Genetic basis of bad behaviour in adolescents

THE LANCET

Genetic basis of bad behaviour in adolescents

A 120 **

Skin perfusion (AU)

Forearm

100

Dorsum

80

Peter McGuffin, Anita Thapar *

Pulp

*

60

** *

40 20 0

B

Skin oxygen saturation (%)

70 *

†

60

†

50 40 30 20 10 0 0

0·5

1·0

1·5

SNAG (%) Changes in skin (A) perfusion (arbitrary units) and (B) oxygenation in six healthy subjects during transdermal application of SNAG Significant changes in perfusion over baseline were seen at the forearm (p<0·01, ANOVA) and dorsum of the finger (p<0·005, ANOVA). Oxygenation changed significantly at the forearm only (p<0·001, ANOVA). Values are means (SE). *p<0·01, **p<0·02, †p<0·05 (post hoc paired t-test).

whether SNAG decomposes on the surface of the skin, and NO travels through the skin, or if SNAG is itself absorbed. Transdermal delivery of NO may prove to be beneficial in treating microvascular disorders, such as Raynaud’s phenomenon, where vasospasm occurs. We have demonstrated diminished NO-mediated vasodilatation in patients with Raynaud’s phenomenon,5 so SNAG may be a useful treatment. This work was supported by grants from the Arthritis and Rheumatism Council and Tenovus Tayside. 1 2

3

4

5

Coffman JD. Effects of endothelium-derived nitric oxide on skin and digital flow in humans. Am J Physiol 1994; 267: 2087–90. Noon JP, Haynes WG, Webb DJ, Shore AC. Local inhibition of nitric oxide generation in man reduces blood flow in finger pulp but not in hand dorsum skin. J Physiol 1996; 490: 501–08. Bauer JA, Fung HL. Differential hemodynamic effects and tolerance properties of nitroglycerine and S-nitrosothiol in experimental heart failure. J Pharmacol Exp Ther 1991; 256: 249–54. Butler AR, Field RA, Greig IR, et al. An examination of some derivatives of S-nitroso-l-thiosugars as vasodilators. Nitric Oxide Biol Chem (in press). Khan F, Litchfield SJ, McLaren M, Veale DJ, Littleford RC, Belch JJF. Oral l-arginine supplementation and cutaneous vascular responses in patients with primary Raynaud’s phenomenon. Arthrit Rheum 1997; 40: 352–57.

University Department of Medicine (F Khan), and Vascular Laboratory, Department of Medical Physics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK; and School of Chemistry, University of St Andrews, Fife

Vol 350 • August 9, 1997

Disorders of conduct are the commonest reasons for referral to child psychiatry services.1 Although children with a conduct disorder do not necessarily grow up to be antisocial adults, a history of early onset delinquent behaviour persisting through adolescence is a necessary prerequisite for developing antisocial personality disorder. 2 There is no clear demarcation between conduct disorder and bad behaviour among children or adolescents who never come to psychiatric attention. Most research on conduct disorder has focused on social causation with a particular emphasis on intrafamilial factors1 and there have been few studies aimed at discovering whether conduct disorder has a genetic component. Previously, using the Cardiff Twin Register, we found that there were substantial correlations for parental reports of antisocial activities such as stealing, destruction of property, disobedience, telling lies, and bullying in samesex twins aged 8–16 years,3 all explained by shared environment with social class accounting for a small proportion of the variance. Genetic research on human behaviour shows that genetic effects change during development. For example, cognitive ability shows a progressively increasing heritable component throughout life.4 We examined antisocial behaviour in adolescent twins in greater detail using a self-report questionnaire. 5 The sample was ascertained from the Cardiff Births Survey.3 Self-reported measures of antisocial behaviour 5 were obtained on 43 monozygotic (MZ) and 38 same-sex dizygotic (DZ) pairs. The data were analysed with a structural equation-modelling approach 3 to estimate the proportion of variance accounted for by additive genetic, shared environmental, and non-shared environmental factors. Analyses were based on a composite score of common antisocial behaviours arbitrarily defined as those items endorsed by 15% or more of those studied (table). The scores (x) were positively skewed and were transformed to approximate normality by taking f(x)=Ln(1+x). Intraclass correlation co-efficients were 0·814 for MZ and 0·293 for DZ twins. A model with additive genetic factors fixed at 0 gave an estimate of shared environmental factors of 0·81 but with a poor fit and a likelihood ratio ␹2 compared with the general model of 40·32 (1 df, p<0·0001). An additive genetic model with shared environmental factors fixed at 0 gave an estimate of additive genetic factors of 0·814 and a likelihood ratio ␹2 of 0·999 (1 df, not significant). A model allowing for dominance variance, which we estimated as 0·452 with an additive genetic factor of 0·362, did not improve the likelihood ratio ␹2 (0·99, 1 df, not significant). On grounds Item

