Embed Size (px)
Citation preview
Cynthia M. Bulik, PhD
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, USA
WHAT THE CLINICIAN NEEDS TO KNOW ABOUT NATURE AND NURTURE IN EATING DISORDERS
OVERVIEW
• Obligatory DSM-‐5 update
• The fundamental quesHon
• DisHlling geneHc studies for clinicians,
families, and paHents
• Cycle of Risk
• Myths and misconcepHons
OBLIGATORY DSM-‐5 REVIEW
ANOREXIA NERVOSA 307.1A. RestricHon of energy intake relaHve to requirements leading to a significantly
low body weight in the context of age, sex, developmental trajectory, and physical health. Significantly low weight is defined as a weight that is less than minimally normal, or, for children and adolescents, less than that minimally expected.
B. Intense fear of gaining weight or becoming fat, or persistent behavior that interferes with weight gain, even though at a significantly low weight.
C. Disturbance in the way in which one's body weight or shape is experienced, undue influence of body weight or shape on self-‐evaluaHon, or persistent lack of recogniHon of the seriousness of the current low body weight.
Specify current type:
Restric@ng Type: during the last three months, the person has not engaged in recurrent episodes of binge eaHng or purging behavior (i.e., self-‐induced vomiHng or the misuse of laxaHves, diureHcs, or enemas)
Binge-‐Ea@ng/Purging Type: during the last three months, the person has engaged in recurrent episodes of binge eaHng or purging behavior (i.e., self-‐induced vomiHng or the misuse of laxaHves, diureHcs, or enemas)
N.B. Amenorrhea is GONE!!!
BULIMIA NERVOSA 307.51A. Recurrent episodes of binge eaCng. An episode of binge eaCng is characterized by
both of the following:
(1) EaCng, in a discrete period of Cme (for example, within any 2-‐hour period), an amount of food that is definitely larger than most people would eat during a similar period of Cme and under similar circumstances.
(2) A sense of lack of control over eaCng during the episode (for example, a feeling that one cannot stop eaCng or control what or how much one is eaCng).
B. Recurrent inappropriate compensatory behavior in order to prevent weight gain, such as self-‐induced vomiCng; misuse of laxaCves, diureCcs, or other medicaCons, fasCng; or excessive exercise.
C. The binge eaCng and inappropriate compensatory behaviors both occur, on average, at least once a week for 3 months.
D. Self-‐evaluaCon is unduly influenced by body shape and weight.
E. The disturbance does not occur exclusively during episodes of anorexia nervosa.
BINGE EATING DISORDER FINDS A HOME
A. Recurrent episodes of binge eaCng. SAME AS BULIMIA NERVOSA
B. The binge-‐eaCng episodes are associated with three (or more) of the following:
1. eaCng much more rapidly than normal
2. eaCng unCl feeling uncomfortably full
3. eaCng large amounts of food when not feeling physically hungry
4. eaCng alone because of feeling embarrassed by how much one is eaCng
5. feeling disgusted with oneself, depressed, or very guilty a[erwards
C. Marked distress regarding binge eaCng is present.
D. The binge eaCng occurs, on average, at least once a week for three months.
E. The binge eaCng is not associated with the recurrent use of inappropriate compensatory behavior (for example, purging) and does not occur exclusively during the course of bulimia nervosa or anorexia nervosa.
• Generated lifeCme prevalence esCmates for BN and BED in the Swedish Twin Registry across eight binge eaCng frequencies • From 1 to at least 8 Cmes per month
• Cox proporConal hazard models • To assess risk of BN to the co-‐twin for each of the eight frequency criteria
• We expect to see a threshold at which risk to co-‐twin for BN is maximized across the various frequency criteria
WILL FREQUENCY CRITERION OPEN THE FLOODGATES?
• LifeCme prevalence of binge eaCng 5.8%
• Relaxing the frequency criterion from at least 8 per month to at least 4 Cmes per month increased populaCon prevalence by:
•0.3% for BN •0.1% for BED
RESULTS
RELATIVE RISK ESTIMATES IN CO-‐TWIN FOR BN AT VARIOUS BE FREQUENCIES
Binging FrequencyPer Month
RR esHmates (95% CI)
≥ 1 Hme
≥ 2 Hmes
≥ 3 Hmes
≥ 4 Hmes
≥ 5 Hmes
≥ 6 Hmes
≥ 7 Hmes
≥ 8 Hmes
10.3 (4.4, 24.0)
9.4 (3.9, 22.3)
9.0 (3.6, 22.6)
10.1 (3.8, 27.0)
15.7 (5.7, 43.1)
17.7 (6.4, 48.9)
15.6 (5.3, 45.9)
13.5 (4.3, 41.9)
THE NEW EDNOS
• Atypical Anorexia Nervosa
All AN criteria but weight is within or above the normal range.
• Subthreshold Bulimia Nervosa (low frequency or limited dura@on)
• Subthreshold BED (low frequency or limited dura@on)
• Purging Disorder
• Night Ea@ng Syndrome
Recurrent episodes of night eaCng, as manifested by eaCng a[er awakening from sleep or excessive food consumpCon a[er the evening meal. There is awareness and recall of the eaCng.
