Association of catechol-O-methyl transferase (COMT) gene 287AG polymorphism with susceptibility to obsessiveЦcompulsive disorder in Chinese Han population.код для вставкиСкачать
RESEARCH ARTICLE Neuropsychiatric Genetics Association of Catechol-O-Methyl Transferase (COMT) Gene 287A/G Polymorphism With Susceptibility to Obsessive–Compulsive Disorder in Chinese Han Population Shiguo Liu,1,2,3 Yanhui Liu,4,5 Haiping Wang,6 Ruiling Zhou,7 Jinbao Zong,6 Changgui Li,1,2 Xinhua Zhang,4,8* and Xu Ma9,10,11** 1 Shandong Provincial Key Laboratory of Metabolic Disease, The Afﬁliated Hospital of Medical College, Qingdao University, Qingdao, China 2 Institute of Clinical Research, The Afﬁliated Hospital of Medical College, Qingdao University, Qingdao, China 3 Genetic Laboratory, The Afﬁliated Hospital of Medical College, Qingdao University, Qingdao, China Department of Psychiatry, Medical College, Qingdao University, Qingdao, China 4 5 Binzhou Youfu Hospital, Shandong, China 6 The Afﬁliated Hospital of Medical College, Qingdao University, Qingdao, China Rizhao People’s Hospital, Shandong, China 7 8 Psychological Clinic, The Afﬁliated Hospital of Medical College, Qingdao University, Qingdao, China 9 Graduate School, Peking Union Medical College, Beijing, China National Research Institute for Family Planning, Beijing, China 10 11 World Health Organization Collaborating Centre for Research in Human Reproduction, Beijing, China Received 29 July 2010; Accepted 3 January 2011 How to Cite this Article: Several studies suggested a genetic component in the etiology of obsessive–compulsive disorder (OCD). COMT involves in the degradation of dopamine and norepinephrin. As another functional SNP locus, COMT 287A/G polymorphism showed an effect on enzyme activity, suggesting that it may inﬂuence brain dopamine levels. To identify association of COMT 287A/ G polymorphism with susceptibility to OCD in Chinese Han population. We evaluate the genetic contribution of the COMT 287A/G polymorphism in 200 OCD patients and 403 OCD-free control of Chinese Han population by PCR-RFLP. In addition, we investigate whether COMT 287A/G polymorphism is associated with one or more of these symptom dimensions or other characteristics such as sex, age of onset, and tic-relatedness and evaluate the association of the factorial structure of OCD symptoms from the Y-BOCS checklist with the COMT 287A/G polymorphism. A statistical difference was found in the genotypic frequencies of COMT 287A/G between the OCD and control groups (c2 ¼ 13.99, DF ¼ 2, P ¼ 0.00091) and in the genotypic frequencies of GG genotype versus AA and AG genotypes of COMT 287 (c2 ¼ 13.49, DF ¼ 1, P ¼ 0.00024, OR ¼ 3.43, 95% CI ¼ 1.78–6.62). There was a trend for an association in the genotypic distributions of COMT 287A/G polymorphism of males (c2 ¼ 27.81; DF ¼ 2; P < 0.001) and females (c2 ¼ 7.31; DF ¼ 2; P ¼ 0.026) between the OCD patients and the controls. Using principal component analysis, we derived 5 factors from 12 main contents of OCD symptoms 2011 Wiley-Liss, Inc. Liu S, Liu Y, Wang H, Zhou R, Zong J, Li C, Zhang X, Ma X. 2011. Association of Catechol-O-Methyl Transferase (COMT) Gene 287A/G Polymorphism With Susceptibility to Obsessive–Compulsive Disorder in Chinese Han Population. Am J Med Genet Part B 156:393–400. Grant sponsor: National Basic Research Program of China; Grant number: 2007CB511905; Grant sponsor: National Infrastructure Program of Chinese Genetic Resources; Grant number: 2006DKA21300; Grant sponsor: National Natural Science Foundation of China; Grant number: 30470953. Shiguo Liu and Yanhui Liu contributed equally to this work. *Correspondence to: Xinhua Zhang, M.D., Department of Psychology