Framingham Heart Study Enters New Phase: Third Generation Participants Being Recruited

Background: There is growing interest in the pathophysiological processes of preclinical Alzheimer’s disease (AD), including the potential role of leptin. Human studies have shown that both low and high levels of leptin can be associated with worse neurocognitive outcomes, suggesting this relationship may be moderated by another risk factor. Objective: We examined the association between plasma leptin levels and both neuropsychological test performance and structural neuroimaging and assessed whether body mass index (BMI) is an effect modifier of these associations. Methods: Our study sample consisted of 2,223 adults from the Framingham Heart Study Third Generation Cohort (average age = 40 years, 53% women). Results: Among the entire sample, there was no association between leptin and any of the neuropsychological domain measures or any of the MRI brain volume measures, after adjustment for BMI, APOE4, and other clinical factors. However, we did observe that BMI category was an effect modifier for the association between leptin and verbal memory (p for interaction = 0.03), where higher levels of leptin were associated with better performance among normal weight participants (BMI 18.5–24.9) kg/m2 (beta = 0.12, p = 0.02). No association was observed between leptin level and verbal memory test performance among participants who were overweight or obese. Conclusion: These findings suggest that the association between leptin and cognitive function is moderated by BMI category. Prospective examination of individuals transitioning from middle age to older adulthood will help to clarify the contribution of leptin to AD and other neurodegenerative conditions.

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Quantile-specific heritability of sibling leptin concentrations and its implications for gene-environment interactions

Scientific Reports ◽

10.1038/s41598-020-79116-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Paul T. Williams

Keyword(s):

Environmental Effects ◽

Framingham Heart Study ◽

Leptin Receptor ◽

Genetic Variant ◽

Third Generation ◽

Gene Environment ◽

Heart Study ◽

Soluble Leptin Receptor ◽

Regression Slopes ◽

Age And Sex

Abstract“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., leptin) is high or low relative to its distribution. Leptin concentrations are strongly related to adiposity, whose heritability is quantile dependent. Whether inheritance of leptin concentrations is quantile dependent, and whether this explains the greater heritability in women than men in accordance with their greater adiposity, and explains other gene-environment interactions, remains to be determined. Therefore, leptin and leptin receptor concentrations from 3068 siblings in 1133 sibships from the Framingham Heart Study Third Generation Cohort were analyzed. Free leptin index (FLI) was calculated as the ratio of leptin to soluble leptin receptor concentrations. Full-sib (βFS) regression slopes were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. The analyses showed βFS increased significantly with increasing percentiles of the offspring’s age- and sex-adjusted leptin distribution (Plinear = 0.0001), which was accelerated at the higher concentrations (Pquadratic = 0.0003). βFS at the 90th percentile (0.418 ± 0.066) was 4.7-fold greater than at the 10th percentile (0.089 ± 0.032, Pdifference = 3.6 × 10−6). Consistent with quantile-dependent expressivity, the βFS was greater in female sibs, which was attributable to their higher leptin concentrations. Reported gene-environment interactions involving adiposity and LEP, LEPR, MnSOD, PPARγ, PPARγ2, and IRS-1 polymorphisms were consistent with quantile-dependent expressivity of leptin concentrations. βFS for leptin receptor concentrations and free leptin index also increased significantly with increasing percentiles of their distributions (Plinear = 0.04 and Plinear = 8.5 × 10−6, respectively). In conclusion, inherited genetic and shared environmental effects on leptin concentrations were quantile dependent, which likely explains male–female differences in heritability and some gene-environment interactions.

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