Genetic Analysis of Bulimia Nervosa: Methods and Sample Description

Transcription

Genetic Analysis of Bulimia Nervosa: Methods and Sample Description
Genetic Analysis of Bulimia Nervosa: Methods
and Sample Description
Walter H. Kaye,1* Bernie Devlin,1 Nicole Barbarich,1 Cynthia M. Bulik,2
Laura Thornton,1 Silviu-Alin Bacanu,1 Manfred M. Fichter,3 Katherine A. Halmi,4
Allan S. Kaplan,5,6 Michael Strober,7 D. Blake Woodside,5 Andrew W. Bergen,8
Scott Crow,9 James Mitchell,10 Alessandro Rotondo,11 Mauro Mauri,12
Giovanni Cassano,11 Pamela Keel,13 Katherine Plotnicov,1 Christine Pollice,1
Kelly L. Klump,14 Lisa R. Lilenfeld,15 J. Kelly Ganjei,16 Norbert Quadflieg,3
and Wade H. Berrettini17
1
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina
3
Roseneck Hospital for Behavioural Medicine affiliated with the University of Munich,
Prien, Germany
4
New York Presbyterian Hospital, Weill Medical College of Cornell University,
White Plains, New York
5
Program for Eating Disorders, Toronto General Hospital, Toronto, Canada
6
Department of Psychiatry, Toronto General Hospital, Toronto, Canada
7
Department of Psychiatry and Behavioral Science, University of California at
Los Angeles, Los Angeles, California
8
Core Genotyping Facility, Advanced Technology Center, National Cancer Institute,
Gaithersburg, Maryland
9
Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota
10
Neuropsychiatric Research Institute, Fargo, North Dakota
11
Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies,
University of Pisa, Pisa, Italy
12
Institute of Psychiatry, University of Pisa, Pisa, Italy
13
Department of Psychology, Harvard University Cambridge, Boston, Massachusetts
14
Department of Psychology, Michigan State University, East Lansing, Michigan
15
Department of Psychology, Georgia State University, Atlanta, Georgia
16
Biognosis U.S., Inc., USA
17
Center of Neurobiology and Behavior, University of Pennsylvania,
Philadelphia, Pennsylvania
2
Accepted 3 September 2003
Abstract: Objective: Twin and family studies suggest that genetic variants contribute to the
pathogenesis of bulimia nervosa (BN) and anorexia nervosa (AN). The Price Foundation has
supported an international, multisite study of families with these disorders to identify these
*Correspondence to: Walter H. Kaye, M.D., Department of Psychiatry, University of Pittsburgh Medical Center,
Suite 600 Iroquois Building, 3600 Forbes Ave., Pittsburgh, PA 15213. E-mail: [email protected]
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/eat.10271
#
2004 by Wiley Periodicals, Inc.
Genetics and Bulimia Nervosa
557
genetic variations. The current study presents the clinical characteristics of this sample as
well as a description of the study methodology. Method: All probands met modified criteria
for BN or bulimia nervosa with a history of AN (BAN) as defined in the 4th ed. of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric
Association, 1994). All affected relatives met DSM-IV criteria for BN, AN, BAN, or eating
disorders not otherwise specified (EDNOS). Probands and affected relatives were assessed
diagnostically using both trained-rater and self-report assessments. DNA samples were
collected from probands, affected relatives, and available biologic parents. Results: Assessments were obtained from 163 BN probands and 165 BAN probands. Overall, there were
365 relative pairs available for linkage analysis. Of the affected relatives of BN probands, 62
were diagnosed as BN (34.8%), 49 as BAN (27.5%), 35 as AN (19.7%), and 32 as EDNOS
(18.0%). For the relatives of BAN probands, 42 were diagnosed as BN (22.5%), 67 as BAN
(35.8%), 48 as AN (25.7%), and 30 as EDNOS (16.0%). Discussion: This study represents the
largest genetic study of eating disorders to date. Clinical data indicate that although there are
a large number of individuals with BN disorders, a range of eating pathology is represented
in the sample, allowing for the examination of several different phenotypes in molecular
genetic analyses. # 2004 by Wiley Periodicals, Inc. Int J Eat Disord 35: 556–570, 2004.
Key words: bulimia nervosa; anorexia nervosa; eating disorders; genetics; linkage analysis;
affected relative pairs
INTRODUCTION
Bulimia nervosa (BN) is a disorder that most commonly occurs in women who are of
normal body weight (American Psychiatric Association [APA], 1994). BN usually has its
onset in adolescence or early adulthood and is characterized by repeated episodes of
binge eating followed by inappropriate compensatory behaviors such as self-induced
vomiting or misuse of laxatives. Individuals with BN place undue emphasis on weight
and shape and often have comorbid disturbances of mood, anxiety, alcohol and other
substance abuse, and extremes of impulse control (APA, 1994).
Developmental, social, and biologic processes influence the etiology of these disorders
(Garner, 1993; Treasure & Campbell, 1994). However, the exact nature of these interactive
processes is obscure. Cultural attitudes toward thinness are critical (Becker, Grinspoon,
Klibanski, & Herzog, 1999), but they are not sufficient to account for pathogenesis.
