A Search for Susceptibility Loci for Anorexia Nervosa: Methods and Sample Description
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ORIGINAL ARTICLES A Search for Susceptibility Loci for Anorexia Nervosa: Methods and Sample Description Walter H. Kaye, Lisa R. Lilenfeld, Wade H. Berrettini, Michael Strober, Bernie Devlin, Kelly L. Klump, David Goldman, Cynthia M. Bulik, Katherine A. Halmi, Manfred M. Fichter, Allan Kaplan, D. Blake Woodside, Janet Treasure, Katherine H. Plotnicov, Christine Pollice, Radhika Rao, and Claire W. McConaha Background: Eating disorders have not traditionally Conclusions: The present study represents the first large- been viewed as heritable illnesses; however, recent family scale molecular genetic investigation of AN. Our success- and twin studies lend credence to the potential role of ful recruitment of over 500 subjects, consisting of affected genetic transmission. The Price Foundation funded an probands, affected relatives, and their biological parents, international, multisite study to identify genetic factors will provide the basis to investigate genetic transmission contributing to the pathogenesis of anorexia nervosa (AN) of eating disorders via a genome scan and assessment by recruiting affective relative pairs. This article is an of candidate genes. Biol Psychiatry 2000;47:794–803 overview of study methods and the clinical characteristics © 2000 Society of Biological Psychiatry of the sample. Methods: All probands met modified DSM-IV criteria for Key Words: Anorexia nervosa, bulimia nervosa, eating AN; all affected first, second, and third degree relatives disorders, genetics, linkage analysis, affected relative pairs met DSM-IV criteria for AN, bulimia nervosa (BN), or eating disorder not otherwise specified (NOS). Probands and affected relatives were assessed diagnostically with Introduction the Structured Interview for Anorexia and Bulimia. DNA was collected from probands, affected relatives and a norexia nervosa (AN) is characterized by an obses- subset of their biological parents. Asively morbid dread of body fat that drives, then Results: Assessments were obtained from 196 probands sustains, an unrelenting avoidance of normal body weight and 237 affected relatives, over 98% of whom are of (American Psychiatric Association 1994). It is widely Caucasian ancestry. Overall, there were 229 relative pairs assumed to have a complex, multifactorial etiology, yet who were informative for linkage analysis. Of the pro- psychological theories of pathogenesis have largely pre- band-relative pairs, 63% were AN-AN, 20% were AN-BN, vailed in explanatory paradigms put forward in recent and 16% were AN-NOS. For family-based association decades. Likewise, social influences have been implicated analyses, DNA has been collected from both biological in its causation in the light of mainstream cultural attitudes parents of 159 eating-disordered subjects. Few significant in industrialized countries favoring thinness as a beauty differences in demographic characteristics were found between proband and relative groups. ideal. Although a role for causal psychosocial factors is not in From The Price Foundation Collaborative Group: Eating Disorders Module, question, certain well-established observations regarding Western Psychiatric Institute & Clinic, University of Pittsburgh School of AN presentation argue persuasively for its qualitative Medicine, Pittsburgh, Pennsylvania (WHK, BD, KLK, KHP, CP, RR, CWM); Department of Psychology, Georgia State University, Atlanta (LRL); Center distinction from mere extreme dieting, and against an for Neurobiology and Behavior, Department of Psychiatry, University of etiological focus on nonbiological determinants alone in Pennsylvania School of Medicine, Philadelphia (WHB); Neuropsychiatric Institute and Hospital, School of Medicine, University of California at Los accounting for its development, progression, and morbid- Angeles, Los Angeles (MS); National Institute on Alcohol Abuse and Alco- ity. For example, weight-loss efforts in the general female holism (NIAAA), National Institutes of Health (NIH), Bethesda, Maryland (DG); Virginia Institute for Psychiatric and Behavioral Genetics, Department population are frequent, yet AN is hardly a common of Psychiatry, Virginia Commonwealth University, Richmond (CMB); New illness—its lifetime prevalence among females is esti- York Presbyterian Hospital-Westchester, Weill Medical College of Cornell University, White Plains, New York (KAH); Klinik Roseneck, Hospital for mated to be 0.1%–0.7% (Hoek 1998). Second, in the Behavioral Medicine, Munich, Germany (MMF); Department of Psychiatry, majority of acutely ill patients, dietary restriction is highly The Toronto Hospital, Toronto, Canada (AK, DBW); and the Institute of Psychiatry, Maudsley and Bethlem Royal Hospital, London, England (JT). entrenched, and resistance to initial therapeutic interven- Address reprint requests to Walter H. Kaye, M.D., Western Psychiatric Institute and tion is reflected in an unusually protracted time to achieve Clinic, 3811 O’Hara Street E-724, Pittsburgh PA 15213. Received December 14, 1998; revised May 5, 1999; revised August 16, 1999; full remission of illness (Strober et al 1997). Third, AN accepted August 30, 1999. appears to covary with other psychopathological risk © 2000 Society of Biological Psychiatry 0006-3223/00/$20.00 PII S0006-3223(99)00240-1 Genes and Anorexia Nervosa BIOL PSYCHIATRY 795 2000;47:794–803 factors, as it occurs frequently in association with Axis Methods and Materials I psychiatric disorders, mood and anxiety disorders in particular (Lilenfeld et al 1997), that have no evident Collaborative Arrangements connection to cultural attitudes relating to body weight. Under the principal direction of Walter Kaye of the University of Fourth, neurobiological abnormalities have been docu- Pittsburgh, and supported through funding provided by The Price mented that persist in a proportion of cases after normal Foundation in Geneva, Switzerland, this initiative was developed through a cooperative arrangement between The Price Foundation, body weight has been restored (Kaye and Strober 1999). the University of Pittsburgh, and other academic sites in North These aspects of AN thus underscore convincingly the America and Europe. The number and location of sites were validity of comprehensive and integrative paradigms determined by several factors. First, we needed academic collabo- designed to elucidate the nature and identity of discrete rators who were experienced in assessing eating-disordered individ- risk and vulnerability factors in its etiology and uals in order to establish consistent behavioral assessment proce- pathogenesis. dures across sites. Second, we had to find sites with records of 1000 Moreover, for eating disorders, several convergent lines to 1500 individuals who had previously been treated for AN over of evidence suggest greater familial transmission of eating the past 10 or more years, because programs typically treat less than disorders than dieting, making a search for genes confer- 100–200 AN patients per year. Thus, the only way to gather the ring susceptibility to AN warranted. First, psychometric necessary pool of subjects was to contact those people who had studies (Brewerton et al 1993; Bulik et al 1995; Kaye and previously been in treatment at several well-established eating disorders treatment centers. Third, sites needed to be geographically Strober 1999; O’Dwyer et al 1996; Sohlberg and Stober distributed such that they could advertise and collect subjects from 1994; Srinivasagam et al 1995; Strober 1980; Vitousek a region of several hundred miles or more. Six sites were identified and Manke 1994; Von Ranson et al in press) have that had well-established programs for the treatment of AN. The consistently linked the illness to a cluster of moderately clinical sites included University of Pittsburgh (WK), Cornell heritable (Heath et al 1994) personality and temperamental University (KH), University of California at Los Angeles (MS), traits, specifically obsessionality, perfectionism, neopho- University of Toronto (AK and BW), University of London (JT), bia, and harm avoidance. In this regard, it has been and University of Munich (MF). An additional site included for its speculated (Strober 1991, 1995; Vitousek and Manke expertise in molecular genetic research on psychiatric illness was at 1994) that phenotypic similarities between these traits and Thomas Jefferson University (WB). A small number of subjects the rigidly persevering, obsessional, and anxiety-reducing were recruited at the Thomas Jefferson University site as well. The core site at Pittsburgh, in collaboration with all of the character of the anorexic’s dietary restraint may be based investigators, developed a model protocol for ascertaining probands on shared genetic and environmental factors. Second, with AN who might have an affected blood relative (excluding recent controlled family studies (Gershon et al 1984; parents), conducting psychological assessments, collecting periph- Lilenfeld et al 1998; Strober et al 1990, in press) have eral blood samples for DNA, and obtaining informed consent. The found a higher lifetime prevalence of AN or subthreshold model protocol was sent to each individual site to be modified as cases of eating disorder in first-degree relatives of pro- necessary by each site’s principal investigators and Institutional bands (3%–12%) than in the first-degree relatives of Review Board (IRB). IRB approval was obtained separately by each psychiatric and normal controls (0%–3.7%), and a higher site from its own institution’s Human Subjects Committee.