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Eur Psychiatry 1999 ; 14 : 189-98 © Elsevier, Paris

REVIEW

Genetic factors in anorexia nervosa
A. Kipman1,3, P. Gorwood2,3, M.C. Mouren-Siméoni1,2, J. Adès2,3
1

Hospital Robert Debré, Service de psychopathologie de l’enfant; 2 CNRS UMR 7593, Laboratoire ‘personnalité et conduites adaptatives’, Paris; 3 Hospital Louis Mourier, Service de psychiatrie adulte, 178, rue des Renouillers, 92701 Colombes, France (Received 28 January 1999; final version 15 March 1999; accepted 3 May 1999)

Summary – Anorexia nervosa is a severe and complex disorder with incompletely known vulnerability factors. It is generally recognized that anorexia nervosa is a familial disorder, but the majority of twin studies have shown that the concordance rate for monozygotic twins is higher (on average 44%) than for dizygotic twins (on average 12.5%). This difference in concordance rates shows that genetic factors, more than common familial environment, may explain why the ‘anorexia nervosa’ phenotype runs in families. In order to estimate the heritability in the broad sense of anorexia nervosa according to published familial and twin studies, we first assessed the intrapair correlation between monozygotic and dizygotic twins, and secondly calculated the deviation threshold of relatives of affected probands from the relative mean. In this review, we obtained an estimation of the heritability at 0.72 according to all published controlled familial studies (six references quoted in MEDLINET), and 0.71 for all published twin studies (59 references quoted in MEDLINET). This estimation is close to the ones previously proposed, between 0.5 and 0.8. Familial and twin studies may also help to define the boundaries of the phenotype, shedding light on the complex relationship between anorexia nervosa on the one hand, and bulimia nervosa, mood disorders, and alcoholism on the other. Demonstrating the importance of genetic factors in anorexia nervosa, and more specifically for anorexia of the restrictive type, requires not only prospective and adoption studies (which are still lacking), but also genetic polymorphisms analyses, which began very recently. © 1999 Elsevier, Paris anorexia nervosa / bulimia / familial studies / genetics / heritability / twin studies

INTRODUCTION Anorexia nervosa is a severe illness, with mortality rates ranging from 10 to 15%. The prevalence of this disorder in ‘developed’ countries is about 1/1,000, most cases being female, with only 5 to 15% men among affected patients [48, 55, 114, 115]. Although there have been important advances in the understanding of anorexia nervosa as a complex and multifactorial disorder, the precise mechanisms determining its vulnerability remain elusive. Epidemiological research on anorexia nervosa is fairly rare, mainly because a consensus on diagnosis has only recently been made, with the manual of diagnostic

criteria DSM [2] for example. The DSM-IV anorexia nervosa diagnosis needs to establish a refusal to maintain body weight above a minimal normal weight, with intense fear of becoming fat because of the disturbance in attitude to body shape, associated with amenorrhoea in post-menarchal women of at least three consecutive months duration. Although this classification allows evaluation and comparisons in epidemiological analyses, it can artificially diminish the observed etiopathogenic heterogeneity of the disease. Different clinical forms, which might have specific etiological factors, are actually collected in the same diagnosis category, which makes it more difficult to identify the etiopathological factors concerned. Distinguishing certain subgroups