Dieting behavior is quite common in industrialized countries throughout the world, yet
only an estimated 1.7%–2.5% of females in the general population have disordered eating
behavior characterized as BN (APA, 1994). Instead, the introduction of Western ideals of
thinness may serve to release a biologic propensity toward eating disorders, possibly by
increasing behaviors such as dieting that may trigger the spiral of disordered eating.
Controlled family studies indicate that a vulnerability for BN is transmitted in families
(Lilenfeld et al., 1998; Stein et al., 1999; Strober, Freeman, Lampert, Diamond, & Kaye, 2000).
Because first-degree relatives share both genes and environments, family studies cannot
differentiate genetic versus environmental causes for the observed familiality. However,
with certain assumptions, studies of twins can disentangle these influences. Twin studies
generally find that approximately 54%–83% of the variance in the liability to BN (Bulik,
Sullivan, & Kendler, 1998; Kendler et al., 1991; Wade et al., 1999) and greater than 50% of
the variability in anorexia nervosa (AN; Klump, Miller, Keel, McGue, & Iacono, 2001; Wade,
Bulik, Neale, & Kendler, 2000) are attributable to the additive effects of genetic variants.
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Kaye et al.
Although the confidence intervals on these estimates are generally wide, consistent findings
across studies support moderate heritability of these disorders (Bulik et al., 1998). The eating
disorder symptoms themselves also appear to be moderately heritable. Twin studies of binge
eating, self-induced vomiting, and dietary restraint suggest that between 46% and 72% of the
variance in liability of these behaviors is due to additive genetic effects (Klump, McGue, &
Iacono, 2000; Sullivan, Bulik, & Kendler, 1998a). Likewise, pathologic attitudes, such as body
dissatisfaction, eating and weight concerns, and weight preoccupation, show heritabilities of
approximately 32%–72% (Klump et al., 2000; Rutherford, McGuffin, Katz, & Murray, 1993;
Wade, Martin, & Tiggemann, 1998; Wade, Neale, et al., 1999), with some suggestion that
weight concerns may be influenced by common environmental factors (Wade et al., 1998).
Taken together, these findings suggest a significant genetic component to AN and BN, as well
as the attitudes and behaviors that contribute to, and correlate with, clinical eating pathology.
It is important to emphasize that BN and AN are related disorders. Family studies
(Lilenfeld et al., 1998; Strober et al., 2000) show that diagnoses of AN, BN, and eating
disorders not otherwise specified (EDNOS) aggregate and are cross-transmitted in the
first-degree relatives of subjects with AN or BN. Evidence from twin studies (Kendler
et al., 1991; Weeks & Lathrop, 1995) shows that AN and BN may share genetic vulnerabilities. Moreover, approximately 50% of women with AN develop BN during the
course of their illness and approximately 30% of women with BN report a history of
AN (Bulik, Sullivan, Fear, & Pickering, 1997; Eckert, Halmi, Marchi, Grove, & Crosby,
1995; Garfinkel, Moldofsky, & Garner, 1980; Strober, Freeman, & Morrell, 1997). Finally,
subthreshold forms of eating disorders lie on a continuum of liability with frank eating
disorders (Kendler et al., 1991; Sullivan et al., 1998a). These findings suggest the existence
of a broad eating disorder phenotype with possible shared genetic predispositions.
In the mid 1990s, the Price Foundation initiated the support of a multicenter, international collaborative group to study the genetics of eating disorders. From 1996 to 1998
the collaborative group collected 198 probands with AN and 237 affected relatives (Kaye
et al., 2000) where the affected relative had AN or a broad-spectrum eating disorder. Our
collaborative group then completed (1998–2000) the collection of BN affected relative
pairs (ARP) reported in the current study. Our overarching aim has been to generate a
combined AN and BN ARP dataset to understand factors that contribute to eating
disorder risk as well as factors that distinguish subtypes.
Despite the evidence for heritability, psychiatric disorders are complex and the impact
of any single gene is likely subtle. In our genetic studies of BN and AN, we employed
several strategies to increase the likelihood of associating behavioral phenotypes with
genetic variants. For example, clear entry and exclusion criteria were established for
binging and purging and other eating disorder-related behaviors.
BN and AN could be a syndrome comprising multiple interrelated phenotypes with
somewhat varying etiologies (Reichborn-Kjennerud et al., 2003). Therefore, a major focus
of this investigation was to ensure that traits that might contribute to susceptibility to BN
or AN were assessed, so that they could be utilized to enrich genetic analyses (Devlin,
Bacanu, et al., 2002a). We targeted personality traits that are known to be prominent in
individuals with BN and AN, but not restricted in their expression to the acute phase of
the illness. Given that malnutrition can exacerbate certain traits (e.g. depression and
obsessionality), we selected traits that have been identified in family members of BN
(and AN) probands (Klump et al., 2000; Stein & Kaye, 2002), that persist after recovery
(Casper, 1990; Collings & King, 1994; Fallon, Walsh, Sadik, Saoud, & Lukasik, 1991;
Johnson-Sabine, Reiss, & Dayson, 1992; Kaye et al., 1998; Klump, Kaye, Plotnikov,
Pollice, & Rao, 1999; Norring & Sohlberg, 1993; O’Dwyer, Lucey, & Russell, 1996;
Genetics and Bulimia Nervosa
559
Srinivasagam et al., 1995; Strober, 1980; Ward, Brown, Lightman, Campbell, & Treasure,
1998), and are moderately heritable (Tellegen et al., 1988). Several traits met these criteria,
including harm avoidance, perfectionism, obsessionality, and negative emotionality (Bulik,
Sullivan, Weltzin, & Kaye, 1995; Casper, 1990; Kleifield, Sunday, Hurt, & Halmi, 1994a,
1994b; Klump, Bulik, et al., 2000; O’Dwyer et al., 1996).
