We examined the impact of comorbid depression and anxiety disorders on the severity of anorexia nervosa (AN) in adolescent girls. Adolescent girls with AN (N = 88) were divided into one group with and another group without comorbid disorders, and selected subjective and objective measures of illness severity were compared between the two groups. The comorbid group had significantly higher scores than the noncomorbid group for all four subscales and total scores of the Eating Disorders Examination as well as for all Eating Disorders Inventory-2 subscales, except for bulimia. The comorbid group also had significantly more suicide attempts and hospitalizations compared with the noncomorbid group. There were no significant group differences for the lowest ever body mass index, duration of AN symptoms, and age at AN onset. Our findings suggest that AN with comorbid depression and anxiety disorder is a more severe clinical variant of the disorder, especially with respect to severity of psychological symptoms and suicide risk.
Keywords: eating disorders; catechol-O-methyltransferase (COMT); polymorphism; haplotype relative risk (HRR); transmission disequilibrium test (TDT)Anorexia nervosa (AN) is a common, severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance. 1 Family and twin studies indicate a significant genetic contribution 2,3 and pharmacological data suggest possible dysfunction of the serotonergic 4,5 and dopaminergic 6-9 pathways. Catechol-O-methyltransferase (COMT) is a candidate gene for mediating susceptibility to AN since it is involved in the dopamine catabolism 10 and because its functional polymorphism (Val/Met 158) determines high (H) and low (L) enzymatic activity alleles. 11 Fifty-one Israeli AN patients and their parents were genotyped with the COMT polymorphism. Using the haplotype relative risk (HRR) method it was found that the frequency of the H allele among alleles transmitted to AN patients from their parents was significantly higher than in those not transmitted (68% vs 51% 2 = 5.20, df = 1, P = 0.023, odds ratio: 2.01). Transmission disequilibrium test (TDT) revealed that out of 49 heterozygote parents the H allele was transmitted to AN patients 33 times while the L allele was transmitted only 16 (McNemar's 2 = 5.90, df = 1, P = 0.015). Our study suggests that the COMT gene is associated with genetic susceptibility to AN, and that individuals homozygous for the high activity allele (HH) have a two-fold increased risk for development of the disorder. Molecular Psychiatry (2001) 6, 243-245.Fifty-one DSM-IV anorexia nervosa female patients and both their parents were genotyped for the COMT gene (valine to methionine at codon 158) polymorphism. In the light of inherent problems facing association studies, we used the haplotype relative risk (HRR) 12 and the transmission disequilibrium test (TDT) 13 methods that are robust to artifacts caused by population stratification. The genotypes in each family were examined and analyzed so as to determine which of the parents' alleles were transmitted to the affected daughters. The non-transmitted alleles were used to construct the nontransmitted genotypes. According to the HRR method, genotypes and alleles in the patient population are compared with the non-transmitted alleles and genotypes that form the optimal ethnically matched control population. The distribution of the transmitted and non-transmitted genotypes and alleles in the fifty-one trios is presented in Table 1.Homozygotes for the high activity allele (HH) were significantly more frequent among AN patients than in the non-transmitted controls (51% vs 29%, 2 = 4.01, df = 1, P = 0.043; odds ratio: 2.50, 95% CI 1.10-5.64). When allelic distribution was compared, it was found that the high activity allele is significantly more common among patients than in the non-transmitted alleles (68% vs 51%, 2 = 5.20, df = 1, P = 0.023, odds ratio: 2.01, 95% CI 1.39-3.55). The parent population did not differ from the 172 healthy Israeli controls in terms of genotypic and...
Keywords: hSKCa3(KCNN3); polymorphism; CAG repeats; haplotype relative risk (HRR); transmission disequilibrium test (TDT); eating disorders Familial and twin studies have suggested that anorexia nervosa (AN) is a multifactorial disorder with a substantial genetic contribution. 1-5 The hSKCa3 potassium channel gene, which contains polymorphic CAG repeats in the coding region and is involved in the regulation of neuronal activity, may be a candidate gene for AN because alleles with longer repeats have been found to be associated with mental disorders. 6 Forty Israeli AN family trios were genotyped for the hSKCa3 CAG repeat polymorphism using the haplotype relative risk (HRR) method. The distribution of alleles transmitted to the patients was found to be significantly different from that of the non-transmitted parental alleles, with the longer alleles being over-represented in the patients (Wilcoxon rank test, P = 0.008). The transmission disequilibrium test (TDT) revealed that longer (Ͼ19) repeat alleles were preferentially transmitted to AN patients (McNemar's 2 = 10.31, P = 0.0013). These results were corroborated by comparing the distribution of alleles between patients and healthy controls (Mann-Whitney test, P = 0.005). Our study suggests that the longer repeat alleles of the hSKCa3 gene may contribute to the genetic susceptibility to AN. Molecular Psychiatry (2002) 7, 82-85.
Anorexia nervosa (AN) is a severe and complex psychiatric disorder with a significant genetic contribution. Previously, we found an association between AN and the 158Val/Met polymorphism of the catechol-O-methyltransferase (COMT) gene in a family-based study of 51 Israeli AN trios. In the present study, we extended the original sample to include 85 family trios [66 AN restricting (AN-R) and 19 bingeing/purging (AN-BP) subtype] and performed a family-based transmission disequilibrium test (TDT) analysis for five SNPs in the COMT and two in the adjacent ARVCF gene. Association was found between AN-R and several SNPs in the COMT-ARVCF region including the 158Val/Met polymorphism. TDT analysis of 5-SNP haplotypes in AN-R trios revealed an overall statistically significant transmission disequilibrium (P < 0.001). Specifically, haplotype B [COMT-186C-408G-472G(158Val)-ARVCF-659C(220Pro)-524T(175Val)] was preferentially transmitted (P < 0.001) from parents of AN-R patients to their affected daughters, while haplotype A [COMT-186T-408C-472A(158Met)-ARVCF-659T(220Leu)-524C(175Ala)] was preferentially (P = 0.01) not transmitted. Haplotype B was associated with increased risk (RR 3.38; 0.95CI 1.98-6.43) while haplotype A exhibited a protective effect (RR 0.40; 0.95CI 0.21-0.70) for AN-R. Preferential transmission of the risk alleles and haplotypes from the parents was mostly contributed by the fathers. No significant transmission disequilibrium of alleles or haplotypes was found for AN-BP trios. The risk and protective haplotypes may carry molecular variations in the COMT gene or its vicinity that are relevant to the pathophysiology of restrictive anorexia nervosa in the Israeli-Jewish population.
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