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Original Investigation |

Association of a Genetic Risk Score With Body Mass Index Across Different Birth Cohorts

Stefan Walter, PhD1; Iván Mejía-Guevara, PhD2; Karol Estrada, PhD3; Sze Y. Liu, PhD2; M. Maria Glymour, ScD1
[+] Author Affiliations
1Department of Epidemiology and Biostatistics, University of California, San Francisco
2Harvard Center for Population and Development Studies, Harvard University, Cambridge, Massachusetts
3Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
JAMA. 2016;316(1):63-69. doi:10.1001/jama.2016.8729.
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Importance  Many genetic variants are associated with body mass index (BMI). Associations may have changed with the 20th century obesity epidemic and may differ for black vs white individuals.

Objective  Using birth cohort as an indicator for exposure to obesogenic environment, to evaluate whether genetic predisposition to higher BMI has a larger magnitude of association among adults from more recent birth cohorts, who were exposed to the obesity epidemic at younger ages.

Design, Setting, and Participants  Observational study of 8788 adults in the US national Health and Retirement Study who were aged 50 years and older, born between 1900 and 1958, with as many as 12 BMI assessments from 1992 to 2014.

Exposures  A multilocus genetic risk score for BMI (GRS-BMI), calculated as the weighted sum of alleles of 29 single nucleotide polymorphisms associated with BMI, with weights equal to the published per-allele effects. The GRS-BMI represents how much each person’s BMI is expected to differ, based on genetic background (with respect to these 29 loci), from the BMI of a sample member with median genetic risk. The median-centered GRS-BMI ranged from −1.68 to 2.01.

Main Outcomes and Measures  BMI based on self-reported height and weight.

Results  GRS-BMI was significantly associated with BMI among white participants (n = 7482; mean age at first assessment, 59 years; 3373 [45%] were men; P <.001) and among black participants (n = 1306; mean age at first assessment, 57 years; 505 [39%] were men; P <.001) but accounted for 0.99% of variation in BMI among white participants and 1.37% among black participants. In multilevel models accounting for age, the magnitude of associations of GRS-BMI with BMI were larger for more recent birth cohorts. For example, among white participants, each unit higher GRS-BMI was associated with a difference in BMI of 1.37 (95% CI, 0.93 to 1.80) if born after 1943, and 0.17 (95% CI, −0.55 to 0.89) if born before 1924 (P = .006). For black participants, each unit higher GRS-BMI was associated with a difference in BMI of 3.70 (95% CI, 2.42 to 4.97) if born after 1943, and 1.44 (95% CI, −1.40 to 4.29) if born before 1924.

Conclusions and Relevance  For participants born between 1900 and 1958, the magnitude of association between BMI and a genetic risk score for BMI was larger among persons born in later cohorts. This suggests that associations of known genetic variants with BMI may be modified by obesogenic environments.

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Figure 1.
Model-Predicted Age Trajectories of Average Body Mass Index for White and Black Participants in 4 Birth Cohorts

For additional information, see eTable 3 (model 3) in the Supplement.

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Figure 2.
Association of Genetic Risk Score and Body Mass Index at Age 65 Years for White Participants and at Age 67 for Black Participants in 4 Birth Cohorts

For additional information, see eTable 3 (model 4) in the Supplement.

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