We provide an overview of the design and implementation of this multisite, international
collaborative study designed to map genetic susceptibility loci involved in BN. Although
similar in conceptualization to our previous study of AN (Kaye et al., 2000), the current study
has several methodologic advancements that could enhance our ability to identify genes that
contribute to the susceptibility to BN. We will focus on a description of the clinical characteristics of the BN ARP sample as well as on new or changed methods, but we will not repeat the
description of methods included in our previous article on AN ARP (Kaye et al., 2000).
METHODS
Collaborative Arrangements
The current study was supported through funding provided by the Price Foundation
under the principal direction of Walter H. Kaye (University of Pittsburgh). Wade Berrettini
(University of Pennsylvania) provided direction for genetic methods. This initiative
was developed through a cooperative arrangement among the Price Foundation, the
University of Pittsburgh, and other academic sites in North America and Europe. The
sites of collaborative arrangement, selected on the basis of experience in the assessment
of eating disorders and geographic distribution, included the University of Pittsburgh,
Cornell University, University of California at Los Angeles, University of Toronto, Roseneck Hospital for Behavioural Medicine affiliated with the University of Munich, University of Pisa, University of North Dakota, University of Minnesota, Harvard University,
and the University of Pennsylvania. Each site obtained institutional review board
approval separately from its own institution’s human subjects committee.
Phenotypic Assessment
Inclusion criteria for probands and affected relatives were agreed upon through a
series of consensus meetings involving all participating investigators. Acceptance into
the study was not restricted by gender of the proband or affected relative and did not
require active illness at the time of assessment. In addition, current use of medication did
not affect the eligibility of probands or affected relatives.
For probands, acceptance into the study required that they had a lifetime diagnosis of BN,
purging type, as defined in the 4th ed. of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV; American Psychiatric Association, 1994). Purging had to include regular vomiting, with other means of purging optional, and binging and vomiting must have
occurred at least twice a week for a duration of at least 6 months. In addition, they were to be
13–65 years old and primarily of European descent. A current or lifetime history of AN was
acceptable (i.e., BN with a history of AN [BAN]). Potential probands were excluded if they
had a lifetime history of any of the following: mental retardation, dementia, organic brain
syndromes, psychotic disorders, Turner’s syndrome, or any medical condition that could
affect appetite, body weight, or eating (e.g., diabetes and thyroid conditions were excluded
if the onset of the disease preceded the onset of the eating disorder). Bipolar I and Bipolar II
were excluded only if symptoms of BN occurred exclusively during manic or hypomanic
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Kaye et al.
episodes. Probands with neurologic disorders, such as seizure disorder, were excluded
unless seizures developed as a result of trauma and clearly after the onset of the eating
disorder. Individuals whose premorbid weight exceeded the body mass index (BMI) for
the 95th percentile for their age and gender for a comparable epidemiologic sample
(Hebebrand, Himmelmann, Heseker, Schafer, & Remschmidt, 1996) or whose high lifetime
BMI > 35 were excluded from the study.
Affected relatives were biologically related to the proband (e.g., siblings, half siblings,
cousins, aunts, uncles, grandparents, second cousins). Inclusion criteria for affected relatives
were age between 13 and 65 years and at least one of the following lifetime eating disorder
diagnoses: (1) DSM-IV BN, purging or nonpurging type; (2) DSM-IV AN, restricting type or
binge eating/purging type (criteria were modified for this study to include individuals with
and without amennorhea); (3) EDNOS-1, defined as subclinical AN with the presence of at
least two of the three criterion symptoms of low body weight, extreme fear of fatness, or
body image disturbance (i.e., undue influence of body weight and shape on self-evaluation
or denial of the seriousness of low body weight), no lifetime history of binge eating, and a
lifetime ideal body weight (IBW) < 125% according to the Metropolitan Height and Weight
Tables (1959); (4) EDNOS-2, defined as subthreshold BN in which the frequency or duration
of eating binges and/or purging fell below the specified DSM-IV criteria (twice per week
and 3 months, respectively); and (5) EDNOS-3, defined as a clinical mix, in which individuals of normal weight purged (e.g., vomited or abused laxatives, diuretics, enemas), fasted,
or exercised excessively due to extreme fear of weight gain or undue influence of body
weight on self-esteem, but did not binge eat. Exclusion criteria for affected relatives included
all exclusion criteria listed for the probands with the following additional criteria: (1)
monozygotic twin of the proband; (2) biologic parent with an eating disorder, unless there
was another family member with whom the proband could be paired; and (3) a diagnosis of
binge eating disorder as the only lifetime eating disorder diagnosis.
