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The Genetics of Anorexia Nervosa TK Clarke1, ARD Weiss1 and WH Berrettini1 Anorexia nervosa (AN) is a disease defined by inappropriate weight loss and maintenance of body weight 85% of that which is expected for height (corresponding to body mass index (BMI)), intense fear of gaining weight, a disturbance in the perception of body weight/shape, and the presence of amenorrhea for a minimum of three consecutive months (Table 1). Two subtypes of AN are recognized by the DSM-IV: (i) the restricting type, in which individuals limit food intake; and (ii) the binge/ purge subtype, in which a person engages in binge eating followed by subsequent purging behavior (self-induced vomiting/ laxative abuse). The criterion of amenorrhea for three or more months is of questionable utility in making the diagnosis, as many women have difficulty recalling such events, especially when the time frame is years ago. The prevalence of AN in the general population is estimated to be 0.3%1; however, there are nine females affected for every male. Indeed, rates of AN diagnoses are highest among females aged 15–19 years, and the incidence rates within this demographic have been estimated as high as 20 per 100,000 (females aged 12–25 years).2 AN is a chronic, relapsing disease, and the risk of premature death among patients with AN has been shown to be threefold greater than that for the rest of the population.3 Environmental factors are known to increase the risk for AN; these include female gender, dieting, childhood sexual abuse, early childhood eating and digestive problems,4 and the
presence of psychiatric disorders such as obsessive-compulsive disorder and anxiety.5 Societal influences were typically believed to influence AN risk, and the disease was often considered an affliction of modern Western societies. Epidemiological studies have proven this not to be the case, as AN has been documented across many cultures,6 and the disorder itself was described in the nineteenth century.7 The genetic epidemiology of AN demonstrates strong evidence for familial aggregation8; the rate of AN in first-degree relatives of AN probands is six times higher than in relatives of non-AN controls.9 However, population-based twin studies10,11 do not indicate strong evidence for heritability. For example, Walters et al.11 found 35 AN cases among 2,163 female twins, with 2 concordant dizygotic twin pairs but no concordant monozygotic twin pairs. Similarly, Bulik et al.10 studied 12,400 twin pairs, finding 51 AN cases: 1 concordant monozygotic case and 1 concordant dizygotic case. These findings parallel the genetic epidemiology of Parkinson’s disease, where family studies have revealed strong evidence for aggregation (for review see ref. 12), but twin studies have consistently failed to identify strong evidence for high heritability.13,14 Substantial Parkinson’s disease heritability was observed only when cases were defined by onset prior to age 50.14 Despite the limited evidence for heritability from twin studies, the genetic study of Parkinson’s disease has been enormously successful in the past two decades, both in identifying genes for uncommon Mendelian forms as well as alleles that increase risk for more common variants. Despite the limited twin evidence
1Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. Correspondence: TK Clarke (
[email protected])
Received 2 August 2011; accepted 13 September 2011; advance online publication 21 December 2011. doi:10.1038/clpt.2011.253 Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 2 | february 2012
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for heritability, similar success in human AN research can be expected, especially given the recent technical advances in sequencing and genotyping. The purpose of this article is to discuss the various methodologies used to identify the genetic factors that increase the risk for AN and how these approaches can inform researchers of the underlying biological mechanisms that influence AN pathology. The biological systems that control appetite, food intake, and energy regulation are discussed with a focus on hypothalamic neuropeptides. Human genetic studies of AN are reviewed, including candidate gene studies, genome-wide association studies, and the potential for epigenetic approaches. Animal Table 1 Diagnostic and Statistical Manual of Mental Disorders, fourth edition, diagnostic criteria for anorexia nervosa Criterion
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