TY - JOUR
T1 - Bridging the gap
T2 - Short structural variants in the genetics of anorexia nervosa
AU - Berthold, Natasha
AU - Pytte, Julia
AU - Bulik, Cynthia M.
AU - Tschochner, Monika
AU - Medland, Sarah E.
AU - Akkari, Patrick Anthony
N1 - Funding Information:
Open access publishing facilitated by The University of Notre Dame Australia, as part of the Wiley - The University of Notre Dame Australia agreement via the Council of Australian University Librarians.
Funding Information:
Cynthia M. Bulik reports: Shire (grant recipient, Scientific Advisory Board member); Idorsia (consultant); Lundbeckfonden (grant recipient); Pearson (author, royalty recipient); Equip Health Inc. (Clinical Advisory Board). The other authors report no conflicts.
Funding Information:
Sarah E. Medland was supported by an Australian National Health and Medical Research Council Investigator, Grant/Award Number: APP1172917. Funding Information
Publisher Copyright:
© 2022 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
KW - anorexia nervosa
KW - feeding and eating disorders
KW - genetic association studies
KW - genome-wide association study
KW - heritability
KW - mental disorders
KW - microsatellite repeats
UR - http://www.scopus.com/inward/record.url?scp=85129248374&partnerID=8YFLogxK
U2 - 10.1002/eat.23716
DO - 10.1002/eat.23716
M3 - Article
C2 - 35470453
AN - SCOPUS:85129248374
SN - 0276-3478
VL - 55
SP - 747
EP - 753
JO - International Journal of Eating Disorders
JF - International Journal of Eating Disorders
IS - 6
ER -