Screening and Diagnostic Procedures
An initial screening was performed to determine study suitability for each potential
proband. A preliminary verification of the diagnosis of BN was undertaken and eating
disorder histories on possible affected relatives were obtained. If probands satisfied all
inclusion and no exclusion criteria and reported a possible history of an eating disorder in
a nonparent, nonchild, or a nonmonozygotic twin blood relative, the proband was asked to
discuss the study with the affected relative and obtain permission for study personnel to
contact the relative to explain the study and screen for eligibility. If, upon initial screen, both
proband and affected relative satisfied all inclusion and exclusion criteria, informed consent
was obtained and both were scheduled to complete a series of clinical interviews. In
addition, the proband and affected relative were told they would be mailed a packet of
self-report assessments to be completed before the interviews. If participants were in close
proximity to one of the multicenter sites, the interviews and blood draw were completed in
person. Subjects who were unable to travel to a site were interviewed by phone and had
their blood drawn at a local hospital or doctor’s office and sent to the site by overnight mail.
Assessment Instruments
Many of the same assessment instruments were used in both the AN and BN ARP studies
(Table 1). However, some new instruments were added to the BN ARP study as described
below.
Genetics and Bulimia Nervosa
Table 1.
561
Comparison of assessment instruments in AN and BN ARP studies
Category
Format
Assessment Instrument Name
AN ARP
BN ARP
X
Perfectionism
Self-report
Temperament
Self-report
Temperament
Self-report
Impulsivity
Axis II disorder
Self-report
Clinical
interview
Self-report
Structured Interview of Anorexia Nervosa
and Bulimic Syndromes (SIAB-EX)
Module H of Structured Clinical Interview
for DSM-IV Axis I Disorders (SCID-I)
Yale-Brown-Cornell Eating Disorder
Scale (YBC-EDS)
Eating Disorders Inventory-2 (EDI-2)
Demographic Questionnaire for Genetic
Studies
Multidimensional Perfectionism Scale
(Frost MPS)
Temperament and Character Inventory
(TCI)
Revised NEO Personality Inventory
(NEO-PI-R)
Barrett Impulsivity Scale-11 (BIS-11)
Structured Clinical Interview for DSM-IV
Personality Disorders (SCID-II)
State-Trait Anxiety Inventory, Form Y
(STAI-Y)
Yale-Brown Obsessive Compulsive Scale
(Y-BOCS)
Beck Depression Inventory (BDI)
Structured Clinical Interview for DSM-IV
Axis I Disorders (SCID-I)
Fagerstrom Test of Nicotine Dependence
(FTND)
X
ED symptom
severity
Core ED symptoms
Demographics
Clinical
interview
Clinical
interview
Clinical
interview
Self-report
Self-report
ED diagnosis
ED diagnosis
Anxiety
OCD severity
Depression
Axis I disorder
Nicotine dependence
Clinical
interview
Self-report
Clinical
interview
Self-report
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: AN ¼ anorexia nervosa; BN ¼ bulimia nervosa; ED ¼ eating disorder; OCD ¼ obsessive-compulsive disorder;
ARP ¼ affective relative pair. ‘‘X’’ indicates assessment instrument was included in the AN or BN ARP study.
Eating Disorder Phenotypes and General Clinical Information
For both studies, the lifetime diagnoses of eating disorders of probands and affected
relatives were characterized by a modified version of the Structured Interview of Anorexia
Nervosa and Bulimic Syndromes (SIAB; Fichter, Herpertz, Quadflieg, & HerpertzDahlmann, 1998). In addition, for the BN ARP study, eating disorder diagnoses were
made by an expanded version of Module H of the Structured Clinical Interview for DSMIV Axis I Disorders (SCID-I; First, Gibbon, Spitzer, & Williams, 1996), to obtain information such as age of onset, severity of illness, recovery status, and months since last eating
disorder symptoms. The Yale-Brown-Cornell Eating Disorder Scale (YBC-EDS; Sunday,
Halmi, & Einhorn, 1995) was used to assess the severity and types of core obsessions and
compulsions specific to eating disorders. Additional information obtained from probands
and affected relatives included gender, date of birth, height, and weight history. BMI
(kg/m2) was based on self-reports of height and weight. Values were calculated for the
current, minimum, and maximum BMI. Subjects responded to demographic questionnaires designed to elicit information about ethnicity, marital status, religious orientation,
family structure, occupation, and education. The Eating Disorder Inventory-2 (EDI-2;
Garner, 1990), which was included in the AN ARP study, was deleted from the BN
ARP study because we determined that similar information was adequately characterized by other assessments and we wanted to make time for the addition of other new
instruments.
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Kaye et al.
Personality and Temperament
Several self-assessment instruments were used in both the AN and BN ARP studies.
