Univ.-Prof. Dr. Andreas Karwautz
Liste der Publikationen mit kurzen Zusammenfassungen
1) Risk and protection factors for anorexia nervosa.
Invited book chapter in: Rojo-Moreno L: Anorexia nervosa: from it’s origins to
treatment. Ariel Publishers, Barcelona, Chapter 9, 2003 (Spanish)
B Molekulargenetische Arbeiten
1) Human Molecular Genetics 2004 Jun 15;13(12):1205-12.
Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations.
Ribases M, Gratacos M, Fernandez-Aranda F, Bellodi L, Boni C, Anderluh M, Cavallini MC, Cellini E, Di Bella D, Erzegovesi S, Foulon C, Gabrovsek M, Gorwood P, Hebebrand J, Hinney A, Holliday J, Hu X, Karwautz A, Kipman A, Komel R, Nacmias B, Remschmidt H, Ricca V, Sorbi S, Wagner G, Treasure J, Collier DA, Estivill X.
Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN(ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (-270C>T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case-control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the 'Factors in Healthy Eating' project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the -270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.
2) American Journal of Medical Genetics, Neuropsychiatric Genetics 2004 Jan 1;124B(1):68-72.
Combined family trio and case-control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa.
Gabrovsek M, Brecelj-Anderluh M, Bellodi L, Cellini E, Di Bella D, Estivill X, Fernandez-Aranda F, Freeman B, Geller F, Gratacos M, Haigh R, Hebebrand J, Hinney A, Holliday J, Hu X, Karwautz A, Nacmias B, Ribases M, Remschmidt H, Komel R, Sorbi S, Tomori M, Treasure J, Wagner G, Zhao J, Collier DA.
The high activity Val158 (H) allele of the dopamine-metabolizing enzyme catechol-O-methyltransferase (COMT) was associated with anorexia nervosa (AN) in a recent family trio-based study of patients from Israel. In an attempt to replicate this finding, we performed a combined family trio and case-control study in an European population from seven centers in six different countries (Austria, Germany, Great Britain, Italy [Milan], Italy [Florence], Slovenia, and Spain), together contributing a total of 372 family trios, 684 controls and 266 cases. TDT analyses of high (H) and low (L) alleles in family trios showed that H allele and L allele were each transmitted 101 times (chi(2) = 0, ns). Allele-wise case-control analysis using separate samples simply combined from the centers was also not significant, with the frequencies of the H allele 50% in cases and same in controls. Stratified analysis of data from all centers gave an odds ratio of 0.98 (Cornfield 95% confidence limits 0.78-1.24). Analysis by genotype was likewise not significant (overall chi(2) = 0.42). Because we were not able to support the primary hypothesis that Val158Met is a risk factor for AN, we did not perform secondary analysis of minimum body mass index (mBMI), age at onset or illness subtype (restricting or binge purging anorexia). Overall we found no support for the hypothesis that the Val158 allele of COMT gene is associated with AN in our combined European sample.
3) Neuroreport. 2003 May 6;14(6):781-3.
Association of the 5-HT2c gene with susceptibility and minimum body mass index in anorexia nervosa.
Hu X, Giotakis O, Li T, Karwautz A, Treasure J, Collier DA.
The association between a non-conservative Cys23Ser in the 5-HT2c gene and anorexia nervosa in females was examined. We used case-controls and family based association analysis in a sample of 118 patients with DSMIV anorexia nervosa, 244 controls and 47 family trios. There was a significant increase in the frequency of the Ser23 allele in the patients by allele (18.8% vs 12.8%; p = 0.026; OR 1.58, 95% CI 1.0-2.4) and genotype (32.2% vs 19.9%; genotype-wise p = 0.027). There was significant correlation between genotype and minimum BMI (r2 =0.056; p = 0.01), indicating that the Ser23 allele has an effect on severity of illness. We performed TDT analysis using a sub-sample of the cases (58) for whom both parents were available and we found an excess transmission of the Ser23 allele (p = 0.05). Our findings are consistent a role for the Ser23 allele of 5-HT2c in mediating susceptibility to and increasing severity of anorexia nervosa.
4) Molecular Psychiatry 2002;7(3):276-7. (+Erratum in: Mol Psychiatry. 2002;7(7):814.)
Analysis of microsatellite markers at the UCP2/UCP3 locus on chromosome 11q13 in anorexia nervosa.
Hu X, Murphy F, Karwautz A, Li T, Freeman B, Franklin D, Giotakis O, Treasure J, Collier DA.