and Psychiatry, Medical College, Qingdao University, Qingdao 266021, China. E-mail: email@example.com **Correspondence to: Prof. Xu Ma, Center for Genetics, National Research Institute for Family Planning, 12, Dahuisi Road, Haidian, Beijing 100081 China. E-mail: firstname.lastname@example.org Published online 22 February 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ajmg.b.31173 393 394 from the Y-BOCS checklist and found no association with COMT 287A/G polymorphism. Our study supports the involvement of the COMT 287A/G polymorphism in the genetic susceptibility to OCD in Chinese Han population. 2011 Wiley-Liss, Inc. Key words: COMT 287A/G polymorphism; OCD; principal component analysis; genotype and phenotype INTRODUCTION Obsessive–compulsive disorder (OCD) is a common and severe neuropsychiatric illness characterized by anxiety-producing intrusive thoughts and performance of anxiety-reducing rituals and affects an estimated 1% of the Chinese mainland population. With rapid development of science and technology and changes of life style, the prevalence and epidemiology of this disorder is experiencing a dramatically increase in China. Furthermore, OCD is ranked 1 of the 10 most disabling medical conditions by the World Health Organization (WHO). Despite controlled family studies [Bellodi et al., 1992; Pauls et al., 1995] and twin studies [Inouye, 1965; The Clomipramine Collaborative Study Group, 1991; Chouinard, 1992] in OCD suggest a genetic component in the etiology of OCD, the exact disease etiology remains poorly understood. It is believed that susceptibility to OCD is determined by the interactions of multiple genetic loci with unknown environmental factors [Fontenelle and Hasler, 2008]. As a result, a great deal of research has been focused on identifying OCD susceptibility genes. Thus far, two strong linkage loci for OCD including 9p24 [Hanna et al., 2002] and 3q27-28 [Shugart et al., 2006] have been suggested by genomewide screenings. Candidate gene approach has suggested evidence for several genes relevant to neuronal signaling susceptibility to OCD, such as dopamine neurotransmission (including Dopamine transporter gene DAT1, dopamine receptor genes DRD2-4) [Frisch et al., 2000; Hemmings et al., 2003] and serotonin neurotransmission (serotonin transporter gene 5-HTT [McDougle et al., 1998; Hu et al., 2006], serotonin receptor genes 5-HT2A [Nicolini et al., 1996; Walitza et al., 2002], tryptophan hydroxylase (TPH) [Frisch et al., 2000; Han et al., 1999]), metabolism of neurotransmitters cathecholamine-O-methyl transferase (COMT) [Schindler et al., 2000; Pooley et al., 2007], monoamineoxidase A (MAO-A) [Karayiorgou et al., 1999; Camarena et al., 2001]. COMT, located at chromosome 22q11 [Grossman et al., 1992], is a key enzyme which metabolizes monoamine neurotransmitters and involves in the degradation of dopamine and norepinephrin, and is of particular importance for the clearance of dopamine in the prefrontal cortex. It has been previously described that patients with 22q11 microdeletions manifest a number of psychiatric phenotypes, including schizophrenia and OCD, which suggest that COMT may be one of the candidate genes of OCD [Karayiorgou et al., 1999]. A more recent follow-up study on phenotypes observed in patients with the 22q11 deletion reported OCD symptoms in the majority of these patients, thus providing even stronger evidence that the 22q11 locus harbors gene(s) predisposing to OCD [Hemmings and Stein, 2006]. COMT c.472 G>A polymorphism resulting in a valine (Val) to methionine (Met) amino acid substitution, is of particular interest functional SNP of COMT, which affects dopamine regulation in the prefrontal