Frequency (%)

Arrived late for school Yelled at parent Skipped classes Got drunk Kept after school by teacher Been sent to head teacher Skipped school Yelled at teacher Written graffiti Got into fights One or more of the above

41 32 24 24 21 19 18 17 17 15 70

Frequently endorsed antisocial items on Behaviour and Activities Questionnaire5

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THE LANCET

of parsimony and goodness of fit the additive genetic model is the most acceptable. These findings suggest that common bad behaviours of the sort admitted to by the majority of adolescents have a substantially heritable component. Additive genetic effects account for most of the variation with no evidence of a contribution from shared environment. This contrasts with our findings using a briefer parent-rated measure and looking at conduct disorder across a wider age range of children3 where shared environment alone accounted for familial effects. However, the finding of higher heritability in adolescents is in keeping with the tendency for other behavioural traits to show increasing genetic effects over time4 and the absence of a shared environmental effect is in keeping with almost all quantitative genetic studies of adult personality traits. The limitations of our study are that it is based upon self report rather than observed behaviour and had an incomplete response rate of 60%. Nevertheless our findings suggest that bad behaviour in adolescents is probably heritable. This study was supported by an MRC Fellowship (AT). 1

2 3 4 5

Earls F. Oppositional-defiant and cohort disorders. In: Rutter M, Taylor E, Hersov L, eds. Child psychiatry: modern approaches, 3rd edn. Oxford: Blackwell Science, 1994: 308–29. Robins LN. Deviant children grow up. Baltimore: Williams and Wilkins, 1966. Thapar A, McGuffin P. A twin study of antisocial and neurotic symptoms in childhood. Psych Med 1996; 26: 1111–18. Plomin R, Owen MJ, McGuffin P. The genetic basis of complex human behaviours. Science 1994; 264: 1733–39. Olweus D. Prevalence and incidence in the study of antisocial behaviour: definitions and measurements. In: Klein MW, ed. Cross national research in self-reporting crime and delinquency. Kluwer: Academic Publishing, 1989: 187–201.

Division of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK (P McGuffin); and Department of Psychiatry, Royal Manchester Children’s Hospital, Pendlebury, Manchester, UK

Association between 5-HT2A gene promoter polymorphism and anorexia nervosa David A Collier, Maria J Arranz, Tao Li, Dennis Mupita, Nigel Brown, Janet Treasure

In addition to an established role for sociocultural factors, twin studies provide evidence that anorexia nervosa may be heritable,1 although this view is balanced by a population study that indicates familial aggregation but not high heritability.2 Factors related to a desire for weight loss and body dissatisfaction in normal subjects have heritabilities of about 40–50%.3 The most likely model of inheritance involves gene-environment interaction, in which the influence of sociocultural factors leads to the development of the disease in genetically susceptible individuals. Unlike many of the pathophysiological abnormalities of anorexia nervosa which are state (eg, starvation) related phenomena, there are indications that serotonergic dysfunction may be trait-related. Serotonin has an integral role in appetite control, sexual, and social behaviour, and stress responses and these all form part of the clinical picture of anorexia nervosa. Furthermore some animal models of anorexia involve serotonergic mechanisms.4 Many serotonin-related behaviours show sexual dimorphism, which might provide some explanation of why 96% of those affected by anorexia are women and why the onset is peripubertal. A possible

