Psychiatry Research 220 (2014) 1174–1175
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Association between dopamine D2 receptor (DRD2) genetic variants and alcohol dependence in Han Chinese in Taiwan To the Editors: Chronic alcohol intake is associated with down-regulation of central dopamine D2 receptors (DRD2). Previous studies exploring the association between alcohol dependence (AD) and single nucleotide polymorphisms (SNPs) of DRD2 gene, including TaqI B (rs1079597), promoter -141C ins/del (rs1799732), G/T in intron 6 (rs1076560), C957T in exon 7 (rs6275), A1385G in exon 8 (rs6276), and TaqI A (rs1800497), have reported conflicting results. In addition to the results of single markers, DRD2 haplotypes composed of some or all of the six aforementioned markers have been reported to be associated with AD in different ethnic populations (Luo et al., 2005; Kraschewski et al., 2009). The prevalence of AD in Han Chinese in Taiwan is lower than that in Caucasian populations. Considering that the distribution of the minor allele frequencies of DRD2 SNPs may vary among ethnicities, we aimed to examine both single marker and haplotypic associations of the six aforementioned SNPs in DRD2 gene with AD in our population. This study was approved by the Institutional Review Board of Taipei City Psychiatric Center (TCPC). We consecutively recruited patients who identified themselves as having four grandparents of Han Chinese ancestry and fulfilled the DSM-IV criteria for a current diagnosis of AD by two psychiatrists using clinical interview from 2006 to 2009 in TCPC. The control subjects who did not meet the diagnostic criteria of lifetime alcohol abuse or dependence and did not have known physical or psychiatric illnesses identified by interview and laboratory tests were recruited from the Health Examination Center. The inclusion criteria for healthy controls and alcoholic patients were: (1) age between 20 and 65 years; (2) no history of illicit drug use; and (3) no current or past diagnosis of chronic systemic diseases or major psychiatric comorbidities such as schizophrenia, bipolar disorder, or major depressive disorder. Six SNPs in the DRD2 gene (rs1799732, rs1079597, rs1076560, rs6275, rs6276, and rs1800497) were genotyped using methods described previously (Luo et al., 2005). Case–control association analyses were conducted using PLINK (http://pngu. mgh.harvard.edu/ purcell/plink/) at both single marker and haplotype levels. We were aware of the possibility of an inflated type I error because of multiple testing, and a nominal P value o0.01 was considered significant. A total of 303 AD patients (267 men and 36 women, mean age: 42.278.9 years) and 308 controls (192 men and 116 women, mean age: 35.3711.2 years) were enrolled. All markers were in Hardy– Weinberg equilibrium. There we no differences in genotype and allele frequencies between AD and control groups after controlling for variables such as age and gender (Supplementary Table 1). Four
http://dx.doi.org/10.1016/j.psychres.2014.09.011 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
haplotypes, named H1-H4 based on their representative high to low frequencies, were observed with frequencies greater than 5%, comprising 91% of the entire sample. None of the haplotypes showed a significant difference between the AD and control groups (Supplementary Table 1). Our results indicate that there was no significant association between the DRD2 gene and AD in Han Chinese. This finding supplements the existing knowledge regarding DRD2 genotypic or haplotypic associations with AD in Han Chinese by including more SNPs than only TaqI A and TaqI B sites that have been reported previously (Huang et al., 2004; Lu et al., 2001). Although some investigations have reported that specific DRD2 haplotypes confer a genetic vulnerability to AD, our finding of a negative association between the DRD2 haplotypes and AD is consistent with other studies (Gelernter and Kranzler, 1999; Kraschewski et al., 2009). In addition, our results also agree with previous findings in Han Chinese, with comparable allelic frequencies, showing that TaqI A and TaqI B do not convey a genetic susceptibility for AD (Huang et al., 2004; Lu et al., 2001). These negative results may be due to the fact that the effect from a single gene predisposing to AD is small, and it is likely that DRD2 interacts with other genetic or environmental factors during the process of AD development. It is possible that a lack of phenotypic stratification for the alcoholic subjects blurred the real genetic association that may only be demonstrated in a more homogeneous subgroup. For example, DRD2 SNPs have only been associated with AD with distinct subtypes such as a comorbidity with anxiety/depression disorder (Huang et al., 2004) or conduct disorder (Lu et al., 2001). Similarly, a phenotype-specific association has also been observed in haplotype association studies (Luo et al., 2005; Kraschewski et al., 2009). In addition, our results might be biased by the lack of measurement evaluating the potential binge drinking behavior in the control subjects. Another limitation of our study is the moderate statistical power. For the AD vs. control group comparisons, the power of the current analysis ranged from 0.68 to 0.89 if the odds ratios ranged from 1.5 to 1.8. Nevertheless, the number of cases in this study is comparable to previous studies that demonstrated positive associations between DRD2 and AD (Luo et al., 2005). In conclusion, this case–control study in the Han Chinese population in Taiwan did not find an association of DRD2 SNPs and pertinent haplotypes with AD.