cortex by reducing the AMERICAN JOURNAL OF MEDICAL GENETICS PART B activity of the enzyme to one quarter of that encoded by the Val allele to alter the stability of the enzyme activity [Lachman et al., 1996]. However, investigations of a possible role for a COMT V158M polymorphism in OCD pathogenesis have generated conﬂicting results [Hemmings and Stein, 2006]. Some studies have identiﬁed positive associations between the COMT and OCD [Karayiorgou et al., 1997; Niehaus et al., 2001; Denys et al., 2006; Pooley et al., 2007], while others have negative results [Ohara et al., 1998; Erdal et al., 2003; Meira-Lima et al., 2004]. To clarify the global relevance of other functional variants of COMT and OCD development, the possible association needs to be conﬁrmed by independent studies in different ethnic groups. The objective of this present research was as follows: (1) to assess the genetic association of 287A/G (rs2097063) polymorphism in the promoter of COMT with OCD in Chinese Han population. (2) To investigate whether the COMT 287A/G polymorphism is associated with one or more of these symptom dimensions or other characteristics such as sex, age of onset, and tic-relatedness. And (3) to evaluate the association of the factorial structure of OCD symptoms from the Y-BOCS checklist with the COMT 287A/G polymorphism. MATERIALS AND METHODS Patient Population Two hundred unrelated patients with OCD [mean age (SD) ¼ 28.9 (18.7) years; 35.5% females; 64.5% males] were recruited from the Afﬁliated Hospital of Medical College, Qingdao University over a period of 10 years (Table I). All OCD patients met the DSM-IV criteria and clinical records for OCD. In addition, the MiniInternational Neuropsychiatric Interview (MINI, DSM-IV criteria) was used as a diagnostic interview in the groups of patients, as well as in the healthy control group. Subjects were excluded if they presented with a movement disorder other than a tic, schizophrenia, recurrent major depression, bipolar disorder, mental retardation, alcohol or other substance abuses within the last 6 months, or a history of psychosurgery, encephalitis, or signiﬁcant head trauma. Of the 200 subjects, 177 were taking medications (mainly selective serotonin reuptake inhibitors (SSRIs), chlorimipramine, and lowdose benzodiazepines) and/or exposure/response-prevention behavioral therapy. The remaining 23 patients had not received any TABLE I. Demographic Characteristics of OCD Patients and Controls Age, mean (SD) Gender Female Male a OCD patients 28.9 (18.7) Controls 30.2 (11.9) 71 (35.5%) 129 (64.5%) 155 (38.5%) 248 (61.5%) t-Test. Chi-square test (c2 ¼ 0.50, DF ¼ 1). b P-value 0.40a 0.48b LIU ET AL. treatment for their OCD symptoms at least within the previous 1–2 years. Four hundred three unrelated control individuals [mean age (SD) ¼ 30.2 (11.9) years; 38.5%females; 61.5% males], were recruited from at the students and volunteers at Qingdao University. All controls were included after being interviewed with the Diagnostic Interview for Genetic Studies (DIGS) [Nurnberger et al., 1994] and with the Family Interview for Genetic Studies to conﬁrm the absence of both personal and familial history of OCD and other psychiatric disorders. The protocol was approved by the Ethics Committees of the Afﬁliated Hospital of Medical College, Qingdao University, and all subjects provided written informed consent. In 200 cases, obsessions and compulsions were recorded according to the Y-BOCS checklist, including more than 60 items organized in seven categories of obsessions and seven categories of compulsions. Genotyping The primers of COMT 287A/G used for PCR were as fellows: forwards: 50 -TAGTAACAGACTGGCACGAA-30 and