title: Inverse relationship between a genetic risk score of 31 BMI loci and weight change before and after reaching middle age.
abstract: OBJECTIVE
  Genome-wide-association studies have identified numerous body mass index (BMI)-associated variants, but it is unclear how these relate to weight gain in adults at different ages.
  
  
  METHODS
  We examined the association of a genetic risk score (GRS), consisting of 31 BMI-associated variants, with an annual weight change (AWC) and a substantial weight gain (SWG) of 10% by comparing self-reported weight at 20 years (y) with baseline weight (mean: 58 y; s.d.: 8 y) in 21407 participants from the Malmö Diet and Cancer Study (MDCS), and comparing baseline weight to weight at follow-up (mean: 73 y; s.d.: 6 y) among 2673 participants. Association between GRS and AWG and SWG was replicated in 4327 GLACIER (Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk) participants (mean: 45 y; s.d.: 7 y) with 10 y follow-up. Cohort-specific results were pooled by fixed-effect meta-analyses.
  
  
  RESULTS
  In MDCS, the GRS was associated with increased AWC (β: 0.003; s.e: 0.01; P: 7 × 10(-8)) and increased odds for SWG (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00, 1.02); P: 0.013) per risk-allele from age 20y, but unexpectedly with decreased AWC (β: -0.006; s.e: 0.002; P: 0.009) and decreased odds for SWG OR 0.96 (95% CI: 0.93, 0.98); P: 0.001) between baseline and follow-up. Effect estimates from age 20 y to baseline differed significantly from those from baseline to follow-up (P: 0.0002 for AWC and P: 0.0001 for SWG). Similar to MDCS, the GRS was associated with decreased odds for SWG OR 0.98 (95% CI: 0.96, 1.00); P: 0.029) from baseline to follow-up in GLACIER. In meta-analyses (n=7000), the GRS was associated with decreased AWC (β: -0.005; s.e.m. 0.002; P: 0.002) and decreased odds for SWG OR 0.97 (95% CI: 0.96, 0.99); P: 0.001) per risk-allele.
  
  
  CONCLUSIONS
  Our results provide convincing evidence for a paradoxical inversed relationship between a high number of BMI-associated risk-alleles and less weight gain during and after middle-age, in contrast to the expected increased weight gain seen in younger age.
authors.affiliation: Department of Clinical Sciences in Malmö, Lund University Diabetes Center (LUDC), Lund University, Malmö, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Rukh
authors.affiliation: Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Department of Clinical Sciences in Malmö, Lund University Diabetes Center (LUDC), Lund University, Malmö, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Ericson
authors.affiliation: Department of Clinical Sciences in Malmö, Lund University Diabetes Center (LUDC), Lund University, Malmö, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Hindy
authors.affiliation: Department of Clinical Sciences in Malmö, Lund University Diabetes Center (LUDC), Lund University, Malmö, Sweden.|Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Stocks
authors.affiliation: Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Renström
authors.affiliation: Department of Clinical Sciences in Malmö, Lund University Diabetes Center (LUDC), Lund University, Malmö, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Department of Internal Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: P M
authors.initials: PM
authors.lastname: Nilsson
authors.affiliation: Department of Clinical Sciences in Malmö, Lund University Diabetes Center (LUDC), Lund University, Malmö, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Melander
authors.affiliation: Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.|Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.|Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden.
authors.forename: P W
authors.initials: PW
authors.lastname: Franks
authors.affiliation: Department of Clinical Sciences in Malmö, Lund University Diabetes Center (LUDC), Lund University, Malmö, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Orho-Melander
mesh_terms: D000328:Adult; D000483:Alleles; D015992:Body Mass Index; D005260:Female; D005500:Follow-Up Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D055106:Genome-Wide Association Study; D006801:Humans; D008019:Life Style; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology* / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D015430:Weight Gain / Q000235:genetics*; D044465:White People