5) Molecular Psychiatry 2002;7(1):90-4.
The 5-HT(2A) -1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres.
Gorwood P, Ades J, Bellodi L, Cellini E, Collier DA, Di Bella D, Di Bernardo M, Estivill X, Fernandez-Aranda F, Gratacos M, Hebebrand J, Hinney A, Hu X, Karwautz A, Kipman A, Mouren-Simeoni MC, Nacmias B, Ribases M, Remschmidt H, Ricca V, Rotella CM, Sorbi S, Treasure J; EC Framework V 'Factors in Healthy Eating' consortium.
Several case-control association studies have raised the possibility that the A allele of a -1438 G/A polymorphism in the type 2A serotonin receptor (HTR2A) gene may be a risk factor for anorexia nervosa. However the absence of linkage and the existence of negative association studies raise the possibility of false positive findings, resulting from population stratification or lack of statistical power. To address this controversy we recruited a sample of 316 patients with anorexia nervosa from six European centres, and utilised a family-based transmission disequilibrium (TDT) approach to analyse the HTR2A-1438 G/A polymorphism. Age at onset and minimal BMI were also taken into consideration in order to detect clinical heterogeneity or a quantitative trait effect. The TDT approach showed that the A allele was transmitted 133 times and not transmitted 148 times (McNemar chi(2) = 0.29, df = 1, P = 0.59). Also, the haplotype-based haplotype relative risk method showed no evidence for association of the A allele, in samples from each centre (chi(2) < 2.15, df = 1, P > 0.14) and in the total sample (chi(2) = 0.55, df = 1; P = .46). Furthermore, we found no evidence for heterogeneity of the A allele frequency between samples (chi(2) = 2.54, df = 4, P = 0.64), either according to minimal-BMI (F1/242 = 2.14, P = 0.45) or age at onset (F1/224 = 2.39; P = 0.12). QTL-TDT analyses also showed no direct role of the A allele on these traits. We thus found no evidence for a significant role of the 5-HT(2A) gene in anorexia nervosa. Previous results may have been exposed to stratification bias (which we controlled by the TDT method) and/or the risk of type 1 error (from which we were less exposed because of the sample size).
B Psychosoziale Risikofaktoren
1) Psychological Medicine 2001 Feb;31(2):317-29.
Individual-specific risk factors for anorexia nervosa: a pilot study using a discordant sister-pair design.
Karwautz A, Rabe-Hesketh S, Hu X, Zhao J, Sham P, Collier DA, Treasure JL.
The aim of this pilot study was to examine which unique factors (genetic and environmental) increase the risk for developing anorexia nervosa by using a case-control design of discordant sister pairs. METHODS: Forty-five sister-pairs, one of whom had anorexia nervosa and the other did not, were recruited. Both sisters completed the Oxford Risk Factor Interview for Eating Disorders and measures for eating disorder traits, and sib-pair differences. Blood or cheek cell samples were taken for genetic analysis. Statistical power of the genetic analysis of discordant same-sex siblings was calculated using a specially written program, DISCORD. RESULTS: The sisters with anorexia nervosa differed from their healthy sisters in terms of personal vulnerability traits and exposure to high parental expectations and sexual abuse. Factors within the dieting risk domain did not differ. However, there was evidence of poor feeding in childhood. No difference in the distribution of genotypes or alleles of the DRD4, COMT, the 5HT2A and 5HT2C receptor genes was detected. These results are preliminary because our calculations indicate that there is insufficient power to detect the expected effect on risk with this sample size. CONCLUSIONS: A combination of intrinsic and extrinsic factors increases the risk of developing anorexia nervosa. It would, therefore, be informative to undertake a larger study to examine in more detail the unique genetic and environmental factors that are associated with various forms of eating disorders.
C Korrelate- Komorbidität, Persönlichkeit, Ernährung
1) Journal of Personality Disorders 2003 Feb;17(1):73-85.
Personality disorders and personality dimensions in anorexia nervosa.
Karwautz A, Troop NA, Rabe-Hesketh S, Collier DA, Treasure JL.
