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The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.

ABSTRACT: BACKGROUND:Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research. METHODS:ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H. RESULTS:Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable. CONCLUSIONS:Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.govNCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.

SUBMITTER: Thornton LM

PROVIDER: S-EPMC6338222 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.

Thornton Laura M LM Munn-Chernoff Melissa A MA Baker Jessica H JH Juréus Anders A Parker Richard R Henders Anjali K AK Larsen Janne T JT Petersen Liselotte L Watson Hunna J HJ Yilmaz Zeynep Z Kirk Katherine M KM Gordon Scott S Leppä Virpi M VM Martin Felicity C FC Whiteman David C DC Olsen Catherine M CM Werge Thomas M TM Pedersen Nancy L NL Kaye Walter W Bergen Andrew W AW Halmi Katherine A KA Strober Michael M Kaplan Allan S AS Woodside D Blake DB Mitchell James J Johnson Craig L CL Brandt Harry H Crawford Steven S Horwood L John LJ Boden Joseph M JM Pearson John F JF Duncan Laramie E LE Grove Jakob J Mattheisen Manuel M Jordan Jennifer J Kennedy Martin A MA Birgegård Andreas A Lichtenstein Paul P Norring Claes C Wade Tracey D TD Montgomery Grant W GW Martin Nicholas G NG Landén Mikael M Mortensen Preben Bo PB Sullivan Patrick F PF Bulik Cynthia M CM

Contemporary clinical trials 20181001

<h4>Background</h4>Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population res ...[more]

PMID: 30287268

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Project description:Anorexia nervosa (AN) is a devastating disorder with evidence of underexplored heritability. Twin and family studies estimate heritability (h2 ) to be 57%-64%, and genome-wide association studies (GWAS) reveal significant genetic correlations with psychiatric and anthropometric traits and a total of nine genome-wide significant loci. Whether significantly associated single nucleotide polymorphisms identified by GWAS are causal or tag true causal variants, remains to be elucidated. We propose a novel method for bridging this knowledge gap by fine-mapping short structural variants (SSVs) in and around GWAS-identified loci. SSV fine-mapping of loci associated with complex disorders such as schizophrenia, amyotrophic lateral sclerosis, and Alzheimer's disease has uncovered genetic risk markers, phenotypic variability between patients, new pathological mechanisms, and potential therapeutic targets. We analyze previous investigations' methods and propose utilizing an evaluation algorithm to prioritize 10 SSVs for each of the top two AN GWAS-identified loci followed by Sanger sequencing and fragment analysis via capillary electrophoresis to characterize these SSVs for case/control association studies. Success of previous SSV analyses in complex disorders and effective utilization of similar methodologies supports our proposed method. Furthermore, the structural and spatial properties of the 10 SSVs identified for each of the top two AN GWAS-associated loci, cell adhesion molecule 1 (CADM1) and NCK interacting protein with SH3 domain (NCKIPSD), are similar to previous studies. We propose SSV fine-mapping of AN-associated loci will identify causal genetic architecture. Deepening understandings of AN may lead to novel therapeutic targets and subsequently increase quality-of-life for individuals living with the illness. PUBLIC SIGNIFICANCE STATEMENT: Anorexia nervosa is a severe and complex illness, arising from a combination of environmental and genetic factors. Recent studies estimate the contribution of genetic variability; however, the specific DNA sequences and how they contribute remain unknown. We present a novel approach, arguing that the genetic variant class, short structural variants, could answer this knowledge gap and allow development of biologically targeted therapeutics, improving quality-of-life and patient outcomes for affected individuals.

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The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.

Publications

The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.

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