence. A common promoter haplotype (GAGG) exhibited different distribution frequencies between males and females (Type I), however on Bonferroni's multiple-testing correction, this observation proved to be insignificant. Conclusions: Although we report a lack of association between alcohol dependence and five common promoter polymorphisms, and the constituted haplotypes, the analysis tends to indicate gender and sub-type differences. We suggest that a follow up study with larger sample numbers should be performed to improve the power to detect the genetic influences of HTR2C in alcohol dependence.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Alcohol dependence is a genetically influenced behavioural disorder. Twin studies have established an estimated heritability of 50–60% for alcoholism (Kendler et al., 1992Go), which is comparable to the heritability estimates for some other common complex disorders such as non-insulin dependent diabetes mellitus (Poulsen et al., 1999Go) and obesity. The genes currently understood to be associated with risk for developing alcoholism code for alcohol metabolizing enzymes, such as alcohol dehydrogenase and acetaldehyde dehydrogenase (Thomasson et al., 1991Go). Variation within these genes confers a protective influence, largely thought to be mediated through altered alcohol metabolism, and accounts for only a small proportion of the risk. Therefore, it has been suggested that additional genes are involved. Some of these presumably confer their influence by modulating behavioural traits related to substance abuse and loss of control.

Alcohol dependence is a heterogeneous diagnostic category. Late-onset alcoholism or Type 1 found in both men and women, is characterized by a late age of onset of heavy drinking, and anxious personality traits, and has a less severe course. Early-onset alcoholism (defined as onset of heavy alcohol consumption before 25 years of age) or Type 2 is more common in males, and affects 25% of all male alcoholics. Early-onset alcoholics are frequently characterized by a history of hyperactivity, antisocial personality traits, alcoholic fathers, lower mean platelet monoamine oxidase activity, and a strong urge to consume alcohol in response to an intravenous infusion of the serotonin 2C receptor agonist meta-chlorophenyl-piperazine (George et al., 1997Go; Hommer et al., 1997Go).

Serotonergic disturbances and loss of control are common features in suicide attempters (Asberg, 1997Go), violent offenders (Linnoila et al., 1994Go; Virkkunen and Linnoila, 1997Go) and alcoholics (Ballenger et al., 1979Go). Depressed alcoholics, compared with never-depressed alcoholics, have been shown to have a higher daily alcohol intake, more lifetime diagnoses of other anxiety and affective disorders and drug abuse, more suicide attempts, and more reported alcoholism in both parents. There seems to be evidence for a shared serotonergic pathway between obesity and depression (Roberts et al., 2000Go). Feeding disorders, described as a loss of control, have been reported to involve serotonin receptor genes and associations observed for polymorphisms within these genes (Ricca et al., 2002Go; Rosmond et al., 2002Go; von Meyenburg et al., 2003Go; Murphy et al., 2004Go; Pooley et al., 2004Go).

The prevalence of alcohol dependence is markedly gender dependent, with an approximately 3:1 male to female ratio (Kessler et al., 1994Go). This indicates the possible involvement of sex-related factors in the pathogenesis of this syndrome. Additional gender differences may also exist. Women show higher peak blood-alcohol levels than men on the same alcohol dose (Thomasson, 1995Go). A number of imaging studies have investigated gender-specific vulnerability of the brain to alcohol (Jacobson, 1986Go; Mann et al., 1992Go; Hommer et al., 1997Go; Agartz et al., 1999Go; Hommer et al., 2001Go). These studies of alcohol dependent subjects have suggested that alcoholic women have an equal or greater degree of brain damage compared to alcoholic men despite fewer years of heavy drinking. However, studies indicating lack of evidence for a gender difference in the vulnerability of the brain to the effects of alcohol have also been published (Pfefferbaum et al., 2001Go).

Considering the gender differences in the prevalence of alcohol dependence and in responses to alcohol, and a pivotal role of the serotonergic system in behavioural traits related to alcoholism, substance abuse and loss of control, we investigated the role of the gene of an X chromosome localized serotonergic neuroreceptor in an alcohol dependent population of Nordic origin. We designed a classical case–control association study for four promoter single nucleotide polymorphisms and one promoter microsatellite of the serotonin 2C receptor gene (HTR2C). Of the four SNPs, one (rs3813928) (Yuan et al., 2000Go) has earlier been implicated in low BMI in Japanese population. The polymorphisms were genotyped in a population of 317 females (cases = 127; controls = 190) and 392 males (cases = 309; controls = 83), for possible haplotype and allele associations.


    SUBJECTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patients and controls
The total population samples consisted of 709 individuals. The alcohol dependent individuals (n = 436) volunteered while seeking medical care at Addiction Center South, Stockholm, an academic addiction medicine clinic offering medically assisted detoxification and outpatient treatment. Of the 709 individuals, 317 were female (cases = 127; controls = 190) and 392 were male (cases = 309; controls = 83). Individuals with major psychotic episodes were excluded. Healthy male volunteers were recruited by advertisements in local newspapers and paid for their participation. Population controls were in good general health, as established by physical examination, normal erythrocyte and lymphocyte indices, liver enzyme and thyroid hormone levels, and serum electrolyte and creatinine concentrations. Blood DNA extraction was performed at Karolinska Hospital Blood Bank facility.

Diagnostic categories
The main categories for analysis were alcohol dependent (i.e. confirmed DSM-III-R diagnosis of alcohol dependence as described above), or unaffected (i.e. lack of any substance related diagnosis). A subgroup analysis was carried out by independently examining a possible association in Type 1 and Type 2 alcoholics, respectively. For the 127 female cases, 91 could be classified as Type I and 26 as Type II. For the 309 male cases, 145 could be classified as Type I and 90 as Type II. The Structured Clinical Interview for DSM-III-R (SCID) was administered to both alcoholics and controls to establish or exclude a diagnosis of alcohol dependence, respectively. In the dependent subjects, sufficient clinical information was available to additionally allow sub-typing into Type 1 (late onset) and Type 2 (early onset) alcoholism according to Cloninger et al. (1981)Go using the revised criteria published in Hallman et al. (1996)Go. All subjects provided informed consent before entering the study. All the subjects were 17 years or older at the time of the psychiatric interview. These protocols, including patient information and consent forms, were approved by the Stockholm South (patients) and Stockholm North (controls) Human Subjects Ethics Committee.

Genotyping
The genomic sequence and allele information for SNPs in 5-HT2Rc were obtained from the SNP database at the US National Center for Biotechnology Information (NCBI). The SNPs were referred to by their Reference Cluster ID (rs#) as given at the NCBI website (www.ncbi.nlm.nih.gov/SNP/). Genotyping employed the dynamic allele-specific hybrid- ization (DASH) method (Howell et al., 1999Go). Genotypes were scored from fluorescence curves as previously described. Table 2 shows the sequences of the primers and probes used for the DASH assay. The primer sequences used for PCR amplification, were modified to amplify a DNA product with the least stable secondary structures, using Michael Zuker's program mFold (www.bioinfo.math.rpi.edu/~mfold/dna/form1.cgi). Each of the two alleles were probed independently using specific oligo-primers (allelic variations are underlined in Table 2). All PCR reactions were performed on a MJ Research PTC-225 (Wellesley, MA). The DNA polymerase (AmpliTAQGoldTM, Applied Biosystems, Foster City, CA) was activated by heating the PCR mixture at 98°C for 10 min. The amplification was carried out by 40 cycles of 98°C (10 s) and 55°C (30 s). The HTR2C GT microsatellite was genotyped using FAM labeled primers flanking the repeat designed based on Genbank entry GI:4753292, using CPrimer and ordered from Life TechnologiesTM (Table 2). PCRs were carried out implementing the same instrumentation as above, however, denaturing at 95°C and with extension at 72°C. Genotyping was performed at the National Swedish Center for Large-Scale Genotyping (www.genomecenter.uu.se/) using an ABI PRISM® 3700 Capillary DNA Genotyper. Allelic lengths were determined using GeneScan® Genotyper® software (Applied Biosystems).


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Table 2. Primer and probe sequences for amplification of genomic sequences with polymorphisms