Information on the relationship between anorexia nervosa (AN) and personality disorders (PDs) and dimensions of temperament and character (measured by the Temperament and Character Inventory [TCI; Cloninger, Przybeck Svrakic, & Wetzel, 1994]) is limited. This study examines the predictive validity of the TCI for PD diagnoses assessed by the International Personality Disorder Examination-ICD-10 (IPDE-ICD-10; Loranger, Janca, & Sartorius, 1997) interviews of 46 women with DSM-IV-defined AN. Patients with a PD reported higher levels of harm- avoidance and lower levels of self-directedness than those without a PD. Scores on the TCI were predictive of the number of PD features present, particularly for those PDs in the anankastic, anxious, and dependent groups accounting for 40% to 51% of the variance. Cluster analysis based on scores on the TCI identified a subgroup of patients characterized by low levels of novelty seeking, self-directedness, and cooperativeness and high levels of harm avoidance. This cluster included the majority of those with avoidant, anxious, or dependent PDs. Assessment of particular personality dimensions was able to predict PDs in an anorexic sample. Since normal personality dimensions have greater validity than the categorical PDs, a consideration of normal temperament and character may assist in clinical decisionmaking and considerations concerning treatment.
2) European Eating Disorders Review Jul 2002, 10 (4) 255-270.
Pre-morbid psychiatric morbidity, comorbidity and personality in patients with anorexia nervosa compared to their healthy sisters
Karwautz A, Rabe-Hesketh S, Collier DA, Treasure JL
Anorexia nervosa (AN) has been linked with pre-morbid disorders, comorbidity, and specific personality traits in between-family case-control studies. However, these findings have not been replicated in within-family studies, and it is not known whether these factors are linked specifically with AN or are shared familial factors. We aimed to compare pre-morbid disorders, comorbidity, and specific personality traits between sister-pairs discordant for AN. Forty-five families with two sisters discordant for AN were retrospectively assessed by interview and questionnaires. The proband with AN had mood disorders and personality disorders (PDs) more frequently than their sister and had lower scores of novelty seeking, self-directedness and cooperativeness, and' higher scores of harm avoidance, persistence, self-transcendence and of all EDI-2 scales. In conclusion, major depression, cluster C PDs, persistence, harm avoidance, and self-transcendence appear to be specifically linked to AN and to be individual-specific in nature. Major depression seems to be a risk factor for AN.
1) European Child & Adolescent Psychiatry Jun 2003; 12 (3) 128-135.
Perceptions of family relationships in adolescents with anorexia nervosa and their unaffected sisters
Karwautz A, Nobis G, Haidvogl M, Wagner G, Hafferl-Gattermayer A, Wober-Bingol C, Friedrich MH
The family relationships of patients with anorexia nervosa (AN) have been extensively studied over recent years. However, using case-control designs with unrelated controls is subject to various cultural and familial biases. Studying subjective differential perceptions of family relationships in sister-pairs discordant for the disorder may overcome some of these limitations. The aim of the present study was therefore, to investigate subjective perceptions of family environments in a clinically ill sample of female adolescent patients with acute AN and in their healthy sisters using the Subjective Family Image Test. We found significantly lower perceived individual autonomy and higher perceived cohesion in patients compared with their sisters but no difference in perceived emotional connectedness. Lower perceived individual autonomy of the ill children resulted mainly from their relationships with mothers but also in part from their relationships with fathers. This observed pattern might contribute to the maintenance of the disorder and should be addressed in individual and family interventions.
2) Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie 2002 Nov;30(4):251-9.
Subjektives Familienbild bei Anorexia nervosa und Bulimia nervosa im Jugendalter: eine kontrollierte Studie. [Subjective family image in anorexia nervosa and bulimia nervosa in adolescence: a controlled study]
Karwautz A, Haidvogl M, Wagner G, Nobis G, Wober-Bingol C, Friedrich MH.
The family environments of patients with eating disorders have been studied extensively in recent decades. The "Subjective Family Image Test" is an instrument developed especially to measure differential perceptions by family members. Assessments of subjective family image in families of adolescents by means of this test have been carried out in only a few samples. METHODS: We aimed first to investigate subjective perceptions by adolescents of their family relations in a larger clinical sample of female adolescents (n = 118) suffering from anorexia nervosa of either subtype or from bulimia nervosa and to compare these perceptions with those of healthy controls (n = 96). Second we investigated intra-familial differences in perception. RESULTS: The main findings were that bulimia nervosa patients perceived lower individual autonomy and lower emotional connectedness than all other groups, the adolescents with bulimia perceived significantly lower autonomy and emotional connectedness within the family than their fathers, and the restrictive anorexia nervosa patients perceived higher connectedness than their fathers. The relevance of these findings for understanding family dynamics are discussed.