rewards: 50 GTTCAAAGGGCATTTATCATG-30 . The PCR reactions (25 ml) contained 2 ng of genomic DNA, 2.5 ml of 10 PCR buffer, 3 ml of 200 mM dNTPs, 1 ml of 10 pM of sense and antisense primers, 1.2 ml of 2.25 mM MgCl2, 0.4 U of Taq DNA polymerase, and 14.4 ml of ddH2O. PCR were performed using a Thermocycler under the following conditions: enzyme activation step at 94.0 C for 5 min, and 35 alternating cycles of denaturation at 94.0 C for 30 sec and reannealing at 60 C for 1 min and extension at 72.0 C for 1 min, and a ﬁnal extension step at 72 C for 10 min. The products (4 ml) were digested with HindIII (2.5 U) (New England Biolabs, Beijing, China) in a reaction volume of 10 ml. There is no cut with A allele, while the G allele resulted in digestion of the 350 bp fragment into 276 and 74 bp fragments. The restriction fragment products were separated on 2% agarose gels stained with ethidium bromide and viewed under UV light. More than 30 subjects were selected to conﬁrm the genotype by DNA sequencing techniques. Statistical Analysis First, the genotypic and allelic frequency of patients and controls were analyzed by chi-square test. Power analysis was performed with the Genetic Power Calculator program, considering 0.05, twotailed [Purcell et al., 2003]. Second, to determine the number and structural deﬁnition of speciﬁc dimensions, principal component analysis applying a varimax rotation with the data from the Y-BOCS checklist was performed following the methodology of Leckman et al. . Brieﬂy, a score of 0 or 1 was assigned to each of the seven major obsessive symptom categories and to each of the seven major compulsion categories of the Y-BOCS checklist as follows: taking into account items noted as current, Responses on each of the 14 symptom categories of the Y-BOCS were scored 1 if at least one item in the category had a check mark-indicating that the subject presented with that symptom, 0 if none of the items was checked [Feinstein et al., 2003]. Note that miscellaneous obsessions and compulsions were excluded because each contained many heterogeneous symptoms. 395 RESULTS Case–Control Study There were no differences in the age and gender distributions between the OCD and control groups (Table I), and control groups were in Hardy–Weinberg equilibrium (c2 ¼ 2.68, P ¼ 0.10). A statistical difference was found in the genotypic frequencies of COMT 287A/G polymorphism between the OCD and control groups (c2 ¼ 13.99, DF ¼ 2, P ¼ 0.00091) and in the genotypic frequencies of GG genotype versus AA and AG genotypes of COMT 287A/G (c2 ¼ 13.49, DF ¼ 1, P ¼ 0.00024, OR ¼ 3.43, 95% ¼ 1.78–6.62). However, no statistical difference was observed in allelic frequencies between the OCD and control groups (c2 ¼ 3.22, DF ¼ 1, P ¼ 0.07, OR ¼ 1.29, 95% CI ¼ 0.82–2.04). There were also no association between heterozygous AG genotype and homozygous for AA and GG genotype (c2 ¼ 1.91, DF ¼ 1, P ¼ 0.17, OR ¼ 0.78, 95% CI ¼ 0.55–1.11) or AA genotypes versus AG and GG (c2 ¼ 0.18, DF ¼ 1, P ¼ 0.67, OR ¼ 0.93, 95% CI ¼ 0.67–1.30) (Table II). There was a trend for an association in the genotypic distributions of COMT 287A/G polymorphism of males (c2 ¼ 27.81; DF ¼ 2; P < 0.001) and females (c2 ¼ 7.31; DF ¼ 2; P ¼ 0.026) between the OCD patients and the controls, while no association was found in the allele frequencies of female (c2 ¼ 2.72, DF ¼ 1; P ¼ 0.099) or male (c2 ¼ 0.64, DF ¼ 1; P ¼ 0.42). There was no statistical in genotypic (c2 ¼ 2.12, DF ¼ 2; P ¼ 0.35) and allelic (c2 ¼ 2.03, DF ¼ 1; P ¼ 0.16) frequencies on set age subgroups <18 and 18, and between subgroups OCD with tic and without tic in the observed genotypic (c2 ¼ 2.87, DF ¼ 2; P ¼ 0.24) and allelic (c2 ¼ 