WLS-ILIAD: Initial Lifetime’s Impact on ADRD

Between 2021 and 2025, WLS will collect two new waves of data, which will capture detailed measures of cognitive change and dementia as the cohort reaches their early to mid 80s. In this session, I will provide an overview of the data that we’re collecting, as well as opportunities to explore early and mid-life determinants of cognitive change and dementia onset in this unique study. Compared to existing studies, the WLS offers some novel opportunities. First, it will provide one of the only opportunities to study how early and midlife life conditions and experiences, on data gathered prospectively, can shape cognitive trajectories and dementia in later life. Second, its unique sibling design provides significant analytic advantages, improving causal inference. Third, the study includes a large group of rural participants, allowing for closer examinations of how rural conditions may shape risk and resilience against cognitive decline and dementia in later life.

Genetic associations with temporal shifts in obesity and severe obesity during the obesity epidemic in Norway: A longitudinal population-based cohort (the HUNT Study)

Background Obesity has tripled worldwide since 1975 as environments are becoming more obesogenic. Our study investigates how changes in population weight and obesity over time are associated with genetic predisposition in the context of an obesogenic environment over 6 decades and examines the robustness of the findings using sibling design. Methods and findings A total of 67,110 individuals aged 13–80 years in the Nord-Trøndelag region of Norway participated with repeated standardized body mass index (BMI) measurements from 1966 to 2019 and were genotyped in a longitudinal population-based health study, the Trøndelag Health Study (the HUNT Study). Genotyping required survival to and participation in the HUNT Study in the 1990s or 2000s. Linear mixed models with observations nested within individuals were used to model the association between a genome-wide polygenic score (GPS) for BMI and BMI, while generalized estimating equations were used for obesity (BMI ≥ 30 kg/m2) and severe obesity (BMI ≥ 35 kg/m2). The increase in the average BMI and prevalence of obesity was steeper among the genetically predisposed. Among 35-year-old men, the prevalence of obesity for the least predisposed tenth increased from 0.9% (95% confidence interval [CI] 0.6% to 1.2%) to 6.5% (95% CI 5.0% to 8.0%), while the most predisposed tenth increased from 14.2% (95% CI 12.6% to 15.7%) to 39.6% (95% CI 36.1% to 43.0%). Equivalently for women of the same age, the prevalence of obesity for the least predisposed tenth increased from 1.1% (95% CI 0.7% to1.5%) to 7.6% (95% CI 6.0% to 9.2%), while the most predisposed tenth increased from 15.4% (95% CI 13.7% to 17.2%) to 42.0% (95% CI 38.7% to 45.4%). Thus, for 35-year-old men and women, respectively, the absolute change in the prevalence of obesity from 1966 to 2019 was 19.8 percentage points (95% CI 16.2 to 23.5, p < 0.0001) and 20.0 percentage points (95% CI 16.4 to 23.7, p < 0.0001) greater for the most predisposed tenth compared with the least predisposed tenth, defined using the GPS for BMI. The corresponding absolute changes in the prevalence of severe obesity for men and women, respectively, were 8.5 percentage points (95% CI 6.3 to 10.7, p < 0.0001) and 12.6 percentage points (95% CI 9.6 to 15.6, p < 0.0001) greater for the most predisposed tenth. The greater increase in BMI in genetically predisposed individuals over time was apparent after adjustment for family-level confounding using a sibling design. Key limitations include a slightly lower survival to date of genetic testing for the older cohorts and that we apply a contemporary genetic score to past time periods. Future research should validate our findings using a polygenic risk score constructed from historical data. Conclusions In the context of increasingly obesogenic changes in our environment over 6 decades, our findings reveal a growing inequality in the risk for obesity and severe obesity across GPS tenths. Our results suggest that while obesity is a partially heritable trait, it is still modifiable by environmental factors. While it may be possible to identify those most susceptible to environmental change, who thus have the most to gain from preventive measures, efforts to reverse the obesogenic environment will benefit the whole population and help resolve the obesity epidemic.

The association between maternal and offspring preterm birth. Results from a sibling design

IntroductionPrevious studies have reported an intergenerational association between maternal and offspring preterm birth (PTB) but the nature of the association remains unclear. Objectives and ApproachThe objective was to revisit the association between maternal and offspring preterm birth using a quasi-experimental sibling design and distinguishing between preterm birth types. We conducted a retrospective intergenerational cohort study of 39,573 women born singleton in Manitoba, Canada (1980-2002) who gave birth to 79,198 singleton infants (1995-2016). To account for familial confounding we defined a matched subcohort of 1033 sister mothers with discordant PTB status and compared offspring PTB rates between 2,499 differentially exposed cousins using log-binomial fixed-effects generalized estimating equation models. PTB was defined as a delivery < 37 gestation weeks, divided into spontaneous and provider-initiated. ResultsIn the population, mothers born preterm were more likely to give birth preterm [Adjusted Relative Risk (ARR): 1.39; 95\% Confidence Interval (CI): 1.25, 1.54]. The intergenerational association was not apparent among births to sisters with discordant PTB status [ARR: 1.02; 95\% CI: 0.77, 1.34]. However, the lack of association in the sibling analyses is explained by the fact that infants whose maternal aunts, but not their mothers, were born preterm had similarly elevated risk of PTB (10\%) than infants whose mothers were born preterm. Intergenerational patterns were observed for spontaneous PTB but not for provider-initiated PTB. Conclusion/ImplicationsThese findings suggest that it is not the fact of having been born preterm that puts women at higher risk of delivering preterm, but the fact of having been born to a mother who ever delivered a preterm baby. Consideration of family history of PTB may better identify women-at-risk.

Use of glucocorticoids during pregnancy and risk of attention-deficit/hyperactivity disorder in offspring: a nationwide Danish cohort study

ObjectivePrenatal exposure to excess endogenous glucocorticoid (GC) has been linked to attention-deficit/hyperactivity disorder (ADHD). We investigated whether prenatal exposure to exogenous GC is associated with ADHD.DesignNationwide cohort study.SettingA cohort of 875 996 singletons born alive between 1996 and 2009 in Denmark. Data were obtained from national registries.ExposuresWe identified children exposed prenatally to GCs, children unexposed prenatally and born to maternal former users, and children unexposed and born to maternal never users.Main outcome measuresWe compared ADHD risk in children prenatally exposed to GCs and in children of former GC users with risk in unexposed children of never users. We computed cumulative incidence at 10 years of age and adjusted HRs (aHRs). In addition, we compared exposed children with unexposed siblings in a sibling design.ResultsWe identified 875 996 children, among whom 5319 were prenatally exposed to systemic GCs and 36 780 to local/inhaled GCs. Cumulative incidences of ADHD at 10 years of age were 2.65% in prenatally exposed children and 2.03% in unexposed children of never users. At the general population level, prenatal exposure was associated with ADHD compared with unexposed, with aHR of 1.43(95% CI 1.24 to 1.65) for systemic exposure and 1.23 (95% CI 1.15 to 1.31) for local/inhaled exposure. However, our former user analysis (aHR of 1.25 (95% CI 1.20 to 1.29)) and sibling design (aHR of 1.03 (95% CI 0.87 to 1.20)) indicated that these findings were due to confounding.ConclusionThis study provides no evidence of a causal association between prenatal exposure to GCs and risk of ADHD.