• Other Feeding or Ea@ng Condi@on Not Elsewhere Classified
This is a residual category for clinically significant problems meeCng the definiCon of a Feeding or EaCng Disorder but not saCsfying the criteria for any other Disorder or CondiCon.
BEFORE AND AFTER
ANBN
AN BN BED
EDNOS
EDNOS
EDNOS+ PDEDNOS+ PD
+NE +++
V
IV
WHY HAS THE PURELY SOCIOCUTURAL MODEL OF EATING DISORDERS PERSISTED FOR SO LONG?
THE TYRANNY OF FACE VALIDITY
• Blaming the mother/family • Blaming society
The Fundamental QuesHon
ANOREXIA NERVOSA: UBIQUITOUS EXPOSURE; RARE OUTCOME
• 100 12 year old girls
• All go on a diet
• Most hate it
• One finds peace and relief from her anxious dysphoria
• She develops anorexia nervosa
BULIMIA NERVOSA: IMPULSE DYSCONTROL; UNCOMMON OUTCOME
• 100 12 year old girls• One is an “early adapter”
• Smokes, drinks, diets, early sexual encounters
• She noHces her tendency to gain weight
• AppeHte “breaks through” diet
• Impulsive/inhibited
• A wallflower who dances on the tables
• She develops bulimia
BINGE EATING DISORDER: EARLY MANIFESTATIONS; COMMON OUTCOME
• 100 12 year old girls
• Two already have loss of control eaCng
• > 100 percenCle % in weight
• Early puberty
• They develop binge eaCng disorder
GeneCc Factors
NATURE
EATING DISORDERS GENETICS: THE HISTORYFAMILY STUDIESEa#ng disorders run in families Rela#ve risk 10-‐20 (AN)Rela#ve risk >2 BED ?? Nature OR Nurture ??
TWIN STUDIESEa#ng disorders are heritableAN and BN 40-‐80% BED 40-‐60% ?? Which genes and how ??
LINKAGE STUDIESChromosome 1 ANChromosome 10 BN Approach lost favor
CANDIDATE GENE STUDIESA priori knowledge requiredParade of underpowered Nonreplicated studiesNO UNIQUE RELIABLE FINDINGS
GWASOne complete one underwayMore later
Gene expressionEpigeneHc studies
WHAT IS GENOMEWIDE ASSOCIATION (GWAS)?
Single-‐Gene Associa@on
• Cases versus Controls
• 1 or a few genes
• Prior knowledge/ guesswork essen@al
• Samples in the hundreds
GWAS
• Cases versus Controls
• ~1,000,000 gene@c markers
• No prior knowledge; no guesswork
• Samples in the thousands and tens of thousands
Bulik, Collier, Zeggini, Sullivan, GCAN ConsorHum
Members
GENETIC CONSORTIUM FOR ANOREXIA NERVOSA / WTCCC3
Samples idenHfiedAN = 4015+
GCAN AIMS
To find unequivocal evidence of associaHons between DNA sequence variaHons and AN.
Primary GWAS Conduct GWAS genotyping on female AN cases on the Illumina 660W-‐Quad array and ancestrally matched controls.
Meta-‐analyses
Within-‐disorder meta-‐analysis with independent GWAS;
Cross-‐disorder with the Psychiatric GWAS ConsorHum (including bipolar disorder, ADHD, auHsm, and major depressive disorder); Cross-‐disorder with obesity.
CASES CONTROLS
DSM IV AN, BN with history of AN, EDNOS-‐AN-‐type
Structured interview or ques#onnaires based on DSM IV
Illumina 660W-‐Quad array
Female
European ancestry
Biobanked/consented
Standard approach
Popula#on based samples same countries as cases
Genotyped on similar genera#on Illumina pla[orm
Not screened for AN (low prevalence, small loss of power, conserva#ve bias)
Careful evalua#on to show similar ancestry
GCAN/WTCCC3 SAMPLES
• Individual analyses across 15 strata
• Uncorrected lambda 1.024
• One SNP on chr5 exceeded genome-‐wide significance
• 94 SNPs with p-‐value < 10-‐4
• Frequency and effect size classes expected for common diseases
GCAN/WTCCC3 MANHATTAN PLOT
GCAN TODAY?