0.19, DF ¼ 1; P ¼ 0.66) frequencies of 287A/G polymorphism (Table III). Factor Analysis In the category level factor analysis, we revealed ﬁve symptom dimensions in the Y-BOCS checklist using principal component analysis. Our factor solution shows a wide degree of consistency with the data published previously, conﬁrming the potential multidimensional structure of OCD [Baer, 1994]. The principal component analysis on OC contents from the Y-BOCS checklist yielded the following ﬁve-factor solution (Table IV) that accounted for 71.80% of the total variance. The ﬁrst factor accounted for 17.22% of the variance and included hoarding obsessions and compulsions. The second factor accounted for 15.89% and included contamination obsessions and cleaning compulsion. The third factor accounted for 14.95% and included symmetry obsessions and ordering compulsions. The fourth factor accounted for 14.60% and included aggressive obsession and checking compulsion. The ﬁfth factor accounted for 9.15% and included somatic obsession and repeating compulsion. Association Between Obsessive–Compulsion Contents and Genotypes of COMT 287A/G Polymorphism We estimated the association between obsessive–compulsion contents and genetic distributions of COMT 287A/G polymorphism. 396 AMERICAN JOURNAL OF MEDICAL GENETICS PART B TABLE II. Genotype and Allele Frequency of the COMT Gene Polymorphism in OCD Patients and Controls Genotype Total AA AG GG AG AA þ GG AA AG þ GG GG AA þ AG Allele Total G A OCD patients Controls 200 115 (57.5%) 63 (31.5%) 22 (11.0%) 63 (31.5%) 137 (68.5%) 115 (57.5%) 85 (42.5%) 22 (11.0%) 178 (89.0%) 403 239 (59.3%) 150 (37.2%) 14 (3.5%) 150 (37.2%) 253 (62.8%) 239 (59.3%) 164 (40.7%) 14 (3.5%) 389 (96.5%) 400 107 (26.8%) 293 (73.3%) 806 178 (22.1%) 628 (77.9%) x2 DF P-value 13.99 2 0.00091* 1.91 1 0.18 OR 95% CI 0.17 0.78 0.55–1.11 1 0.67 0.93 0.67–1.30 13.49 1 0.00024* 3.43 1.78–6.62 3.22 1 0.07 1.29 0.82–2.04 P < 0.001. a Our ﬁndings suggest that there is no association between the category-based factor of obsession–compulsion and genotypic (Table V) and allelic frequencies (data of allele frequency not shown). We also evaluate the association between ﬁve factors score followed by principal component analysis and genetic distributions of COMT 287A/G polymorphism, and no association was found in genotypic (Table VI) and allelic frequencies (data of allele frequency not shown). DISCUSSION Many studies indicate that catecholamine plays a major function in the pathophysiology of OCD [Karayiorgou et al., 1997; Poyurovsky et al., 2005; Denys et al., 2006; Pooley et al., 2007; Katerberg et al., 2010]. COMT, as one of major genes that modulate CA neurotransmission, has become as a candidate gene for OCD for many years. However, previous investigations in different population on the role of the COMT polymorphism in the development of OCD have produced inconsistent results [Ohara et al., 1998; Erdal et al., 2003; Meira-Lima et al., 2004]. Some research groups reported that COMT V158M polymorphism was associated with OCD [Karayiorgou et al., 1997; Poyurovsky et al., 2005; Denys et al., 2006; Pooley et al., 2007; Katerberg et al., 2010], while many others found no association with susceptibility to OCD [Ohara et al., 1998; Erdal et al., 2003; Meira-Lima et al., 2004]. Thus, it is necessary to reevaluate the global relevance of other functional variants of COMT and OCD development in different ethnic groups. As another functional SNP locus, COMT 287A/G polymorphism showed an effect on enzyme activity, suggesting that it may indeed inﬂuence brain dopamine levels [Chen et al., 2004; Funke et al., 2005]. Several studies suggested that variations in the COMT 287A/G