47]. The use of genetics in research into anorexia nervosa is nevertheless dependent on the existence of three facts. These first molecular genetic studies also revealed the importance of defining the phenotype. and this was rapidly followed by other association studies with heterogeneous results. the estimation of the percentage of variance explained by additive genetic factors. or more recently. and some positive [32. and the other positive association showed similarities between anorexia nervosa and obsessivecompulsive disorder [32]. which should conclude in the presence of a significant and consistent role of genetic factors. 119]. for example into ‘restricting’ vs. and biologic bases. self-induced vomiting or the misuse of laxatives or diuretics). The role of the serotonin receptors [8. The role of genetics in anorexia has only been lately emphasized in the history of anorexia nervosa. and have focused on metabolic. Kipman et al. The positive association study showed a significant association in a specific sub-sample. For example. More criteria have therefore been proposed for subtyping anorexia nervosa. 102]. it is anorexia nervosa per se (excluding comorbidity with addictive or mood disorders for example) that increases the risk for anorexia nervosa in relatives. 22. psychoanalytic. For example. [18]. i. These different aspects are evaluated one by one. or with a biological dysregulation of appetite [10]. familial aggregation should be observed. a neuroendocrinological pathology [24. dopamine. familial occurrence of anorexia nervosa could be explained by the ‘contagion of delusional ideas’ and the phenom- . Finally. the consequence of idealized thin body image in accordance with some cultures [28]. 89. 19. Secondly. More recently. for example.. after considering how genetic factors were historically suggested as potentially involved in the risk for anorexia nervosa. an increase in familial concentration and an excess of concordance in twins should be observed. monozygotic twins would be more concordant for the disorder than dizygotic twins. 63. i. familial coaggregation should be mainly explained by genetics factors.. If monoamines. 11. psychodynamic. 15.. 65. Firstly. This familial aggregation could nevertheless have two epigenetic explanations (in which non-genetic factors are mainly involved). the result of environmental stress and familial conflicts [60]. FAMILIAL CONCENTRATION It is generally recognized that anorexia nervosa is a familial disorder. Although the core symptoms of the illness have re- mained relatively stable since the initial medical descriptions of Reynolds in 1669 and Morton in 1689. HISTORICAL ASPECTS OF THE GENETICS OF ANOREXIA NERVOSA Analyzing the role of genetic factors in complex disorders requires a valid definition of the phenotype with homogenous and specific etiopathogenic factors. cholecystokinin [84. 82. Both familial and twin studies permit an estimation of heritability.e. 59. satiety. and endorphins has thus been analyzed [40]. and weight regulation.e. based on the presence or absence of binge-eating and/or purging (i.. Firstly. for some authors. but it may also reflect genetic variability (trait) which increases the risk to develop the disorder. ‘bingeeating/purging’ types. and historical descriptions of anorexia have frequently emphasized this fact [91].e. research has focused on the key role of monoamines which are involved in appetite. some negative [16.e. 118. This statement may be problematic in anorexia nervosa as various theoretical concepts have been proposed.. The variability of monoamines in affected individuals may be explained by the presence of anorexia nervosa (state dependent). 98]. could however help to understand further the physiopathology of anorexia nervosa. have a role in the risk for anorexia nervosa. genes coding for these proteins (or related enzymes and transporters) may be considered as candidate genes. 45. If genes are partially but significantly involved in the risk for anorexia nervosa. genetic factors. The definitions of anorexia nervosa have changed according to periods in time and authors. 103].190 A. the risk for anorexia nervosa should be specifically transmitted to relatives.e. very different ways of considering the disorder were found historically [7]. the association between a polymorphism in the 5HT2A gene promoter (–1438 G/A) and anorexia nervosa has been shown by Collier et al. anorexia nervosa has been viewed as a psychoneurosis disorder [64]. Progress since the 1970s has made possible the use of genetics in analyzing vulnerability factors potentially involved in anorexia nervosa. namely anorexia nervosa of the restrictive type [102]. i. i. the frequency of anorexia nervosa in relatives of probands should be significantly above that observed in relatives of controls. Several familial studies have reported a higher risk for anorexia nervosa in female relatives of probands with anorexia nervosa than in female relatives of control subjects.

