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

REVIEW

Genetic factors in anorexia nervosa

A. Kipman1,3, P. Gorwood2,3, M.C. Mouren-Simoni1,2, J. Ads2,3
1

Hospital Robert Debr, Service de psychopathologie de lenfant; 2 CNRS UMR 7593, Laboratoire personnalit 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 classication allows evaluation and comparisons in epidemiological analyses, it can articially diminish the observed etiopathogenic heterogeneity of the disease. Different clinical forms, which might have specic etiological factors, are actually collected in the same diagnosis category, which makes it more difficult to identify the etiopathological factors concerned. Distinguishing certain subgroups

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

Genetic factors in anorexia nervosa Table I. Frequency of anorexia nervosa among relatives of anorexic subjects (uncontrolled studies). Author Cantwell et al. [17] Crisp et al. [21] Garnkel et al. [36] Hudson et al. [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 % 1.45 ND 6.5 4.14 ND ND ND

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At least one affected relative % ND 29.0 ND ND 12.5 10.0 6.6

Table II. Frequency of anorexia nervosa among relatives of anorexic subjects from controlled studies. Author proband n Gershon et al. [37] Herpertz-Dahlmann [46] Logue et al. [68] Stern et al. [107] Strober et al. [109] Strober et al. [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 4.0 0.0 1.3 10.0 2.1 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 0.0 0.0 0.0 0.0 3.2 0.0

enon of induction, once dened as anorexia deux [96], or anorexia by proxy [95]. Secondly, other authors [120] have emphasized the common pathogenic role of the family such as over-protectiveness, authority, and/or passivity from the father and/or the mother. Nevertheless, several studies do not show conclusions which are in favor of specic anomalies among mothers of probands vs. control subjects [35, 42, 104], and there is only one controlled study which shows a difference among parents of anorexic patients. However, this difference was limited to parents of anorexic patients of the restrictive type, i.e., without bulimic behaviors [108]. Furthermore, 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, e.g., for cousins, uncles and aunts [46, 115]. In conclusion, the family pathology may be the result of the disorder, rather than its cause, although these conclusions would need prospective studies which are difficult to carry out because of the low prevalence of anorexia nervosa. The increased incidence of the pathology among members of affected families can also be explained by a common genetic liability. It is a fact that rst degree relatives of anorexic patients are more at risk of developing the illness than could be expected at random

(1/1,000) (tables I and II). Furthermore, it can be stated that the closer the relative, the higher the risk [116]. For controlled studies, the life-time risk of developing an eating disorder for a rst degree relative of an anorexic patient is 6% vs. 1% for the relatives of control subjects [37]. Other studies have found an increased percentage of anorexia nervosa among relatives of the anorexic patients, except for one study based on a small group which did not nd any affected relative [68]. In summary, the familial concentration of anorexia nervosa is more important for the relatives of the probands (101/718, or 14.1% for the six uncontrolled studies), when compared to what would be expected at random (about 1/1,000). The six controlled studies showed a frequency of 3% for the rst degree relatives of anorexic patients (27/900), and 0.3% for the control group (3/1,300), which is a highly signicant difference (2 = 30.3, df = 1, P < 0.0001). 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. Some authors [33] have used this statement to measure heritability on the basis of categorical traits (such as morbidity), and categorical morbidity reecting dimensional liability. We applied this method (described in appendix 1) in order to evaluate the heritability in the narrow sense for anorexia

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nervosa on the bases of published controlled family studies. The evaluated heritability is high (h2 = 0.72, SD = 0.06), and is in the same range as other published estimations of heritability for anorexia nervosa (0.54, 0.64, 0.76 and 0.80) with variable techniques [50, 69, 85, 110, 116]. Twin studies may more specically help to elucidate whether this familial concentration is explainable by genetic factors. TWIN STUDIES A familial concentration of features can depend on genetic factors as well as on a common familial environment. Many twin studies have tried to estimate the concordance for the illness depending on zygoticity, 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). According to twin studies which described single cases or small samples (55 references quoted in MEDLINEt), in can be noted (in studies representing 90 twin pairs) that the concordance rate for monozygotic twins is higher (44%, 29 concordant pairs out of 66), than that for dizygotic twins (12.5%, three pairs out of 24; 2 = 7.6; df = 1, P = 0.006; table III). Drawing a conclusion from these articles is difficult because some information remains uncertain (for example, originality of the cases described, diagnostic tests used, zygoticity establishment). Nevertheless, the results remain close to controlled studies when considering the concordance rates. For example, the academic study of Holland et al. [50] established a higher concordance rate with the illness among monozygotic twin sisters than among dizygotic twin sisters (55% vs. 7%). Other twins series published (table III) show the same trend; for the total of 95 pairs of monozygotic twins, 54 are concordant for the illness (57%), whereas from the total of 79 pairs of dizygotic twins, only two are concordant for the disease (3%; 2 = 58.3, df = 1, P < 0.0001). Twin studies are more prone than familial studies to truly evaluate the heritability for a disorder. The technique consists of comparing the correlation for a trait in monozygotic twins vs. dizygotic twins [85], an excess of concordance in monozygotic compared to dizygotic twins being in favor of a signicant role of genetic factors. The respective role of familial education, additive genetic factors, and individual environment may thus be evaluated (described in appendix 2). Once more, the observed categorical morbidity was used as