These included the Multidimensional Perfectionism Scale (MPS; Frost, Marten, Lahart,
& Rosenblate, 1990) and the Temperament and Character Inventory (TCI; Cloninger,
Svrakic, & Przybeck, 1993). The MPS assesses six specific dimensions of perfectionism,
including concern over mistakes, high personal standards, high perceived parental
expectations, high perceived parental criticism, doubts about quality of performance,
and organization, order, and precision. The TCI measures seven dimensions of personality, including novelty seeking, harm avoidance, reward dependence, persistence, selfdirectedness, cooperativeness, and self-transcendence.
In addition, several new instruments were added to the BN ARP study. The Revised
NEO Personality Inventory (NEO PI-R; Costa & McCrae, 1992), a 243-item questionnaire
based on the Five-Factor model of personality, was added to obtain a measure of
neuroticism. It measures the five major domains of personality (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness), as well as the six
facets or traits that define each domain and permit more detailed analysis. The NEO PI-R
has shown excellent internal consistency and long-term stability. To characterize impulsivity, we added the Barrett Impulsivity Scale-11 (BIS-11; Barrett, 1983). The BIS is a 30item self-report measure of impulsiveness, currently in its 11th revision. This scale
provides three measures of impulsivity: motor, cognitive, and nonplanning. No measures, of which we are aware, specifically assess extremes of impulsivity in women. Bulik,
Sullivan, Fear, and Joyce (1997) have shown that this measure successfully discriminates
the degree of impulse control in subgroups of women with eating disorders.
Considerable data suggest that specific types of personality disorders may commonly
cluster in subtypes of eating disorders, for example, obsessive-compulsive personality
disorder (OCD) in restricting-type AN (Lilenfeld et al., 1998) and Cluster B disorders in
multiimpulsive BN subjects (Rossiter, Agras, Telch, & Schneider, 1993). Therefore, the BN
ARP subjects completed the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II; First et al., 1996), a semistructured clinical interview used to diagnose the
DSM-IV personality disorders. We assessed only Cluster B and C personality disorders
because Cluster A disorders occur much less commonly in women with eating disorders.
Comorbid Psychiatric Disorders
Both clinical and epidemiologic studies indicate that women with BN and AN, and their
first-degree relatives, commonly suffer from comorbid anxiety disorders (particularly OCD)
and major depression (Lilenfeld et al., 1998). These symptoms often persist after recovery
from an eating disorder (Kaye et al., 1998; Stein & Kaye, 2002). In addition, women with BN
and their family members have increased risk for substance use disorders (Bulik, 1987; Kaye
et al., 1996). Twin studies suggest shared genetic liability between BN and major depression
(Walters & Kendler, 1995) and between BN and panic disorder (Kendler et al., 1995).
Therefore, we included a comprehensive assessment of mood disorders, anxiety disorders
(including OCD), and substance use disorders in probands and relatives to further characterize potential phenotypic and genetic heterogeneity within the sample.
Similar to the AN ARP study, subjects in the BN ARP study completed the State-Trait
Anxiety Inventory (STAI Form Y-1; Spielberger, Gorsuch, & Lushene, 1970) and the YaleBrown Obsessive Compulsive Scale (Y-BOCS; Goodman et al., 1989). The STAI is a
40-item instrument that assesses states of anxiety both ‘‘at this moment’’ and how the
individual ‘‘generally feels.’’ The Y-BOCS is a semistructured interview designed to
Genetics and Bulimia Nervosa
563
rate the presence and severity of obsessive thoughts and compulsive behaviors typically
found among individuals with OCD.
New instruments added to the BN ARP study included the Beck Depression Inventory
(BDI; Beck, Ward, Mendelson, Mock, & Erbaugh, 1961), a 21-item questionnaire that has been
widely used to assess the intensity and symptoms of depression in adolescents and adults. To
characterize lifetime major Axis I disorders, such as depression, anxiety, and substance use
disorders, subjects in the BN ARP study completed the SCID-I. The SCID-I is a semistructured
clinician-administered interview designed to generate DSM-IV Axis I diagnoses. Interrater
reliability for the SCID has been reported to be generally consistent with that of other
diagnostic instruments for Axis I disorders (First et al., 1996). The Fagerstrom Test of Nicotine
Dependence (FTND; Heatherton, Kozlowski, Frecker, & Fagerstrom, 1991) was used to obtain
quantitative and diagnostic information about nicotine dependence. The FTND uses six of the
original eight questions from the Fagerstrom Tolerance Questionnaire (FTQ; Fagerstrom &
Schneider, 1989).
Samples and Analysis
Samples of blood were collected from each proband, affected relative, and participating
biologic parent. DNA samples were extracted using Gentra Systems (Minneapolis, MN)
reagents according to the manufacturer’s specifications. Kaye et al. (2000) provided a detailed
discussion of the rationale for the current study design and planned genetic analysis. Our
initial target of 400 affected sibling pairs/ARP was based on power analyses of Hauser,
Boehnke, Guo, and Risch (1996). They showed that such a sample would yield good power
to detect variants in genes having a modest impact on liability. Even though we did not meet
this target, the power to detect genetic variants in genes having a modest impact on liability
should be adequate.