several studies do not show conclusions which are in favor of specific anomalies among mothers of probands vs. It is a fact that first degree relatives of anorexic patients are more at risk of developing the illness than could be expected at random (1/1. the familial concentration of anorexia nervosa is more important for the relatives of the probands (101/718. authority. or ‘anorexia by proxy’ [95]. We applied this method (described in appendix 1) in order to evaluate the ‘heritability in the narrow sense’ for anorexia .45 ND 6. although these conclusions would need prospective studies which are difficult to carry out because of the low prevalence of anorexia nervosa. the hypothesis of the pathogenic role of family environment cannot explain why familial concentration remains higher among relatives who do not belong to the same educational milieu... control subjects [35. Author Cantwell et al. 42. without bulimic behaviors [108].14 ND ND ND 191 At least one affected relative % ND 29. once defined as ‘anorexia à deux’ [96].0001). Nevertheless. For controlled studies. [17] Crisp et al. for cousins. Secondly. Author proband n Gershon et al. uncles and aunts [46. other authors [120] have emphasized the common pathogenic role of the family such as over-protectiveness.5 10.0 3.0 0. this difference was limited to parents of anorexic patients of the restrictive type. when compared to what would be expected at random (about 1/1.0 2. and categorical morbidity reflecting dimensional liability. rather than its cause.0 0.2 0.000) (tables I and II).e. Other studies have found an increased percentage of anorexia nervosa among relatives of the anorexic patients.0 4. [111] 24 42 17 34 60 97 Relatives of affected proband affected relatives n % 2/99 3/69 0/132 2/153 6/60 16/387 2.0 ND ND 12. or 14.0 0. The six controlled studies showed a frequency of 3% for the first degree relatives of anorexic patients (27/900).3% for the control group (3/1. [52] Jensen [54] Morgan and Russel [75] Theander [115] Probands n 26 102 141 34 8 41 94 Affected relatives n 1/69 ND 28/437 7/169 ND ND 7/106 % 1. except for one study based on a small group which did not find any affected relative [68]. and/or passivity from the father and/or the mother. and 0. which is a highly significant difference (χ2 = 30. Furthermore. [36] Hudson et al. Variation of a trait in relatives of affected probands compared to the evaluation of the same trait in relatives of controlled probands indirectly depends on genetic liability for this trait.0 enon of induction. and there is only one controlled study which shows a difference among parents of anorexic patients.3. df = 1. 1% for the relatives of control subjects [37].Genetic factors in anorexia nervosa Table I. e. [109] Strober et al. Frequency of anorexia nervosa among relatives of anorexic subjects (uncontrolled studies).5 4. it can be stated that the closer the relative.0 1. [68] Stern et al. [21] Garfinkel et al. the higher the risk [116]. the life-time risk of developing an eating disorder for a first degree relative of an anorexic patient is 6% vs.1% for the six uncontrolled studies).300). i. Furthermore. 115]. In summary. [107] Strober et al.1 Relatives of controlled proband proband affected relatives n n % 43 37 13 34 95 107 0/265 0/61 0/107 0/140 3/95 0/738 0. the family pathology may be the result of the disorder. In conclusion. P < 0. The increased incidence of the pathology among members of affected families can also be explained by a common genetic liability. Some authors [33] have used this statement to measure heritability on the basis of categorical traits (such as morbidity).6 Table II.g. [37] Herpertz-Dahlmann [46] Logue et al. Frequency of anorexia nervosa among relatives of anorexic subjects from controlled studies. 104].0 6.0 0.000). However.3 10.

