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Porto, Portugal | September 20-22, 2012
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40
WTCCC3 and GCAN: A GENOMEWIDE SCAN FOR
ANOREXIA NERVOSA
Cynthia Bulik
1
, David Collier
2
, Eleftheria Zeggini
3
, Patrick
Sullivan
1
, Vesna Boraska
3
, GCAN Consortium
4
, WTCCC
5
1
University of North Carolina at Chapel Hill, Chapel Hill, NC,
USA, ,
2
Kings College London, London, United Kingdom
of Great Britain and Northern Ireland, ,
3
Wellcome Trust
Sanger Institute. Hinxton, Cambridge, United Kingdom of
Great Britain and Northern Ireland, ,
4
Genetic Consortium for
Anorexia Nervosa, Chapel Hill, USA, ,
5
Wellcome Trust Case
Control Consortium, Hinxton, Cambridge, United Kingdom of
Great Britain and Northern Ireland ,
Background: Anorexia nervosa (AN) is a debilitating and
potentially lethal mental illness (prevalence ~1% in women;
sex ratio ~9:1; heritability estimates 22-88%). The Genetic
Consortium for Anorexia Nervosa (GCAN) is a 20-country
consortium dedicated to identifying genes that influence
AN. As part of the WTCCC3, we conducted the largest
genome-wide association study (GWAS) for any eating
disorder ever performed. Methods: As part of the third wave
of the Wellcome Trust Case Control Consortium (WTCCC3),
we conducted a GWAS to identify associations between
common DNA sequence variations and AN. All cases met
DSM IV diagnostic criteria for AN (excluding amenorrhea)
and were genotyped using the Illumina 660W-Quad array.
Fifteen different centers across Europe and North America
contributed AN case samples. Controls were carefully
selected to match for ancestry of each AN site. Control
genotype data were primarily accessed from existing GWAS
that had conducted Illumina platform genotyping. Replication
efforts include in silico and de novo replication studies in ~
2430 independent AN cases and 6216 ethnically matched
controls. Results: Genotypes were obtained for 2,907
AN cases and 14,860 geographically matched controls.
Individual analyses were carried out across 15 strata. Eleven
association analyses were conducted per stratum: one with
no principal components (PC) adjustment and the others
adjusted by up to 10 PCs. On the basis of QQ plots, genomic
inflation factor lambda values and 54 ancestry informative
SNPs, we selected the most appropriate analysis per
stratum for meta-analysis. The uncorrected meta-analysis
genomic inflation factor lambda was 1.024. One SNP on chr5
exceeded genome-wide significance. Ninety-four SNPs with
p-values < 10-4 derived from the fixed effects meta-analysis.
Most of these SNPs are in the frequency and effect size
classes expected for common diseases. Replication studies
are underway. Discussion: Once replication is complete, we
will have a greater understanding of our next steps. Cross
disorder analyses with psychiatric disorders and obesity are
planned. Furthermore, functional analysis of human anorexia
genes in mice will provide novel insights in the neurobiological
mechanisms underlying this perplexing psychiatric disorder.
Update on Progress from the Price Foundation/NIMH
Collaborative studies: Targeted Re-sequencing of Candidate
Genes in an Anorexia Nervosa Cohort W. Berrettini1, A.
A. Scott-Van Zeeland2,3, C.S. Bloss2,3, P. Magistretti5,
A. Bergen6, and N. J. Schork2,3,4,W. Kaye7 , and the
Price Foundation Collaborative Group 1The University of
Pennsylvania; 2The Scripps Translational Science Institute,
3Scripps Health and 4The Scripps Research Institute, La
Jolla, CA; 5The University of Lausanne; 6SRI International;
7The University of California, San Diego, La Jolla, CA Over
the past several years this collaborative group has engaged
in a series of studies to further genotype individuals with
eating disorders collected with the support of the Price
Foundation and the NIMH. Together, this dataset contains
approximately 5000 individuals with an eating disorder
diagnosis, their family members, and matched controls.
Recent studies have included a genome-wide association
study (GWAS) analysis with relatively modest results, and a
study identifying genetic and behavioral factors contributing
to poor outcome from anorexia nervosa. We now provide
the first report of sequencing of candidate genes in anorexia
nervosa (AN), in an attempt to discover novel risk alleles
which might not be detected in GWAS experiments. Agilent
capture technology was used with DNA from 261 severely
affected AN women and 73 control women to sequence 152
candidate AN genes. Promising initial results were selected
for a replication stage, involving 500 AN AND 500 control
DNAs as well as two additional replication studies involving
386 AN cases/296 controls and 58 eating disorder cases/857
controls, respectively. The first presentation of the results of
these studies will be provided.
41
Update on Progress from the Price
Foundation/NIMH Collaborative studies:
Targeted Re-sequencing of Candidate Genes in
an Anorexia Nervosa Cohort
W. Berrettini
1
, A.A. Scott-Van Zeeland
2,3
, C.S. Bloss
2,3
, P.
Magistretti
5
, A. Bergen
6
, N. J. Schork
2,3,4
, W. Kaye
7
, the Price
Foundation Collaborative Group
1
The University of Pennsylvania, ,
2
The Scripps Translational
Science Institute, ,
3
Scripps Health and , ,
4
The Scripps
Research Institute, ,
5
The University of Lausanne, ,
6
SRI
International, ,
7
The University of California,
Over the past several years this collaborative group has
engaged in a series of studies to further genotype individuals
with eating disorders collected with the support of the Price
Foundation and the NIMH. Together, this dataset contains
approximately 5000 individuals with an eating disorder
diagnosis, their family members, and matched controls.
Recent studies have included a genome-wide association
study (GWAS) analysis with relatively modest results, and a
study identifying genetic and behavioral factors contributing
to poor outcome from anorexia nervosa. We now provide
the first report of sequencing of candidate genes in anorexia
nervosa (AN), in an attempt to discover novel risk alleles
which might not be detected in GWAS experiments. Agilent
capture technology was used with DNA from 261 severely
affected AN women and 73 control women to sequence 152
candidate AN genes. Promising initial results were selected
for a replication stage, involving 500 AN AND 500 control
DNAs as well as two additional replication studies involving
386 AN cases/296 controls and 58 eating disorder cases/857
controls, respectively. The first presentation of the results of
these studies will be provided.
42
Significant gene x hormone interactions in the
development of binge eating
Kelly Klump
1
, Pamela Keel
2
, S. Burt
1
, Michael Neale
4
, Cheryl
Sisk
1,3
, Steven Boker
5
1
Department of Psychology, Michigan State University, East
Lansing, MI, ,
2
Department of Psychology, Florida State
University, Tallahassee, FL, ,
3
Neuroscience Program,
Michigan State University, East Lansing, MI , ,
4
Departments
of Psychiatry, Human Genetics, and Psychology, Virginia
Commonwealth University, Richmond, VA, ,
5
Department of
Psychology, University of Virginia, Charlottesville, VA ,
This study used a multi-method approach (twin model fitting,
molecular genetics) to examine the influence of ovarian
hormones on genetic risk for binge eating and related
phenotypes in adult women. Results show significant gene x
hormone interactions suggesting that ovarian hormones can
enhance genetic risk depending upon the particular hormone
(e.g., estradiol, progesterone) or hormone combination
(estradiol:progesterone ratio) examined. Findings dovetail
nicely with known genomic functions of hormones within
the CNS (i.e., gene transcription factors) and animal data
suggesting that hormones have direct and causal influences
on behavioral phenotypes.
PLENARY/ORAL ABSTRACTS