played a signiﬁcant role in the development of some diseases, such as habituation and other psychiatries [Cao et al., 2003]. TABLE III. Difference in Sex, Age of Onset and Presence of Tics of Case–Control Association Study Genotype Group Male OCD Male control Female OCD Female control Onset age <18 Onset age 18 OCD with tic OCD without tic *P < 0.001. **P < 0.05. N 129 248 71 155 108 92 11 189 AA 74 (57.4%) 140 (56.5%) 41 (57.7%) 99 (63.9%) 66 (61.1%) 49 (53.3%) 8 (72.7%) 107 (56.6%) AG 41 (31.8%) 98 (39.5%) 22 (31.0%) 52 (33.5%) 33 (30.6%) 30 (32.6%) 1 (9.1%) 62 (32.8%) Allele GG 14 (10.9%) 10 (4.0%) 8 (11.3%) 4 (2.6%) 9 (8.3%) 13 (14.1%) 2 (18.2%) 20 (10.6%) x2 27.81 P-value 0.00* 7.31 0.026** 2.12 0.35 2.87 0.24 G 69 (26.7%) 118 (23.8%) 38 (26.8%) 60 (19.4%) 51 (23.6%) 56 (30.4%) 5 (22.7%) 102 (27.0%) A 189 (73.3%) 378 (76.2%) 104 (73.2%) 250 (80.6%) 165 (76.4%) 128 (69.6%) 17 (77.3%) 276 (73.0%) x2 P-value OR 95% CI 0.64 0.42 1.17 0.80–1.72 2.72 0.099 1.52 0.92–2.50 2.03 0.16 0.71 0.44–1.14 0.19 0.66 0.80 0.29–2.18 LIU ET AL. 397 TABLE IV. Varimax Ratated Factor Structure of the Yale-Brown Obsessive–Compulsive Scale Symptom Checklist in a Sample of 200 Patients With OCD Obsession Aggressive Contamination Sexual Hoarding Symmetry Somatic Compulsion Cleaning Checking Repeating Counting Ordering Hoarding Variance explained, % Factor1 hoarding Factor2 contamination/cleaning Factor3 symmetry/ordering Factor4 aggressive/checking Factor5 somatic/repeating 0.147 0.042 0.010 0.987 0.037 0.255 0.102 0.925 0.121 0.045 0.101 0.206 0.093 0.125 0.099 0.032 0.919 0.114 0.851 0.141 0.033 0.022 0.052 0.093 0.040 0.060 0.406 0.026 0.055 0.575 0.044 0.096 0.127 0.027 0.018 0.987 17.22 0.939 0.092 0.243 0.127 0.045 0.045 15.89 0.040 0.022 0.160 0.095 0.929 0.032 14.95 0.049 0.884 0.408 0.204 0.048 0.022 14.60 0.037 0.150 0.624 0.423 0.010 0.026 9.15 Factor loadings >0.5; principal component analysis; total variance explained >71.80; Eigenvalues over >1. In our present case–control study, there is a trend for an association between OCD patients and controls in genotypic frequencies, whereas, lack of association between OCD patients and controls in allelic frequencies or between homozygote genotype and heterozygote genotype or between AA genotype versus AG and GG genotypes of the COMT 287A/G polymorphism in Chinese mainland Han population. But there is signiﬁcant difference in genotypic frequencies of GG versus AA and AG. As signiﬁcant risk between 287GG genotype and OCD (OR ¼ 3.43; 95% CI ¼ 1.78–6.62), It suggested that GG genotype have a susceptibility to OCD and may operate a much stronger effect on the vulnerability to OCD. Although our studies found that there was remarkable difference in genotypic frequencies of COMT 287A/G polymorphism between the OCD patients and the controls in both agenda, there was no difference in allelic frequencies between female and male. In several study on association between OCD and COMT V158M polymorphism, Karayiorgou et al. [1997, 1999] reported that the COMT L allele conferred a risk for the development of OCD, particularly in L/L homozygous males. However, in a subsequent study, conducted in a Japanese population, no association between the functional variants of COMT and anxiety disorders, including OCD, was detected [Ohara et al., 1998]. It is speculated that susceptibility genes can operate in unison with one another such that a particular combination of alleles has a much stronger effect on the vulnerability to OCD than each separate allele. Our study also found that there was no difference between OCD with tic and without tic, or between onset age subgroups, <18 years versus 18 years. In the sample power of