06). 110. Furthermore. for the total of 95 pairs of monozygotic twins. whereas from the total of 79 pairs of dizygotic twins. Nevertheless. P < 0.64.80) with variable techniques [50. and an early onset (before 17 years old). Many twin studies have tried to estimate the concordance for the illness depending on zygoticity. or phobic disorders in larger . For example. factors of genetic predisposition may not be specific for this eating disorder. table III).1% of the 56 dizygotic twins. dizygotic twins [85]. On the other hand. and individual environment may thus be evaluated (described in appendix 2). Twin studies are more prone than familial studies to truly evaluate the heritability for a disorder. bulimia. it has been shown that it is the restrictive type of anorexia (and not anorexia with bulimic behaviors or self-induced vomiting) which increases significantly the risk of anorexia nervosa among relatives [37]. 7%). and is in the same range as other published estimations of heritability for anorexia nervosa (0. In fact. Twin studies may more specifically help to elucidate whether this familial concentration is explainable by genetic factors. Moreover. Once more. depression. χ2 = 58. df = 1. The evaluated heritability is high (h2 = 0. Other twins series published (table III) show the same trend. These publications are based on a limited number of families and seem to be more relevant for bulimic patients than for anorexic patients of the restrictive type. and concordance for the disease is more frequent among anorexic twins [116]. 116]. diagnostic tests used. [50] established a higher concordance rate with the illness among monozygotic twin sisters than among dizygotic twin sisters (55% vs. the definition and the limits of the phenotype involved need to be analyzed. nervosa on the bases of published controlled family studies. as 46.192 A. TWIN STUDIES A familial concentration of features can depend on genetic factors as well as on a common familial environment. 69. Drawing a conclusion from these articles is difficult because some information remains uncertain (for example. 0. three pairs out of 24. The respective role of familial education. zygoticity establishment). additive genetic factors. obsessivecompulsive disorder. obsessivecompulsive disorder [99]. 54 are concordant for the illness (57%). df = 1. only two are concordant for the disease (3%. 85. that is to say that other disorders could share the same risk factors.3. subthreshold eating disorders are often found among female relatives of anorexic women [70]. the academic study of Holland et al. According to twin studies which described single cases or small samples (55 references quoted in MEDLINEt). Genetic factors could thus be more specifically involved in a subtype of anorexia nervosa (sometimes called ‘endophenotype’). familial concentration is more important among anorexic women. SD = 0.0001).54. When published twin pairs are considered in total (table III).10). and alcoholism have been studied by many authors because of the high frequency of psychiatric disorders among relatives of anorexic patients: (1) a higher concentration of psychosis [53]. the results remain close to controlled studies when considering the concordance rates. This high heritability in the narrow sense is very close to that derived from the familial concentration studies. Regarding the convergent results on the importance of genetic factors in the risk for anorexia nervosa.6.006. the controlled familial studies found no excess of psychosis. DEFINING THE BOUNDARIES OF THE PHENOTYPE Familial and twin studies may also help to define the boundaries of the phenotype. χ2 = 7.71 (SD = 0. originality of the cases described. Anorexia nervosa has actually been considered as a heterogeneous pathology and not a single entity by certain authors [58]. Nevertheless.72. psychosis. 0.2% of the 106 monozygotic twins were concordant for anorexia.5%. as compared to 7. considering that monozygotic twins (being genetically identical) should show a greater concordance for the illness than dizygotic twins (having only 50% of their genome in common). the heritability is evaluated at 0. or phobic disorders [100] have been identified among the relatives of anorexic patients. 29 concordant pairs out of 66). an excess of concordance in monozygotic compared to dizygotic twins being in favor of a significant role of genetic factors. than that for dizygotic twins (12. The links between anorexia nervosa.76 and 0. Kipman et al. For others it consists of a constellation of symptoms of various psychopathological origins [66]. The technique consists of comparing the correlation for a trait in monozygotic twins vs. P = 0. when there is a major weight loss (less than 15 kg/m2). the observed categorical morbidity was used as reflecting dimensional liability. in can be noted (in studies representing 90 twin pairs) that the concordance rate for monozygotic twins is higher (44%.

[73] Morgan and Russel [75] Mormont and Demoulin[76] Moskovitz et al. [50] Holland et al. [35] Gifford et al.[90] Schepank [92] Schmid and Ritter [93] Schmid-Ott et al. dizygotic twins. . [88] Rutherford et al. [61] Koluch and Davidova [62] Mele et al. [39] Gupta and Sivakumar [41] Hall [43] Halmi and Brodland [44] Hoffmann and kind [49] Holland et al. [38] Gorwood et al. [86] Roberts and Zendel [87] Rota et al. [56] Klotz et al.[125] Ziolko [126] 1 0 0 1 0 0 1 0 0 1 0 0 1 1 0 1 0 0 0 1 0 1 0 9 14 0 1 0 0 0 1 1 1 0 1 1 0 1 2 0 1 0 6 1 2 1 0 1 2 0 1 25 0 0 1 0 0 1 Monozygotic twins Discord 0 1 2 0 0 2 0 1 2 0 2 0 0 0 1 0 0 1 1 0 0 1 1 17 25 1 0 1 1 0 0 0 0 1 0 0 0 0 0 0 0 2 8 0 0 0 1 0 5 1 0 38 1 5 0 1 1 0 Concord 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 1 0 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Dizygotic twins Discord 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 9 0 0 0 1 0 0 17 20 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 5 0 0 0 0 0 0 0 0 30 1 6 0 0 0 0 female ND female female female female female female female female female female male female female female ND female female female mixed female female mixed female female female female female ND female female ND female ND female ND female female mixed female female ND male female female ND female mixed ND female female female female female male ND ND Gender 193 * Ten of the described twins from this sample belonged to the 1984 study. [94] Simmons and Kessler [97] Sonada et al. ** Some twins from this study have been described in the two previous Holland studies. [3] Askevold and Heiberg [4] Bom [9] Brinch [12] Bruch [13] Bruch [14] Crisp [20] Dally [23] Debow [25] Démoulin and Patris [26] Dickens [27] Dowson [29] Dührssen [30] El Badaway et al. [79] Nemeth [80] Nowlin [81] Rivinus et al. [101] Steinberg [105] Suematsu [112] Suzuki [113] Theander [115] Treasure and Holland [116]** Vandereycken and Pierbot [117] Waters et al. [120] Werman and Katz [121] Wiener [122] Yamaoka et al. [51] Kasperowicz et al. [77] Neki et al. [50]* Hsu et al. [71] Meyer [72] Michaud et al. [31] Foster and Kupfer [34] Garfinkel et al. Author Concord Alsen [1] Aoyama et al. Concordance for anorexia nervosa in monozygotic vs.Genetic factors in anorexia nervosa Table III.