RESULTS
Assessment data were collected from 360 probands and their families. All probands were
female with a lifetime diagnosis of purging-type BN. By design, their compensatory behaviors
must have included vomiting, but additional methods of purging were acceptable. In the final
analysis, however, 8 probands did not meet modified DSM-IV criteria for purging bulimia. All
had blood samples collected and 6 had at least one affected relative. These 8 subjects were
excluded from the analyses. Of the 352 probands who met the study diagnostic criteria, 342 had
blood samples collected and 331 had an affected relative, resulting in a total of 328 probands
with blood samples collected who also had at least one affected relative in the study. These
probands had 365 affected relatives, excluding parents, participating in the study. Of the
affected relatives, 254 were full siblings to the proband and 111 had some other relationship.
There were 318 nonindependent affected sibling pairs among the families, as well as numerous
pairs of other, more complex relationships. Among the affected relatives, 15 were males with
the following diagnoses: 3 AN, 3 BAN, 4 BN, 1 EDNOS-1, 1 EDNOS-2, and 3 EDNOS-3
subjects. DNA samples were collected from the biologic parents of the proband when available. Both parents participated in 22% of families and one parent participated in 19.5%. The
majority of these families were included in the molecular analysis for the genome scan (97.6%).
The DNA samples from the other families should prove useful for other linkage/association
analyses. The remaining 2.4% were collected subsequent to the initiation of the scan.
Table 2 summarizes the eating disorder diagnoses of the proband ARP, after dividing
probands into those with BAN or without such a history (BN). When only probands with
564
Table 2.
Kaye et al.
Eating disorder diagnoses of proband ARP: affected relative diagnosis
Proband
BN
BAN
Total pairs
Total pairs (%)
BN
BAN
AN
EDNOS
Total
62 (50.7)
42 (53.3)
104
28.5
49 (56.6)
67 (59.4)
116
31.7
35 (40.5)
48 (42.5)
83
22.7
32 (30.3)
30 (31.8)
62
17.0
178
187
365
100
Note: ARP ¼ affected relative pair; BN ¼ bulimia nervosa; BAN ¼ bulimia nervosa with a history of anorexia
nervosa; AN ¼ anorexia nervosa; EDNOS ¼ eating disorder not otherwise specified. Parenthetical values are the
expected counts under the assumption of independence of diagnoses.
BN were considered, 34.8% of their relatives had a diagnosis of BN, whereas 27.5% had a
diagnosis of BAN and 19.7% had a diagnosis of AN. When only BAN probands were
considered, 22.5% of their relatives had a diagnosis of BN, whereas 35.8% had a diagnosis
of BAN and 25.7% had a diagnosis of AN. It is apparent from these percentiles and the
data in Table 2 that there is a tendency of concordance of diagnosis, with BN probands
being somewhat more likely to identify other BN relatives and BAN probands being
somewhat more likely to identify relatives with a history of AN. This trend is weakly
significant (odds ratio [OR] ¼ 2.0, df ¼ 1, 2 ¼ 8.18, p ¼ .029, number of pairs ¼ 303).
There was no significant difference in age between BN and BAN probands (Table 3).
As expected, BAN probands had significantly lower BMIs for measures of current, past
minimum, and past maximum values.
When affected relatives were stratified by eating disorder subtype, measures of BMI
differed significantly between strata (Table 4). BAN relatives were similar to AN relatives
in terms of past minimum BMI. Given the diagnostic criteria for AN, it was expected that
relatives with a history of AN would have a lower past minimum BMI, irrespective of
additional eating disorder diagnoses. With regard to current and past maximum BMI,
BAN relatives had a significantly lower BMI than BN relatives; they were significantly
higher than AN relatives for past maximum BMI. BN relatives had significantly higher
values than AN and BAN relatives on all measures of BMI.
When the AN and BN ARP datasets were combined (Table 5), there were a total of 594
relative pairs. With regard to pairs in which both had the same diagnosis, there were 86
AN-AN pairs, 67 BAN-BAN pairs, and 62 BN-BN pairs. In terms of mixed pairs, the most
common pairs were AN-BAN (n ¼ 107) followed by BAN-BN (n ¼ 91) and then AN-BN
(n ¼ 82). A total of 1,188 individuals had fairly equally distributed numbers of AN, BAN,
and BN diagnoses.
DISCUSSION
The primary aim of the current study is to identify some of the genetic variants that
influence susceptibility to BN. Our design has several strengths. First, by multisite,
Table 3.
Characteristics of probands, stratified by eating disorder
Characteristics
BN
BAN
t test results
M SD
M SD
t value (p value)
Age (years)
Current BMI
Past Minimum BMI
Past Maximum BMI
27.2 9.5
29.0 9.1
1.7 (ns)
22.4 2.8
20.0 2.6
8.5 (.0001)
19.1 1.4
15.1 2.0
21.9 (.0001)
25.3 3.1
23.1 3.0
6.8 (.0001)
Note: BN ¼ bulimia nervosa; BAN ¼ bulimia nervosa with a history of anorexia nervosa; BMI ¼ body mass index.
