title: Body mass index change in gastrointestinal cancer and chronic obstructive pulmonary disease is associated with Dedicator of Cytokinesis 1.
abstract: BACKGROUND
  There have been a number of candidate gene association studies of cancer cachexia-related traits, but no genome-wide association study (GWAS) has been published to date. Cachexia presents in patients with a number of complex traits, including both cancer and COPD. The objective of the current investigation was to search for a shared genetic aetiology for change in body mass index (ΔBMI) among cancer and COPD by using GWAS data in the Framingham Heart Study.
  
  
  METHODS
  A linear mixed effects model accounting for age, sex, and change in smoking status was used to calculate ΔBMI in participants over 40 years of age with three consecutive BMI time points (n = 4162). Four GWAS of ΔBMI using generalized estimating equations were performed among 1085 participants with a cancer diagnosis, 204 with gastrointestinal (GI) cancer, 112 with lung cancer, and 237 with COPD to test for association with 418 365 single-nucleotide polymorphisms (SNPs).
  
  
  RESULTS
  Two SNPs reached a level of genome-wide significance (P < 5 × 10-8) with ΔBMI: (i) rs41526344 within the CNTN4 gene, among COPD cases (β = 0.13, P = 4.3 × 10-8); and (ii) rs4751240 in the gene Dedicator of Cytokinesis 1 (DOCK1) among GI cancer cases (β = 0.10, P = 1.9 × 10-8). The DOCK1 SNP association replicated in the ΔBMI GWAS among COPD cases (βmeta-analyis= 0.10, Pmeta-analyis= 9.3 × 10-10). The DOCK1 gene codes for the dedicator of cytokinesis 1 protein, which has a role in myoblast fusion.
  
  
  CONCLUSIONS
  In sum, one statistically significant common variant in the DOCK1 gene was associated with ΔBMI in GI cancer and COPD cases providing support for at least partially shared aetiology of ΔBMI in complex diseases.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Merry-Lynn Noelle
authors.initials: MN
authors.lastname: McDonald
authors.affiliation: Department of Public Health Science, Seoul National University, Seoul, South Korea.
authors.forename: Sungho
authors.initials: S
authors.lastname: Won
authors.affiliation: Department of Biomedicine and Centre for integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Division of Primary Care and Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: CIRO+, Centre of Expertise for Chronic Organ Failure, Horn, The Netherlands.
authors.forename: Erica
authors.initials: E
authors.lastname: Rutten
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Hardin
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Wai-Ki
authors.initials: WK
authors.lastname: Yip
authors.affiliation: Department of Medicine, Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.affiliation: UCL Respiratory, Division of Medicine, University College London, London, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: CIRO+, Centre of Expertise for Chronic Organ Failure, Horn, The Netherlands.|Department of Respiratory Medicine, Maastricht University Medical Center Maastricht, Maastricht, The Netherlands.
authors.forename: Emiel F M
authors.initials: EFM
authors.lastname: Wouters
authors.affiliation: Thorax Institute, Hospital Clinic-IDIBAPS, CIBERES, University of Barcelona, Barcelona, Spain.
authors.forename: Alvar
authors.initials: A
authors.lastname: Agusti
authors.affiliation: Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Casaburi
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Lange
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.|Section of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: George
authors.initials: G
authors.lastname: O'Connor
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D000328:Adult; D000368:Aged; D015992:Body Mass Index; D002100:Cachexia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C099818:DOCK1 protein, human; D020744:rac GTP-Binding Proteins
keywords: BMI; COPD; Cachexia; Cancer; GWAS; Longitudinal