as there was no excess of bulimia among the families of restrictive anorexic patients [86. 37. 108]. 52.194 A.0 6. Kipman et al. even without comorbid affective disorder [74. such as loss of appetite. although two studies do not [106. [86] Strober et al. [107]. the risk of depressive disorder seems to be higher in families of anorexic patients. results which were confirmed by Stern et al. Also. Table IV. loss of libido. the frequency of anorexia nervosa has never been shown to be higher among relatives of patients suffering from eating disorders than in relatives of controls. 115].8%) [116]. Strober and Katz [110] has shown that affective disorders could be linked to families of anorexic with bulimic behaviors and not to families of anorexic patients of the restrictive type. (2) a second set of studies analyzed the frequency of another eating disorder (bulimia) based on the hypothesis that the vulnerability factors involved are not specific for a certain type of eating disorder. [52] Logue et al. In fact the two disorders have many diagnostic criteria in common. The authors showed that taking into account the status of the proband (with or without comorbid mood disorder) decreases the initial risk ratio of depression of the relatives (RR = 4. [68] Rivinus et al. and depression among relatives of patients with an eating disorder. the majority of studies which have found a greater frequency of bulimia.2 samples [46. Among the relatives of restric- .2) to one which is non-significant (1.2 22. 86. and not from anorexia nervosa (4. Finally. [17] Gershon et al. (3) a third type of analysis studied the complex link between depression and anorexia nervosa.8 21. and concentration difficulties [66]. Author Biederman et al.3 27. [124] Proband n 38 26 24 45 34 17 40 70 96 25 Frequency amongst relatives n 16/99 ND ND 9/138 29/169 ND 17/106 10/112 20/94 ND % 16. The frequency of bulimia among relatives of anorexic patients was found to increase however. Frequency of affective disorders among first degree relatives of anorexic patients. 124]. The link between affective disorder and eating disorder could thus concern more specifically bulimia and partially anorexia with a bulimic component [57]. estimated that there is 50% alcoholism among first degree relatives of bulimic patients [83]. 115]. showed this excess through probands affected with anorexia with comorbid bulimia. only when the anorexic probands were of the bulimic type. Nevertheless. or anorexia nervosa of the bulimic type.5 17. 110]. Pyle et al. (5) alcoholism has also been found to be more frequent among relatives of patients suffering from bulimia (11. [6] Cantwell et al.7 16. Stern showed a greater frequency of substance abuse amongst the relatives of bulimic patients in comparison to control subjects [106]. Lilenfeld et al. sadness. whatever the subtype. is not always high (9%) [17]. In conclusion.7). [67] recently evaluated the 93 first degree relatives of 20 patients with anorexia nervosa. Rivinus et al. [108] Theander [115] Winokur et al. the incidence of depression in patients with anorexia nervosa ranging between 25 and 88% [66]. 108.5 22. and. there is an important comorbidity between these two disorders. [37] Herpertz-Dahlman [46] Hudson et al.6%). Moreover.2 14. 78.9%). (4) antidepressive treatment seems to improve certain anorexic patients. Strober also confirmed the existence of a more specific link between familial alcoholism and bulimia [108]: the frequency of alcoholism amongst relatives of anorexic patients presenting also a bulimic behavior is greater than that of restrictive type anorexic patients. alcoholism. 86.6%) in comparison to siblings of control subjects (14. Moreover. 123]. Most studies show an increased frequency of affective disorder among relatives of anorexic patients (table IV).0 8. the frequency of alcoholism among relatives of anorexic patients. Affective disorders are two to four times as frequent among first degree relatives of anorexic or bulimic patients as among relatives of controls [17. [86] shows that there is not significantly more substance abuse among siblings of anorexic patients (12. the importance of affective disorders in family history seems to be specifically true among anorexic patients suffering from eating disorders with an associated affective disorder [6. Additionally. sleep disorders.