study, considering genotypic frequencies in our sample, our sample size had a high power (0.706) to detect a small effect size, which suggested the sample size would be sufﬁcient. Distinction between obsessions and compulsions is comfortably established in clinical usage, there is mounting evidence to support a more multidimensional view of OCD. Our principal component analysis revealed ﬁve symptom dimensions in the Y-BOCS checklist. Our factor solution showed a wide degree of consistency with the data published previously, conﬁrming the potential multidimensional structure of OCD [Baer, 1994]. Some minor discrepancies between the studies might be attributable to the differences in sample sizes, in some environmental factors and in the ethnicity of the populations. The principal component analysis on OC contents from the Y-BOCS checklist yielded the following ﬁve-factor solution that accounted for 71.80% of the total variance. The ﬁrst factor accounted for 17.22% of the variance and included hoarding obsessions and compulsions. Hoarding has emerged as an independent factor in most previous factorial studies [Mataix-Cols et al., 2005]. The familiality of hoarding has been previously demonstrated using data from the OCD Collaborative Genetics Study (OCGS) and the Johns Hopkins OCD Family Study, which predated the OCGS. Samuels et al.  reported that the ﬁrstdegree relatives of hoarding probands had a greater prevalence of hoarding behavior than the relatives of non-hoarding probands, and both Hasler et al.  and Cullen et al.  noted a signiﬁcant intrafamiliar sib–sib correlation for the hoarding factor. When used as a predictor in treatment studies, the hoarding factor also stands out as being associated with poorer response to SSRIs [Black et al., 1998; Saxena et al., 2002] and greater likelihood of drop out from cognitive behavior therapy [Pinto et al., 2007], although a recent study found that hoarding and non-hoarding OCD patients responded equally well to paroxetine [Saxena et al., 2007]. In addition, hoarding is the only subphenotype for which genetic linkage results have been reported. Further support for this subphenotype comes from studies of treatment response. The second factor accounted for 15.89% of the variance and included contamination obsessions and cleaning compulsions. The combination of these two categories is commonly supported not only by clinical evidence but also by evidence from other studies [Nothen et al., 398 AMERICAN JOURNAL OF MEDICAL GENETICS PART B TABLE V. Association Between Obsessive–Compulsion Contents (Present/Absent) and COMT 287 Genotypes Obsession Aggressive Present Absent Contamination Present Absent Sexual Present Absent Hoarding/saving Present Absent Symmetry/exactness Present Absent Miscellaneous Present Absent Somatic Present Absent Compulsion Cleaning/washing Present Absent Checking Present Absent Repeating Present Absent Counting Present Absent Ordering/arranging Present Absent Hoarding/collecting Present Absent Miscellaneous Present Absent AA (115) AG (63) GG (22) x2 (DF ¼ 2) P-value 68 (62.96%) 47 (51.09%) 27 (25.00%) 36 (39.13%) 13 (12.04%) 9 (9.78%) 4.60 0.10 27 (57.45%) 88 (57.52%) 15 (31.91%) 48 (31.37%) 5 (10.64%) 17 (11.11%) 0.01 0.99 1 (50.00%) 114 (57.58%) 1 (50.00%) 62 (31.31%) 0 (0.00%) 22 (11.11%) 0.46 0.79 0 (0.00%) 115 (58.08%) 2 (100%) 61 (30.81%) 0 (0.00%) 22 (11.11%) 4.39 0.11 14 (48.28%) 101 (59.06%) 14 (48.28%) 49 (28.65%) 1 (3.45%) 21 (12.28%) 5.29 0.07 53 (54.08%) 62 (60.78%) 33 (33.67%) 30 (29.41%) 12 (12.24) 10 (9.80%) 0.95 0.62 10 (62.50%) 105 (57.07%) 4 (25.00%) 59 (32.07%) 2 (12.50%) 20 (10.87%) 0.34 0.84 27 (56.25%) 88 (57.89%) 15 (31.25%) 48 (31.58%) 6 (12.50%) 16 (10.53%) 