Genetics and Bulimia Nervosa
Table 4.
565
Characteristics of affected relatives (n ¼ 365), stratified by eating disorder
AN
(n ¼ 83)
Age
(years)
Current
BMI
Past
minimum
BMI
Past
maximum
BMI
BAN
BN
(n ¼ 116) (n ¼ 104)
p
Group
EDNOS-1 EDNOS-2 EDNOS-3
X2
(n ¼ 11)
(n ¼ 21) (n ¼ 30) (df ¼ 5) Value Differences
26.6 9.1 29.6 9.7 29.0 9.7 25.3 10.1 27.0 7.6 27.1 8.5
19.1 2.0 20.1 2.5 23.0 3.2 19.8 1.5
7.92
.1883 NS
22.6 2.5 22.1 2.8
15.2 1.6 15.5 1.8 19.6 1.9 18.3 0.9
74.40 <.0001 a,b,d<c,e
a,b,d<f<e
19.9 1.4 18.8 1.8 186.37 <.0001 a,b<d,f<c,e
21.7 2.5 22.8 2.8 25.9 3.4 21.0 2.1
26.2 2.9 23.9 3.0
81.49 <.0001 a,e<d,b<f
a<d,b<c<f
Note: BN ¼ bulimia nervosa; BAN ¼ bulimia nervosa with a history of anorexia nervosa; AN ¼ anorexia
nervosa; EDNOS ¼ eating disorder not otherwise specified; BMI ¼ body mass index. Group differences were
calculated using generalized estimating equation analyses.
multinational collaboration, we recruited a large sample of multiplex families despite the
relatively low prevalence of BN in the general population. Second, by collecting DNA
from available parents, we increased the power for linkage analysis, while also generating a substantial sample for family-based association analysis (Spielman, McGinnis, &
Ewens, 1993). Third, by the use of structured diagnostic instruments and extensive
training and reliability checks across sites, clear eating disorder diagnoses were obtained
that will enable stratification on the basis of the presence or absence of certain core
features. Fourth, by requiring that probands meet rigorous inclusion criteria, including
vomiting as the primary compensatory behavior, and by using obesity as an exclusionary
criterion, we attempted to ensure diagnostic homogeneity in the BN probands. Finally,
by assessing a wide range of psychological traits and behaviors associated with BN, our
objective was to enhance the search for genetic variants by using these traits as covariates
(Devlin, Bacanu, et al., 2002; Devlin, Jones, Bacanu, & Roeder, 2002a) or quantitative
endophenotypes in the linkage and association analyses.
Table 5.
Attributes of both the AN and BN ARP genetic studies
AN ARP Study
AR
AN
BAN
BN
EDNOS
Total
BN ARP Study
N Pairs Proband
86
59
47
37
229
AR
Individual Subjects
N Pairs N Total Pairs N AN N BAN N BN N EDNOS N Total
172
107
82
37
67
91
30
62
32
86
107
82
37
67
91
30
62
32
365
594
398
BAN
BN
AN
AN
48
35
BAN
BAN
BAN
BN
BN
BAN
BN
EDNOS
BN
EDNOS
107
82
37
134
91
30
362
91
30
124
32
32
329
99
1188
Note: ARP ¼ affected relative pair; AR ¼ affected relatives; N ¼ number of pairs or individuals; BN ¼ bulimia
nervosa; BAN ¼ bulimia nervosa with a history of anorexia nervosa; AN ¼ anorexia nervosa; EDNOS ¼ eating
disorder not otherwise specified.
566
Kaye et al.
There are also limitations to this study. Several of the questionnaires (e.g., BIS-11, FTND)
were added to the assessment battery subsequent to the initial collection of data and,
therefore, were not completed by all subjects. In addition, based on the low prevalence of
BN, we had to expand inclusion criteria for affected relatives to include AN, BN, and
EDNOS diagnoses. Inclusion of multiple diagnoses among relatives could reduce power
to detect liability genes of small effect by introducing greater etiologic heterogeneity. We
also recruited families from disparate locations, which could introduce additional genetic
heterogeneity. However, results from our previous studies suggest that heterogeneity due
to geographic separation will be small. Specifically, by evaluating the distributions of alleles
at hundreds of genetic markers, Devlin et al. (2002a) found minimal differentiation among
the seven populations sampled in our AN study (Kaye et al., 2000).
With regard to diagnostic heterogeneity of the BN ARP dataset, the majority of ARP
have a lifetime diagnosis of BN (60.2%), with a much smaller percentage having a
lifetime diagnosis of AN (22.7%) or EDNOS (17.0%). Aside from expected differences
in BMI based on diagnostic categories, there are few significant differences among eating
disorder subtypes in probands, relatives, and between probands and relatives.
Although we plan linkage and association analyses using the broad phenotype (i.e., the
entire sample), we are considering other strategies to diminish etiologic heterogeneity.