and that all published twin studies give an estimation of the heritability at 0. 13. Monozygotic twins concordant for the illness also provide essential information [50] concerning the phenotypic spectrum. there are only a few studies which have compared systematically familial antecedents (of anorexia.2 vs.71. with comorbid affective or addictive disorders). The proband of twins both affected (concordant) shows a difference with the proband of twins where only one sister is anorexic (discordant) by a lower initial weight (21. although there is a clear lack of prospective and adoption studies allowing definite conclusions. Twin studies are also able to pinpoint phenotypic boundaries. the normal deviate xR = deviation of threshold of probands from population mean. Vg = 2͑ Ymz − Ydz ͒ Vf = 2 Ydz − Ymz Vg = 1 − Ymz Vg = total genetic variance Vf = familial variance . The case of an ‘unconcordant’ monozygotic twin pair has been described [40] and may highlight what is inherited in anorexia nervosa. the normal deviate a = mean deviation of probands from population mean Appendix 2 Calculation of h2 on the basis of twin studies. although data are still inconclusive for affective disorders. In this review. there may be specifically more anorexic subjects.Genetic factors in anorexia nervosa 195 tive subtype anorexic women. APPENDIX Appendix 1 Calculation of h2 on the basis of familial aggregation studies.72. was convinced of being too fat.. These criteria are the same as those in familial concentration studies in relation to severity and precocity. which is reflected by the use of the DSM-IV for two types of anorexia nervosa.8 of the explicative variance was due to additive genetic factors. CONCLUSIONS Although anorexia nervosa is a complex disorder with various vulnerability factors. rarer bulimic symptoms (1 vs.4 kg). The expression of the illness emerging only if a stress (such as a severe diet) occurs. 19 years old). The ‘unaffected’ twin sister developed neither amenorrhoea nor anorexia. Different familial and twin studies have shown that 0. i.5 vs.e. and an earlier age at onset (17 vs. The literature shows that the high familial concentration of affective disorders.5 to 0. monozygotic sisters who share common genetic factors may thus not develop the same disorder. These monozygotic twin sisters. No evidence emerges for an excess of any psychiatric disorder in the families of anorexia nervosa of the restrictive type.6 kg). 5 for the EDI). unconcordant for the diagnosis of anorexia nervosa. She explained that having been a witness of her sister’s illness had made her aware of a certain weight under which her body weight should not pass in order _to avoid developing anorexia nervosa. the purely restricting type vs. a more important weight loss (15. Familial and environmental factors thus appear to play a minor role in this disorder. 23. showed the importance of variable penetrance (all subjects predisposed to genetic factors will not systematically develop the illness). no coaggregation studies (searching for the excess of co-transmission of two disorders within families) have been undertaken. the purging/vomiting type. or dependence) and clinical specificities of anorexia nervosa (with or without a bulimic component. Furthermore. dependencies and bulimia may be explained by the selection of probands with anorexia nervosa of the purging/vomiting type. affective disorder. and underwent frequent dieting periods. Familial and twin studies also underline the potential heterogeneity of anorexia nervosa. we have shown that all published controlled familial studies give an estimation of the heritability at 0. genetic factors are significantly involved in the individual risk for this disorder. xP − xR Y= ͱͫ ͓ 1 − ͑ xP − xR ͒ 1 − 2 2 ͩ ͭ ͮ ͪͬ xP a a + xR͑ a − xP ͒ 2 Var ͑ Y ͒ = p − b͑ a ' − x ͒ a ͔ 2 c Wc + p a ͑ ͒ 2 c Wr Y = correlation between relatives in liability xR = deviation of threshold of relatives of probands from relative mean. Nevertheless. but she had a clear body image disturbance. although they have the same genetic risk. like my sister″.

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