412

Genotype-wise

Allele-wise

⫺1438A/A ⫺1438A/G ⫺1438G/G ⫺1438/A Anorexia nervosa (n=81) All controls (n=226) Female controls (n=88)

⫺1438/G

25 (0·31)

33 (0·41)

23 (0·28)

83 (0·51)

79 (0·49)

75 (0·15)

117 (0·52)

34 (0·33)

184 (0·41)

266 (0·59)

11 (0·125)

51 (0·58)

26 (0·295)

73 (0·42)

103 (0·58)

All genotype frequencies were in Hardy-Weinberg equilibrium.

Frequencies of ⫺1567G/A in polymorphism in 5-HT2A gene promoter region in anorexia nervosa

mechanism for this is the finding that the 5-HT2A receptor gene is regulated by oestrogen.5 In order to test the hypothesis that the 5-HT2A gene is involved in the aetiology of anorexia, venous blood was obtained from a series of 81 affected white female patients from the Eating Disorder Unit at the Bethlem Royal and Maudsley Hospital and 226 normal white controls (138 males and 88 females). Anorexia nervosa was defined according to ICD10 criteria. All subjects gave written informed consent, and DNA was prepared from venous blood by standard protocols. We analysed a polymorphism (⫺1438G/A) in the promoter region of the 5-HT2A gene with the following primers: 5'-AAGCTGCAAGGTAGCAACAGC-3' and 5'-AACCAACTTATTTCCTACCAC-3'. The 468 basepair (bp) product was digested with MspI (which cuts the ⫺1438 allele into two fragments of 244 and 224 bp) and the alleles separated in a 2% agarose gel. The frequency of the ⫺1438/A allele was increased in anorexia compared with the controls (␹2=5·18; p=0·022) as was the ⫺1438/A genotype frequency (␹2=7·31; p=0·026) (table). The odds ratio for the ⫺1567/A allele was 1·52 (95% CI 1·04–2·21). These results indicate that the 5-HT2A gene may be a susceptibility factor for anorexia nervosa. However they should be regarded as preliminary until replicated, because of the potential for false-positive findings in case-control studies due to population stratification. These results may be important in understanding the pathophysiology of anorexia. The rise in oestrogen at puberty in the context of stress might destabilise the serotonin-hypothalamic pituitary-adrenal body composition systems and lead to a catabolic response in those with a genetic vulnerability. Since oestrogen levels fall in anorexia nervosa, any trait-related abnormalities in the serotonin system may be exacerbated, leading to a chronic course. This suggests the importance of greater emphasis on the serotonergic system in treatment, and there is preliminary evidence that selective serotonin reuptake inhibitors are effective. As anorexia is one of the most severe psychiatric diseases with a high mortality and morbidity and a poor response to standard treatment, such developments are to be welcomed.

1 2

3

4 5

Holland AJ, Treasure J. Anorexia nervosa: evidence for a genetic base. J Psychosom Res 1988; 32: 561–71. Walters EE, Kendler AS. Anorexia nervosa and anorexic-like syndromes in a population-based female twin sample. Am J Psychiatr 1995; 152: 64–71. Rutherford J, McGuffin P, Katz RJ, Murray RMM. Genetic influences on eating attitudes in a normal female twin population. Psychol Med 1993; 23: 425–36. Treasure J, Owen JB. Intriguing links between animal behaviour and anorexia nervosa. Int J Eat Disord 1997; 21: 307–11. Fink G, Sumner BEH. Oestrogen and mental state. Nature 1996; 383: 306.

Section of Molecular Genetics, Department of Psychological Medicine, Institute of Psychiatry, London SE5 8AF, UK (D A Collier); and Eating Disorders Unit, Institute of Psychiatry, London

Vol 350 • August 9, 1997