Acknowledgment This work was supported by grants from Taipei City Hospital, Taiwan (TCH10301-62-042), and the National Science Council, Taiwan (NSC95-2314-B-532-008 and NSC100-2314-B-532-002 and 101-2314-B-532-002-MY2).
Letter to the Editor / Psychiatry Research 220 (2014) 1174–1175
Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2014.09.011. References Gelernter, J., Kranzler, H., 1999. D2 dopamine receptor gene (DRD2) allele and haplotype frequencies in alcohol dependent and control subjects: no association with phenotype or severity of phenotype. Neuropsychopharmacology 20, 640–649. Huang, S.Y., Lin, W.W., Ko, H.C., Lee, J.F., Wang, T.J., Chou, Y.H., Yin, S.J., Lu, R.B., 2004. Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. Alcoholism: Clinical and Experimental Research 28, 374–384. Kraschewski, A., Reese, J., Anghelescu, I., Winterer, G., Schmidt, L.G., Gallinat, J., Finckh, U., Rommelspacher, H., Wernicke, C., 2009. Association of the dopamine D2 receptor gene with alcohol dependence: haplotypes and subgroups of alcoholics as key factors for understanding receptor function. Pharmacogenet Genomics 19, 513–527. Lu, R.B., Lee, J.F., Ko, H.C., Lin, W.W., 2001. Dopamine D2 receptor gene (DRD2) is associated with alcoholism with conduct disorder. Alcoholism: Clinical and Experimental Research 25, 177–184. Luo, H.R., Hou, Z.F., Wu, J., Zhang, Y.P., Wan, Y.J., 2005. Evolution of the DRD2 gene haplotype and its association with alcoholism in Mexican Americans. Alcohol 36, 117–125.
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Chaio-Chicy Chen Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan Department of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan Chun-Hung Pan Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, No. 309, Songde Road, Xinyi District, Taipei 110, Taiwan Department of Psychology, National Chengchi University, Taipei, Taiwan Wen-Chi Jan, Po-Hsiu Kuo n Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan E-mail address: [email protected] (P.-H. Kuo) Ming-Chyi Huang nn Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, No. 309, Songde Road, Xinyi District, Taipei 110, Taiwan Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan E-mail address: [email protected] 18 September 2014
Pei-Chen Tsai Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, No. 309, Songde Road, Xinyi District, Taipei 110, Taiwan Department of Psychiatry and Psychosomatic medicine, Taiwan Adventist Hospital, Taipei, Taiwan
Available online 11 October 2014
n nn
Corresponding author. Tel.: þ 886 2 3366 8015; fax: þ 886 2 23511955. Corresponding author. Tel.: þ 886 2 27263141x1219; fax: þ 886 2 27285059.
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Association between dopamine D2 receptor (DRD2) genetic variants and alcohol dependence in Han Chinese in Taiwan To the Editors: Chronic alcohol intake is associated with down-regulation of central dopamine D2 receptors (DRD2). Previous studies exploring the association between alcohol dependence (AD) and single nucleotide polymorphisms (SNPs) of DRD2 gene, including TaqI B (rs1079597), promoter -141C ins/del (rs1799732), G/T in intron 6 (rs1076560), C957T in exon 7 (rs6275), A1385G in exon 8 (rs6276), and TaqI A (rs1800497), have reported conflicting results. In addition to the results of single markers, DRD2 haplotypes composed of some or all of the six aforementioned markers have been reported to be associated with AD in different ethnic populations (Luo et al., 2005; Kraschewski et al., 2009). The prevalence of AD in Han Chinese in Taiwan is lower than that in Caucasian populations. Considering that the distribution of the minor allele frequencies of DRD2 SNPs may vary among ethnicities, we aimed to examine both single marker and haplotypic associations of the six aforementioned SNPs in DRD2 gene with AD in our population. This study was approved by the Institutional Review Board of Taipei City Psychiatric Center (TCPC). We consecutively recruited patients who identified themselves as having four grandparents of Han Chinese ancestry and fulfilled the DSM-IV criteria for a current diagnosis of AD by two psychiatrists using clinical interview from 2006 to 2009 in TCPC. The control subjects who did not meet the diagnostic criteria of lifetime alcohol abuse or dependence and did not have known physical or psychiatric illnesses identified by interview and laboratory tests were recruited from the Health Examination Center. The inclusion criteria for healthy controls and alcoholic patients were: (1) age between 20 and 65 years; (2) no history of illicit drug use; and (3) no current or past diagnosis of chronic systemic diseases or major psychiatric comorbidities such as schizophrenia, bipolar disorder, or major depressive disorder. Six SNPs in the DRD2 gene (rs1799732, rs1079597, rs1076560, rs6275, rs6276, and rs1800497) were genotyped using methods described previously (Luo et al., 2005). Case–control association analyses were conducted using PLINK (http://pngu. mgh.harvard.edu/ purcell/plink/) at both single marker and haplotype levels. We were aware of the possibility of an inflated type I error because of multiple testing, and a nominal P value o0.01 was considered significant. A total of 303 AD patients (267 men and 36 women, mean age: 42.278.9 years) and 308 controls (192 men and 116 women, mean age: 35.3711.2 years) were enrolled. All markers were in Hardy– Weinberg equilibrium. There we no differences in genotype and allele frequencies between AD and control groups after controlling for variables such as age and gender (Supplementary Table 1). Four
