In this population of middle-aged and older women of European ancestry, we examined the joint effects of established BMI- or T2D-related risk variants on LTL. After combining data from multiple risk variants, women genetically predisposed to higher BMI or T2D did not possess shortened telomeres after adjustment for age and case status.
While our study is the first to examine the association between genetic predisposition to higher BMI or T2D and telomere length, many cross-sectional studies have directly examined the relation with these metabolic conditions. For BMI, some studies 
, including the present analysis, observed an inverse association with telomere length, while others reported no association 
. Similarly for T2D, most studies 
, including the present analysis, observed an inverse association despite a large variation in the strength of the relation. Although the reasons for these discrepancies are unclear, studies differed in sample size and population characteristics. In addition, these analyses had two important limitations. First, unmeasured confounders may have influenced findings. For example, several studies reported only unadjusted 
or age-adjusted results 
, increasing the possibility of unmeasured confounding by factors such as age, smoking, or physical activity (i.e., potential predictors of higher BMI or T2D and telomere length). Second, cross-sectional analyses were unable to test the direction of the association between higher BMI or T2D and telomere shortening, although several studies hypothesized that telomere shortening may be a consequence of higher body mass or T2D due to elevated oxidative stress and inflammation 
. In the present analysis, we used the genetic risk scores as proxies for BMI and T2D exposure to test the causal role of these metabolic conditions in telomere biology 
. As genetic variants are generally unaffected by environmental factors, our observations were minimally influenced by confounding. More importantly, telomere length is unlikely to affect genotypes, which enabled us to test whether higher BMI or T2D precede telomere shortening. Because neither genetic score was associated with LTL in the present analysis, we did not find evidence of a causal relation of strong magnitude, as findings from some studies suggested 
, between higher BMI or T2D and LTL among middle-aged or older women of European ancestry.
Few prospective studies have examined whether higher BMI or T2D predict telomere shortening. Our findings were consistent with those of Farzaneh-Far et
, who observed no association among 608 individuals between baseline BMI or T2D and subsequent telomere shortening over five years. O'Callaghan et
, however, observed that men who lowered their BMI had increased telomere length over one year, although this study included only 54 men and requires replication in a larger study of women. Findings from recent studies have suggested that telomere length may also play a role in the pathogenesis of these metabolic conditions, which may account in part for previous cross-sectional associations. Njajou et
observed among 2,721 individuals that, unexpectedly, longer telomeres were associated with greater increases in BMI over seven years. In addition, Zee et
observed that genetic variants in telomere-related genes may predict risk of T2D among ~22,000 women of European ancestry. Although requiring replication, these findings and those from the present analysis suggest relations among BMI, T2D, and telomere length are complex. Thus, although higher BMI or T2D may play a causal role of weak or modest magnitude in telomere shortening, these may not completely explain the observed cross-sectional associations.
Our null findings should be interpreted with caution given several limitations of our study. First, although the genetic risk scores captured the combined information from established genetic factors for higher BMI and T2D 
, they accounted for only a small amount of the variability in these conditions – indicating that the influence of these scores on higher BMI or T2D is likely weak relative to the influence of other factors (e.g., environmental predictors, gene-environment interactions). Thus, when examining the null association with LTL it is important to consider that these scores do not capture comprehensively exposure to higher BMI or T2D. More specifically, they reflect a component of the genetic risk to these conditions and do not capture the non-genetic components, which may be relevant for LTL. Although this is an important limitation of our approach, large prospective studies of telomere length are often impractical as they require repeated measurements of LTL over time. Thus, using genetic scores as proxies for exposures to evaluate causal relations, with careful consideration of the limitations, provides a feasible alternative. In addition, future studies can use a similar approach by using telomere-related genetic variants as proxies to evaluate whether shortened telomeres predict higher BMI or risk of T2D, similar to Zee et
Second, because the genetic scores were weak proxies of higher BMI and T2D, our data were underpowered to detect causal relations of weak or modest magnitude among BMI, T2D, and LTL. While our data provided sufficient power to detect large effects, the detection of weak associations using these scores requires large study populations that may only be available in meta-analyses (e.g., N
>33,000 unrelated individuals if BMI or T2D explains 1% of the variability in LTL). Alternatively, future studies can potentially leverage the presence of gene-environment interactions to improve statistical power. For example, studies may be able to detect weak or modest effects on LTL by focusing on populations with unhealthier lifestyles, where genetic factors may better predict BMI or T2D 
. While our data were underpowered to detect interactions, we observed that estimates between the BMI score and LTL appeared more pronounced among women with unhealthy lifestyle patterns expected to increase weight gain, supporting this possibility.
Third, because blood samples were stored on average for 19 years before LTL measurement, LTL degradation during storage is a possible concern. Because technicians were masked to participants' genotypes when measuring LTL, degradation would likely attenuate the results. However, years of sample storage was not correlated with telomere length in our population (rs
0.64), and previous studies in the NHS have identified significant associations with telomere length 
, further supporting the validity of our telomere length measurement.
Lastly, our study population comprised women of European ancestry, which minimized population stratification. However, because telomere dynamics may differ among African Americans and Hispanics 
, our null findings may not be generalizable to women of other ethnicities.
In summary, we found that genetic predisposition to higher BMI or T2D, estimated by genetic risk scores, was not associated with shortened telomeres among middle-aged and older women of European ancestry. Although we cannot exclude weak or modest effects, our findings do not support a causal role of strong magnitude for these metabolic conditions in telomere dynamics. Future efforts to detect causal relations of weaker magnitude will likely require meta-analyses of existing and future genetic studies of telomere length, or large prospective studies with repeated telomere length measurements.