 
Statistics
Genotype and allele frequencies were calculated using Microsoft Excel macro PHARE version 2.1 (developed by David Cox), which can be downloaded at www.bioinformatics.org/macroshack/programs/PHARE/description.html. For all haplotype analyses and pair wise comparison, the Windows version of Arlequin was used. Arlequin can be downloaded from www.lgb.unigene.ch/arlequin. Statistica 6.0 (www.statsoft.com) was used for chi-squared statistical analysis. Pearson's P-values and relative risk values were calculated using web resources i.e. SISA (www.home.clara.net/sisa/two2hlp.htm). Power to detect weak genetic effects (OR < 2.0) in male and female sample groups was calculated using QUANTO version 0.5 (www.hydra.usc.edu/GxE/) (Gauderman, 2002Go). The genetic effects of the X-linked HTR2C polymorphisms were assumed to be dominant in the male sample group where the population risk for alcoholism at the age of 25 is 6% (Caetano and Cunradi, 2002Go). The population risk was assumed to be 2% in the female group under a recessive mode of inheritance.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 1 shows the genotype frequencies for females and allele frequencies for both males and females. Male heterozygotes were eliminated from the dataset as the serotonin 2C receptor is mapped to the X-chromosome. The male heterozygote occurrence was <2%, and this was taken as a measure of genotyping error. The P-values calculated were found not to be significant (<0.05) when controls were compared with the entire patient group. Similar calculations were performed for the male and female patient group sub-categorized in Types I and II (data not shown). No significant association with any of the four SNPs was observed. All four SNPs were in HWE (Hardy–Weinberg equilibrium). Linkage disequilibrium (LD) was calculated using Arlequin. Pair-wise LD measurements between SNPs rs518147 and rs498207 (D' = 0.89), between rs498207 and rs521018 (D' = 0.98) and rs518147 and rs521018 (D' = 0.90) indicated high significance (P < 0.001) whereas SNP rs3813928 was not in LD (D' = 0.2, P-value = 0.8) with any of the other three.


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Table 1. Genotype and allele frequencies and P-values of four promoter SNPs

 
We subsequently calculated the haplotype frequencies (Table 3) for the four promoter SNPs. Haplotype frequencies <0.05% were disregarded, as the EM algorithm used for the calculations is not accurate in predictions for low frequency haplotypes. For female subjects, most common haplotypes from all cases (Types I and II) and controls were included in the calculations. Similarly, for the males, the cases were sub-divided into Types I and II in addition to the entire group of cases (Type I plus Type II) and controls were considered for chi-squared tests. One haplotype (GAGG) is of particular interest. We describe this haplotype as a ‘G’ in position –643 (rs521018), and ‘A’ in position –435 (rs498207), a ‘G’ in position –269 (rs3813928) followed by a ‘G’ in position +32 (rs518147), with respect to the transcription start site. The frequency of this haplotype (GAGG) was 11% (28 counts of 252 cases; Table 3) in male cases (Type I plus Type II) versus 3.6% (3 counts of 83 controls) in male controls, as compared to female cases (5%; 6 counts of 120 cases) and controls (2.9%; 2 counts of 84 controls) (Pearson's P = 0.24). Within the sub-types, the GAGG haplotype occurred more frequently (13%) in Type I males as compared to the same group in females (Pearson's P = 0.36). When all the common male haplotypes were grouped together (case = 213; control = 76) and compared with GAGG haplotype (case = 28; control = 3), we observed a haplotype association between cases and controls (Pearson's P-value = 0.04; Odds ratio with 95% CI = 0.81 < 6.26 < 45.79). Similar comparison of grouped haplotypes versus GAGG haplotype, between controls and Type I cases gave notable association (Pearson's P = 0.02; Odds ratio with 95% CI = 0.82 < 6.2 < 97.13) but not with controls and Type II cases (Pearson's = 0.34). In contrast, for the female cohort, similar comparison of grouped haplotypes (control = 152; Type I = 80) versus GAGG haplotype (control = 3; Type I = 5), failed to give any association (Pearson's = 0.1). Eight independent tests were conducted in this analysis (two genders, two sub-types and four markers). Therefore a Bonferroni's correction (for eight tests) was applied. None of the P-values mentioned above proved to be significant.


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Table 3. Haplotype distribution

 
The di-nucleotide repeat (GC) microsatellite was geno-typed and the two major variations (13 repeats and 16 repeats) were included for association analysis. Repeat variants occurring in low numbers (below five) were eliminated from the calculations. Table 4 displays the lack of significance of association between the di-nucleotide repeat and alcohol dependency in males and females in this population sample. The power of the study, as calculated using QUANTO version 0.5, was 37% with the population risk assumed to be 2% in the female group under a recessive mode of inheritance. For the male sub-group a dominant model was assumed and the power calculated to be 37% with a genetic risk of 1.6 odds ratio.


