title: Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults.
abstract: OBJECTIVE
  We used genetic variants that are robustly associated with adiposity to examine the causal association of adiposity with psychological distress.
  
  
  METHODS
  We examined the association of adiposity with psychological distress in a large (N = 53,221) general population cohort of 20- to 99-year-old adults from Copenhagen, Denmark. Psychological distress was assessed using four questions that asked about: feeling stressed; not accomplishing very much; wanting to give up; and regular use of antidepressants/sedatives. We used the genetic loci FTO rs9939609 and MC4R rs17782313 as instrumental variables for adiposity quantified by body mass index (BMI) and waist to hip ratio (WHR).
  
  
  RESULTS
  In conventional multivariable analyses, BMI and WHR were positively associated with distress. For example, the odds ratio of reporting not accomplishing for each additional standard deviation increase for BMI was 1.11 (95% CI: 1.09, 1.13) and for WHR was 1.10 (95% CI: 1.08, 1.13) in the fully adjusted analyses. In contrast, instrumental variable analyses showed an inverse association of adiposity on distress; corresponding odds ratio in instrumental variable analyses was 0.64 (95% CI: 0.46, 0.89) for BMI and 0.49 (95% CI: 0.25, 0.94) for WHR (P-values for difference between the two approaches both = 0.001).
  
  
  CONCLUSIONS
  The inverse associations of adiposity and psychological distress when genetic variants are used as instrumental variables could be explained by biological pathways linking adiposity and distress. The positive associations of adiposity with distress in multivariable analyses might be explained by residual confounding or reverse causality.
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, UK. d.a.lawlor@bristol.ac.uk
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Roger M
authors.initials: RM
authors.lastname: Harbord
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjaerg-Hansen
authors.forename: Tom M
authors.initials: TM
authors.lastname: Palmer
authors.forename: Jeppe
authors.initials: J
authors.lastname: Zacho
authors.forename: Marianne
authors.initials: M
authors.lastname: Benn
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
mesh_terms: D050154:Adiposity / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D001008:Anxiety Disorders / Q000235:genetics* / Q000523:psychology; D015992:Body Mass Index; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003718:Denmark; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D011506:Proteins / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D012307:Risk Factors; D013315:Stress, Psychological / Q000235:genetics* / Q000523:psychology; D049629:Waist-Hip Ratio; D055815:Young Adult
chemical_list: C470072:MC4R protein, human; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human