• ReplicaHon underway with 3000 independent samples and controls using Sequenom
• Pursuing GWAS meta-‐analysis with independent AN GWAS
• CNV analysis
• Pre-‐planned secondary analyses
• Meta-‐analyses with other psychiatric phenotypes and obesity
DSM UNLIKELY TO CARVE NATURE AT ITS JOINTS
• Depression• AuHsm
• ADHD
• Schizophrenia
• Bipolar disorder• Obsessive-‐compulsive
disorder
• Obesity
GENES WILL BE THE KEY TO UNLOCKING THE ENVIRONMENT• GCAN results within the year• Simple models of gene x environment interac@on have not replicated
• With replicated gene@c risk factors in our pockets we will be able to tackle the environment in a biologically-‐informed way
• Combining animal and human research is key
Cycle of Risk
Mother with ANLabor & Delivery Complica@ons, Prematurity, SGA
PMID: 15852310
Cycle of Risk
Maternal ANLabor & Delivery Complica#ons
Small for Gesta#onal Age
AN Cycle UndernutriHon
Inadequate weight gain
AN Cycle RestricHve feeding
Maternal dietary restraint
Maternal BEDLabor & Delivery Complica#ons
Large for Gesta#onal Age
BED Cycle Greater gestaHonal weight gainNutriHonal dysregulaHon Binge eaHng
BED Cycle Food as RewardMaternal binge eaHng
PREGNANCY EXPOSURE
CHILDHOOD EXPOSURE
Maternal ANLabor & Delivery Complica#ons
Small for Gesta#onal Age
AN Cycle UndernutriHon
Inadequate weight gain
AN Cycle SelecHve feedingParenHng stress
Maternal dietary restraint
Maternal BED
BED Cycle Greater gestaHonal weight gainNutriHonal dysregulaHon Binge eaHng
BED Cycle Food as RewardRestricHve feedingMaternal binge eaHng
PREGNANCY EXPOSURE
CHILDHOOD EXPOSURE
Labor & Delivery Complica#ons Large for Gesta#onal Age
THE ENVIRONMENT (NURTURE)
• Environment can exert both posi@ve and nega@ve influences
ENVIRONMENT (NEGATIVE)
• Environment can INCREASE RISK• Sports with appearance focus
• Sports with weight focus
• Die@ng
• Modeling
• Obsessed with looks
• Teasing
ENVIRONMENT (POSITIVE)
Environment can DECREASE RISK• Model healthy ea@ng
• Separa@ng body-‐esteem from self-‐esteem
• Role models for body respect
• Family involvement
• Suppor@ve peers who value who you are not how you look
• But you CAN’T control everything!!
TALKING WITH FAMILIES AND PATIENTS ABOUT NATURE AND NURTURE
GENE X ENVIRONMENT INTERACTION
Environment PhenotypeGenotype
aabb
AABB
PerfecHonism Harm avoidance AppeHte RegulaHon
Obesity risk AcHvity Level Obsessionality
Binge-‐eaHng Anxiety
Self-‐esteem
ConsHtuHonal thinness
Die@ng
Teasing
Ease of vomiHng
PLAYING WITH A STACKED DECK
Risk Genes Risk Environments
Protective EnvironmentsProtective Genes
X
MISPERCEPTIONS
• Gene@c determinism • Just because you have high risk genes doesn’t
mean you will get the disorder
• Environment doesn’t maler Environment does ma:er and it may ma:er more if you are at increased gene<c risk
• Biological disorders require pharmacologic treatments • E<ology/treatment fallacy
• A new form of parent blaming• You can’t be held responsible for the genes you
pass on
• Mothers who have a history of ea@ng disorders worry
• Safer to steer towards protec@ve environments
• Dangers of saying “no”
• Carefully interview and monitor coaches and peers
QuesHon:Should I let my daughter do gymnasCcs?
QuesHon: How can we help parents with eaHng disorders?
• Support during pregnancy and post-‐partum
• Adequate nourishment during pregnancy
• Help with breasoeeding
• Help with feeding their children
• What’s normal???
• How to discuss their history with their children
QuesHon: Are there geneHc tests for eaHng disorders?
• No!
• Gene@c tests probably at least 20 years in the future
• Even if available, would just be probabili@es not definites
• Once available, could help iden@fy individuals at greatest risk and lead to ra@onal preven@on and interven@on
CONVEYING ACCURATE INFORMATION
• Empower parents and pa@ents with accurate informa@on
• Learn from other fields (breast cancer, depression) to use biology to improve care and understanding
• New approaches to exploring gene-‐environment interplay
• Use biology to underscore seriousness of ea@ng disorders and to influence policy!
Maternal AN Offspring of AN
WHAT CAN WE DO NOW?
Offspring of BED
Perinatal screening
Dietary counseling during
pregnancy
ParenHng IntervenHons
Early DetecHon
Early IntervenHon
Couple
Interve
nHons
Psycho
therap
y
during
pregna
ncy
Maternal BED
Build t
he
Eviden
ce
Base
• WTCCC3 (Collier, Bulik, Sullivan Zeggini, GCAN ConsorHum)
• MoBa R01HD047186 (Bulik: PI)• MoBa (grant no N01-‐ES-‐85433), NIH/NINDS
(grant no.1 UO1 NS 047537-‐01), and and the Norwegian Research Council/FUGE (grant no. 151918/S10).
• Dr. Zerwas (K12-‐HD01441) • Dr. Reba-‐Harrelson NRSA (F31MH083312)• Dr. Perrin (K23-‐HD051817)• Mothers, fathers, and children who have
parHcipated and conHnue to parHcipate in MoBa
• Colleagues at UNC, Norwegian InsHtute of Public Health, Karolinska, and in 17 member countries of GCAN
ACKNOWLEDGEMENTS