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Table 4. Di-nucleotide repeat association analysis

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Loss of control and substance abuse has been shown to involve the serotonergenic receptor genes and associations observed for polymorphisms within some of these genes (Ricca et al., 2002Go; Rosmond et al., 2002Go; von Meyenburg et al., 2003Go; Murphy et al., 2004Go; Pooley et al., 2004Go). Serotonergenic neuroreceptors have been implicated in a range of neurological and psychiatric disorders, and among them the HTR2C gene has been well studied (Cloninger et al., 1981Go; Lappalainen et al., 1999Go; Schuckit et al., 1999Go; Himei et al., 2000Go; Parsian and Cloninger, 2001Go; Hill et al., 2002Go). Early-onset alcoholics are frequently characterized by a history of hyperactivity, antisocial personality traits, alcoholic fathers, lower mean platelet monoamine oxidase activity, and a strong urge to consume alcohol in response to an intravenous infusion of the serotonin 2C receptor agonist meta-chlorophenyl-piperazine (George et al., 1997Go; Hommer et al., 1997Go). Serotonergic disturbances and loss of control are common features in suicide attempters (Asberg, 1997Go), violent offenders (Linnoila et al., 1994Go; Virkkunen et al., 1997) and alcoholics (Ballenger et al., 1979Go). However, despite the established role of serotonergic transmission in alcoholism and the heritability of this condition, the possibility of an association of genetic variations in promoter HTR2C gene with alcohol-related traits has not been investigated previously. A coding polymorphism (Cys23Ser) has been shown to significantly contribute to cerebrospinal fluid concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), the major metabolite of norepinephrine, which is found in higher concentrations in alcoholic violent offenders with the Ser23 genotype (Lappalainen et al., 1999Go). However, this same study along with several others (Pandey et al., 1996Go; Schuckit et al., 1999Go; Himei et al., 2000Go) have confirmed the lack of genetic association between alcohol dependence or alcoholism and Cys23Ser. Therefore, in our current work, we decided not to include Cys23Ser, but instead to genotype the promoter variants in this gene, which have thus far never been studied in the context of alcohol dependence. Since there have been several reports that the levels of brain 5-HT receptor are inversely related to alcohol consumption (Pandey et al., 1992Go; LeMarquand et al., 1994Go; Himei et al., 2000Go) promoter SNPs likely to influence expression of HTR2C were considered as prime candidates in this association study for alcohol dependence. Several common variations within HTR2C have been sequenced and documented in the Nordic population (manuscript in preparation), including four single nucleotide polymorphisms and one microsatellite in the promoter. Of the five promoter variants, one of the SNPs (rs3813928) maps to two transcription factor binding sites (MZF and SP1), and could possibly play a role in transcription of HTR2C (Yuan et al., 2000Go). The di-nucleotide repeat polymorphism rs3834996, although not functionally influencing promoter activity, has previously been implicated as a possible marker for susceptibility for leanness in a Japanese population sample (Yuan et al., 2000Go). Three other polymorphisms, rs518147, rs498207 and rs521018 have thus far not been reported in any association studies with alcohol dependence. Considering the possibility of co-operative effects between different transcription factors and transcript regions of a promoter, we decided to include SNPs mapped to the known promoter of HTR2C. The SNP rs3813928, which is known to influence the promoter activity of HTR2C, was also included. Pair-wise linkage disequilibrium (LD) was quantified across the region using D'. Promoter SNPs rs518147 (position +32), rs498207 (position –435) and rs521018 (position –643) displayed reliable LD. SNP rs3813928 (position –269) indicated no LD with the other markers within the promoter. The LD pattern across this region indicates genomics rearrangements (our manuscript in preparation). A complete haplotype analysis was performed for the four SNPs.

Individual SNP analysis in this study showed no significant association with alcohol dependence, neither when the whole population was considered, nor when sub-groups of males, females, Type 1 and Type 2 were individually tested.

The frequencies of the most common haplotypes for the gender-based subgroups of the cases and controls were calculated but failed to show significant differences between the groups. On correction for multiple testing, no significant association with alcohol-dependence could be observed for any of the haplotypes in any of the groups within this population. The power of this study to detect weak genetic effects of HTR2C in alcohol dependence in both males and females was hampered by the initial sample size. Under these conditions, considering a dominant model in males the power to detect genetic risks of 1.6 (OR) was 37%. However, if controls were increased to match the number of cases there would be sufficient power (81%) to detect such genetic influences. In conclusion, although this study reports a lack of association between the markers tested and alcohol dependency, there seems to be a clear tendency indicative of a haplotype selection in males Type I which could be significantly apparent in a follow up study with more power.


    ACKNOWLEDGEMENTS
 
This work was supported by grants from the Swedish National Science Foundation.


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 DISCUSSION
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