0.15 0.93 76 (59.84%) 39 (53.42%) 34 (26.77%) 29 (39.73%) 17 (13.39%) 5 (6.85%) 4.60 0.10 8 (50.00%) 107 (58.15%) 4 (25.00%) 59 (32.07%) 4 (25.00%) 18 (9.78%) 3.5 0.17 2 (100%) 113 (57.07%) 0 (0.00%) 63 (31.82%) 0 (0.00%) 22 (11.11%) 1.49 0.47 9 (50.00%) 106 (58.24%) 9 (50.00%) 54 (29.67%) 0 (0.00%) 22 (12.09%) 4.52 0.10 0 (0.00%) 115 (58.08%) 2 (100%) 61 (30.81%) 0 (0.00%) 22 (11.11%) 4.39 0.11 42 (62.69%) 73 (54.89%) 18 (26.87) 45 (33.83) 7 (10.45%) 15 (11.29%) 1.19 0.55 Percentages of each content characterized by a speciﬁc genotype in (parentheses): Bonferroni correction for multiple testing P ¼ a/14 ¼ 0.0036. 1993; Baer, 1994; Leckman et al., 1997; Mataix-Cols et al., 1999]. The third factor accounted for 14.95% of the variance and included symmetry obsession and ordering compulsion. The fourth factor accounted for 14.60% of the variance and included aggressive obsessions and checking compulsion. The combination of these two categories is commonly supported by evidence from the study of Mataix-Cols et al. [1999, 2002]. The ﬁfth factor accounted for 9.15% of the variance and included somatic obsession and repeat- ing compulsion. Mataix-Cols et al. classiﬁed obsessions with hoarding and symmetry and compulsions with hoarding, ordering, repeating, and counting into a single factor [Pinto et al., 2007]. However, unlike the results of Mataix-Cols et al. [Pinto et al., 2007], in our study, we classiﬁed obsessions with hoarding and symmetry and compulsions with hoarding, ordering, repeating, and somatic into three factors, sexual obsession and counting compulsion was not included in any of the ﬁve factors. The slight variations between LIU ET AL. 399 TABLE VI. Analysis of Variance for the Three COMT 287 Genotype Factor score Hoarding Contamination Symmetry Aggressive Somatic (115) AA 0.092 0.169 0.012 0.994 0.043 0.953 0.084 0.998 0.025 1.042 (63) AG 0.212 1.754 0.008 0.994 0.199 1.193 0.190 0.987 0.074 0.943 (22) GG 0.129 0.213 0.038 1.090 0.346 0.293 0.104 1.019 0.343 0.900 F 2.106 0.025 2.719 1.677 1.511 P-value 0.124 0.976 0.068 0.190 0.223 DF 2,197 2,197 2,197 2,197 2,197 P < 0.01. studies on the inclusion of obsessions and compulsions in factors reﬂect differences in sample sizes, social and cultural backgrounds, and research methods. We estimated the association between obsessive–compulsion contents and genetic distributions of COMT 287A/G polymorphism. Our ﬁndings suggest that there is no association between the category-based factor of obsession–compulsion and genotypic and allelic frequencies (data of allele frequency not shown). This might be the result of phenotypic heterogeneity of some of the categorybased symptom dimensions. A recent study by Pinto et al.  suggests that aggressive obsessions may be heterogeneous. In conclusion, we found there were remarkable differences in the genotypic frequencies of COMT 287A/G between the OCD and control groups, and in the genotypic frequencies of GG genotype versus AA and AG genotypes of COMT 287. There was a trend for an association in the genotypic distributions of COMT 287A/G polymorphism of males and females between the OCD patients and the controls. Using principal component analysis, we derived ﬁve factors from 12 main contents of OCD symptoms from the Y-BOCS checklist and found no association with COMT 287A/G polymorphism. Our study supports the involvement of the COMT 287A/G polymorphism in the genetic susceptibility to OCD in Chinese Han population. However, further investigations will be needed to determine the association between COMT polymorphisms and OCD by using a larger sample size, different population, and other SNPs. 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