reecting dimensional liability. When published twin pairs are considered in total (table III), the heritability is evaluated at 0.71 (SD = 0.10), as 46.2% of the 106 monozygotic twins were concordant for anorexia, as compared to 7.1% of the 56 dizygotic twins. 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, the denition and the limits of the phenotype involved need to be analyzed. DEFINING THE BOUNDARIES OF THE PHENOTYPE Familial and twin studies may also help to dene the boundaries of the phenotype. In fact, when there is a major weight loss (less than 15 kg/m2), and an early onset (before 17 years old), familial concentration is more important among anorexic women, and concordance for the disease is more frequent among anorexic twins [116]. Moreover, it has been shown that it is the restrictive type of anorexia (and not anorexia with bulimic behaviors or self-induced vomiting) which increases signicantly the risk of anorexia nervosa among relatives [37]. On the other hand, subthreshold eating disorders are often found among female relatives of anorexic women [70]. Anorexia nervosa has actually been considered as a heterogeneous pathology and not a single entity by certain authors [58]. For others it consists of a constellation of symptoms of various psychopathological origins [66]. Genetic factors could thus be more specically involved in a subtype of anorexia nervosa (sometimes called endophenotype). Furthermore, factors of genetic predisposition may not be specic for this eating disorder, that is to say that other disorders could share the same risk factors. The links between anorexia nervosa, bulimia, depression, psychosis, 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], obsessivecompulsive disorder [99], or phobic disorders [100] have been identied among the relatives of anorexic patients. 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. Nevertheless, the controlled familial studies found no excess of psychosis, obsessivecompulsive disorder, or phobic disorders in larger

Genetic factors in anorexia nervosa Table III. Concordance for anorexia nervosa in monozygotic vs. dizygotic twins.
Author Concord Alsen [1] Aoyama et al. [3] Askevold and Heiberg [4] Bom [9] Brinch [12] Bruch [13] Bruch [14] Crisp [20] Dally [23] Debow [25] Dmoulin and Patris [26] Dickens [27] Dowson [29] Dhrssen [30] El Badaway et al. [31] Foster and Kupfer [34] Garnkel et al. [35] Gifford et al. [38] Gorwood et al. [39] Gupta and Sivakumar [41] Hall [43] Halmi and Brodland [44] Hoffmann and kind [49] Holland et al. [50] Holland et al. [50]* Hsu et al. [51] Kasperowicz et al. [56] Klotz et al. [61] Koluch and Davidova [62] Mele et al. [71] Meyer [72] Michaud et al. [73] Morgan and Russel [75] Mormont and Demoulin[76] Moskovitz et al. [77] Neki et al. [79] Nemeth [80] Nowlin [81] Rivinus et al. [86] Roberts and Zendel [87] Rota et al. [88] Rutherford et al.[90] Schepank [92] Schmid and Ritter [93] Schmid-Ott et al. [94] Simmons and Kessler [97] Sonada 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.[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

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* Ten of the described twins from this sample belonged to the 1984 study. ** Some twins from this study have been described in the two previous Holland studies.

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Table IV. Frequency of affective disorders among first degree relatives of anorexic patients. Author Biederman et al. [6] Cantwell et al. [17] Gershon et al. [37] Herpertz-Dahlman [46] Hudson et al. [52] Logue et al. [68] Rivinus et al. [86] Strober et al. [108] Theander [115] Winokur et al. [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 % 16.2 22.5 22.0 6.5 17.2 14.7 16.0 8.8 21.3 27.2

samples [46, 86, 108, 115]; (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 specic for a certain type of eating disorder. The frequency of bulimia among relatives of anorexic patients was found to increase however, only when the anorexic probands were of the bulimic type, as there was no excess of bulimia among the families of restrictive anorexic patients [86, 108]; (3) a third type of analysis studied the complex link between depression and anorexia nervosa. In fact the two disorders have many diagnostic criteria in common, such as loss of appetite, sadness, sleep disorders, loss of libido, and concentration difficulties [66]. Moreover, there is an important comorbidity between these two disorders, the incidence of depression in patients with anorexia nervosa ranging between 25 and 88% [66]; and, (4) antidepressive treatment seems to improve certain anorexic patients, even without comorbid affective disorder [74, 78, 123]. Additionally, the risk of depressive disorder seems to be higher in families of anorexic patients. Affective disorders are two to four times as frequent among rst degree relatives of anorexic or bulimic patients as among relatives of controls [17, 37, 52, 86, 124]. Most studies show an increased frequency of affective disorder among relatives of anorexic patients (table IV), although two studies do not [106, 115]. Nevertheless, 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. Moreover, the importance of affective disorders in family history seems to be specically true among anorexic patients suffering from eating disorders with an associated affective disorder [6, 110]. Lilenfeld et al. [67] recently evaluated the 93 rst degree relatives of 20 patients with