For example, when we used the broad diagnostic category for AN in a previous linkage
study (Grice et al., 2002), we did not yield evidence for even suggestive linkage (Lander
& Kruglyak, 1995) anywhere in the genome. However, by analyzing 37 families that had
at least one pair of relatives with the narrow phenotype of restricting-type AN, we found
evidence for linkage to chromosome 1p34 (Grice et al., 2002). Additional microsatellite
genotyping increased evidence for linkage, with a nonparametric linkage score ¼ 3.45
(p .00028) near marker D1S255. Additional single nucleotide polymorphisms in candidate genes enhanced the linkage signal further (Bergen et al., in press).
Although we are considering linkage analysis using only narrow phenotypes, such as
families with pairs diagnosed with BN (or BAN), we have some reservations. As is
evident in Table 2, BN-BN and BAN-BAN pairs are not common, nor does proband
status appear to be a potent discriminator of relative pair status. By contrast, when we
recruited AN probands, 63.3% of the affected relatives had a diagnosis of AN (Kaye et al.,
2000). Therefore, we continue to evaluate the data for critical subsets. For example,
because clear behavioral indicators, such as self-induced vomiting, improve the reliability of the diagnosis of BN (Wade et al., 1999) and because vomiting behavior has been
shown to be a strongly heritable component of the BN syndrome (Sullivan et al., 1998a,
1998b), an intriguing subset could be families in which multiple individuals exhibit
severe and persistent self-induced vomiting.
Another avenue to diminish etiologic heterogeneity is through the use of covariates in the
linkage analysis, an approach we used to good effect in our analysis of the AN linkage
sample (Devlin et al., 2002a). In that study, we identified two covariates that appeared to
create discernible subpopulations among the AN affected sibling pairs: drive for thinness
and obsessionality. It seemed plausible to us that affected sibling pairs who are congruently
high for these covariates could have a distinct etiologic basis compared with affected sibling
pairs without such scores. When we incorporated these covariates into the affected sibling
pair linkage analysis by using the methods of Devlin et al. (2002a,b), we found several
regions of suggestive linkage: one close to genome-wide significance on Chromosome 1 (at
202 cM, D1S1660; logarithm of the odds [LOD] ¼ 3.46, p ¼ 0.00003), another on Chromosome 2 (at 102 cM, D2S1779; LOD ¼ 2.22; p ¼ 0.00070), and a third region on Chromosome 13
(at 102 cM, GATA121A08; LOD ¼ 2.50; p ¼ 0.00035). We will explore the battery of
Genetics and Bulimia Nervosa
567
psychological traits and behaviors collected in the BN sample to determine if any show
evidence for defining noteworthy subpopulations. If we find evidence for subpopulations
defined by covariates, we will use these covariates in linkage analyses.
The AN ARP study previously reported (Kaye et al., 2000) and the current BN/BAN
ARP study used similar diagnostic criteria for all of the eating disorders. In addition,
many of the assessment instruments were used in both studies (Table 1). Finally, both
samples were genotyped using the Weber Screening Set 9. These similarities should
facilitate combining information over datasets. The total number of ARP and individual
subjects for the combined datasets is shown in Table 5. Weighing against a simple
combination of the data is the possibility of introducing even greater etiologic heterogeneity, which could overwhelm linkage signals. Therefore, although we plan to combine
the AN and BN ARP datasets in some way, most likely through the use of common,
informative covariates, the decision about exactly how they will be combined awaits
further phenotypic analysis. We are currently investigating multivariate methods to
explore the high dimensional phenotypic space to identify possible covariates.
Relatively little is known about risk factors in eating disorders and hypotheses for
disentangling complex phenotypes remain speculative. Nonetheless, some intriguing
hypotheses have been proposed, and they could be useful for frameworks for genetic analyses. For example, Westen and Harnden-Fischer (2001) proposed that three populations of
eating disorder individuals exist, which cross subtype boundaries: a high functioning,
perfectionistic group; a constricted, overcontrolled group; and an emotionally dysregulated,
undercontrolled group. Studies from our laboratory are consistent with family (Lilenfeld
et al., 1998; Strober et al., 2000) and twin data (Kendler et al., 1991; Walters & Kendler, 1995)
suggesting that AN and BN share common susceptibility factors. For example, women who
have recovered from AN and/or BN show a similar persistence and magnitude of body
image distortion, perfectionism, anxiety, harm avoidance, obsessions with symmetry and
exactness, as well as disturbances of serotonin activity (Kaye, 1997; Kaye et al., 1998).
Together, these data suggest that such clusters of traits create susceptibility to AN or BN,
with additional factors determining the exact presentation (subgroup) of the eating disorder. For example, extreme self-control, asceticism, and inflexibility in restricting-type AN
may be related to additional traits for OCD (Lilenfeld et al., 1998) and disturbances of
dopamine systems that may modulate reward (Kaye, Frank, & McConaha, 1999).
In summary, the current project is the largest genetic study of eating disorders to date.
Using the data collected in this study and our earlier study (Kaye et al., 2000), our goal is
to refine the clinical picture of eating disorders and, in doing so, provide an additional
theoretic framework for genetic analyses.
The authors thank the Price Foundation for the support of the clinical collection of subjects and
genotyping. The authors are indebted to the participating families for their contribution of time and
effort in support of this study and to Eva Gerardi for administrative support.
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