http://dx.doi.org/10.1016/j.psychres.2014.09.011 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
haplotypes, named H1-H4 based on their representative high to low frequencies, were observed with frequencies greater than 5%, comprising 91% of the entire sample. None of the haplotypes showed a significant difference between the AD and control groups (Supplementary Table 1). Our results indicate that there was no significant association between the DRD2 gene and AD in Han Chinese. This finding supplements the existing knowledge regarding DRD2 genotypic or haplotypic associations with AD in Han Chinese by including more SNPs than only TaqI A and TaqI B sites that have been reported previously (Huang et al., 2004; Lu et al., 2001). Although some investigations have reported that specific DRD2 haplotypes confer a genetic vulnerability to AD, our finding of a negative association between the DRD2 haplotypes and AD is consistent with other studies (Gelernter and Kranzler, 1999; Kraschewski et al., 2009). In addition, our results also agree with previous findings in Han Chinese, with comparable allelic frequencies, showing that TaqI A and TaqI B do not convey a genetic susceptibility for AD (Huang et al., 2004; Lu et al., 2001). These negative results may be due to the fact that the effect from a single gene predisposing to AD is small, and it is likely that DRD2 interacts with other genetic or environmental factors during the process of AD development. It is possible that a lack of phenotypic stratification for the alcoholic subjects blurred the real genetic association that may only be demonstrated in a more homogeneous subgroup. For example, DRD2 SNPs have only been associated with AD with distinct subtypes such as a comorbidity with anxiety/depression disorder (Huang et al., 2004) or conduct disorder (Lu et al., 2001). Similarly, a phenotype-specific association has also been observed in haplotype association studies (Luo et al., 2005; Kraschewski et al., 2009). In addition, our results might be biased by the lack of measurement evaluating the potential binge drinking behavior in the control subjects. Another limitation of our study is the moderate statistical power. For the AD vs. control group comparisons, the power of the current analysis ranged from 0.68 to 0.89 if the odds ratios ranged from 1.5 to 1.8. Nevertheless, the number of cases in this study is comparable to previous studies that demonstrated positive associations between DRD2 and AD (Luo et al., 2005). In conclusion, this case–control study in the Han Chinese population in Taiwan did not find an association of DRD2 SNPs and pertinent haplotypes with AD.
Acknowledgment This work was supported by grants from Taipei City Hospital, Taiwan (TCH10301-62-042), and the National Science Council, Taiwan (NSC95-2314-B-532-008 and NSC100-2314-B-532-002 and 101-2314-B-532-002-MY2).
Letter to the Editor / Psychiatry Research 220 (2014) 1174–1175
Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2014.09.011. References Gelernter, J., Kranzler, H., 1999. D2 dopamine receptor gene (DRD2) allele and haplotype frequencies in alcohol dependent and control subjects: no association with phenotype or severity of phenotype. Neuropsychopharmacology 20, 640–649. Huang, S.Y., Lin, W.W., Ko, H.C., Lee, J.F., Wang, T.J., Chou, Y.H., Yin, S.J., Lu, R.B., 2004. Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. Alcoholism: Clinical and Experimental Research 28, 374–384. Kraschewski, A., Reese, J., Anghelescu, I., Winterer, G., Schmidt, L.G., Gallinat, J., Finckh, U., Rommelspacher, H., Wernicke, C., 2009. Association of the dopamine D2 receptor gene with alcohol dependence: haplotypes and subgroups of alcoholics as key factors for understanding receptor function. Pharmacogenet Genomics 19, 513–527. Lu, R.B., Lee, J.F., Ko, H.C., Lin, W.W., 2001. Dopamine D2 receptor gene (DRD2) is associated with alcoholism with conduct disorder. Alcoholism: Clinical and Experimental Research 25, 177–184. Luo, H.R., Hou, Z.F., Wu, J., Zhang, Y.P., Wan, Y.J., 2005. Evolution of the DRD2 gene haplotype and its association with alcoholism in Mexican Americans. Alcohol 36, 117–125.
1175
Chaio-Chicy Chen Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan Department of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan Chun-Hung Pan Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, No. 309, Songde Road, Xinyi District, Taipei 110, Taiwan Department of Psychology, National Chengchi University, Taipei, Taiwan Wen-Chi Jan, Po-Hsiu Kuo n Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan E-mail address: [email protected] (P.-H. Kuo) Ming-Chyi Huang nn Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, No. 309, Songde Road, Xinyi District, Taipei 110, Taiwan Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan E-mail address: [email protected] 18 September 2014
Pei-Chen Tsai Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, No. 309, Songde Road, Xinyi District, Taipei 110, Taiwan Department of Psychiatry and Psychosomatic medicine, Taiwan Adventist Hospital, Taipei, Taiwan
Available online 11 October 2014
n nn
Corresponding author. Tel.: þ 886 2 3366 8015; fax: þ 886 2 23511955. Corresponding author. Tel.: þ 886 2 27263141x1219; fax: þ 886 2 27285059.