anorexia nervosa. 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 = 4.2) to one which is non-signicant (1.7). 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. The link between affective disorder and eating disorder could thus concern more specically bulimia and partially anorexia with a bulimic component [57]. Finally, (5) alcoholism has also been found to be more frequent among relatives of patients suffering from bulimia (11.9%), and not from anorexia nervosa (4.8%) [116]. Pyle et al. estimated that there is 50% alcoholism among rst degree relatives of bulimic patients [83]. Stern showed a greater frequency of substance abuse amongst the relatives of bulimic patients in comparison to control subjects [106]. Strober also conrmed the existence of a more specic 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. Also, the frequency of alcoholism among relatives of anorexic patients, whatever the subtype, is not always high (9%) [17]. Rivinus et al. [86] shows that there is not signicantly more substance abuse among siblings of anorexic patients (12.6%) in comparison to siblings of control subjects (14.6%), results which were conrmed by Stern et al. [107]. In conclusion, the majority of studies which have found a greater frequency of bulimia, alcoholism, and depression among relatives of patients with an eating disorder, showed this excess through probands affected with anorexia with comorbid bulimia, or anorexia nervosa of the bulimic type. Among the relatives of restric-

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tive subtype anorexic women, there may be specically more anorexic subjects. Nevertheless, there are only a few studies which have compared systematically familial antecedents (of anorexia, affective disorder, or dependence) and clinical specicities of anorexia nervosa (with or without a bulimic component, with comorbid affective or addictive disorders). Twin studies are also able to pinpoint phenotypic boundaries. The case of an unconcordant monozygotic twin pair has been described [40] and may highlight what is inherited in anorexia nervosa. The unaffected twin sister developed neither amenorrhoea nor anorexia, but she had a clear body image disturbance, was convinced of being too fat, and underwent frequent dieting periods. She explained that having been a witness of her sisters illness had made her aware of a certain weight under which her body weight should not pass in order _to avoid developing anorexia nervosa, like my sister. These monozygotic twin sisters, unconcordant for the diagnosis of anorexia nervosa, showed the importance of variable penetrance (all subjects predisposed to genetic factors will not systematically develop the illness). The expression of the illness emerging only if a stress (such as a severe diet) occurs, monozygotic sisters who share common genetic factors may thus not develop the same disorder, although they have the same genetic risk. Monozygotic twins concordant for the illness also provide essential information [50] concerning the phenotypic spectrum. 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 (21.5 vs. 23.4 kg), a more important weight loss (15.2 vs. 13.6 kg), rarer bulimic symptoms (1 vs. 5 for the EDI), and an earlier age at onset (17 vs. 19 years old). These criteria are the same as those in familial concentration studies in relation to severity and precocity. CONCLUSIONS Although anorexia nervosa is a complex disorder with various vulnerability factors, genetic factors are signicantly involved in the individual risk for this disorder. Different familial and twin studies have shown that 0.5 to 0.8 of the explicative variance was due to additive genetic factors. In this review, we have shown that all published controlled familial studies give an estimation of the heritability at 0.72, and that all published twin studies give an estimation of the heritability at 0.71.

Familial and environmental factors thus appear to play a minor role in this disorder, although there is a clear lack of prospective and adoption studies allowing denite conclusions. Familial and twin studies also underline the potential heterogeneity of anorexia nervosa, which is reected by the use of the DSM-IV for two types of anorexia nervosa, i.e., the purely restricting type vs. the purging/vomiting type. The literature shows that the high familial concentration of affective disorders, dependencies and bulimia may be explained by the selection of probands with anorexia nervosa of the purging/vomiting type. No evidence emerges for an excess of any psychiatric disorder in the families of anorexia nervosa of the restrictive type, although data are still inconclusive for affective disorders. Furthermore, no coaggregation studies (searching for the excess of co-transmission of two disorders within families) have been undertaken. APPENDIX Appendix 1 Calculation of h2 on the basis of familial aggregation studies. xP xR

Y=

1 xP xR 1
2 2

xP a

a + xR a xP
2

Var Y = p b 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, the normal deviate xR = deviation of threshold of probands from population mean, the normal deviate a = mean deviation of probands from population mean Appendix 2 Calculation of h2 on the basis of twin studies. Vg = 2 Ymz Ydz Vf = 2 Ydz Ymz Vg = 1 Ymz Vg = total genetic variance Vf = familial variance

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