title: Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease.
abstract: In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain.
  
  
  
  To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes.
  
  
  
  A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322 154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111 986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149 821 individuals and 184 305 individuals, respectively, combined with individual-level data from the UK Biobank.
  
  
  
  Genetic predisposition to increased WHR adjusted for BMI.
  
  
  
  Type 2 diabetes and CHD.
  
  
  
  Among 111 986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58 845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1-mm Hg higher systolic blood pressure (each P < .001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40 530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66 440).
  
  
  
  A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes.
authors.affiliation: Center for Genomic Medicine and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston2Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Connor A
authors.initials: CA
authors.lastname: Emdin
authors.affiliation: Center for Genomic Medicine and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston2Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Amit V
authors.initials: AV
authors.lastname: Khera
authors.affiliation: Center for Genomic Medicine and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston2Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Natarajan
authors.affiliation: Center for Genomic Medicine and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston2Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Derek
authors.initials: D
authors.lastname: Klarin
authors.affiliation: Center for Genomic Medicine and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston2Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Seyedeh M
authors.initials: SM
authors.lastname: Zekavat
authors.affiliation: Department of Economics, Massachusetts Institute of Technology, Cambridge.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Hsiao
authors.affiliation: Center for Genomic Medicine and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston2Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
mesh_terms: D001786:Blood Glucose / Q000032:analysis / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics; D015992:Body Mass Index; D016022:Case-Control Studies; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D056128:Obesity, Abdominal / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood; D049629:Waist-Hip Ratio
chemical_list: D001786:Blood Glucose; D014280:Triglycerides