Birthweight, Type 2 Diabetes and Cardiovascular Disease: Addressing the Barker Hypothesis with Mendelian randomization
Background: Low birthweight (BW) has been associated with a higher risk of hypertension, type 2 diabetes (T2D) and cardiovascular disease (CVD) in epidemiological studies. The Barker hypothesis posits that intrauterine growth restriction resulting in lower BW is causal for these diseases, but causality and mechanisms are difficult to infer from observational studies. Mendelian randomization (MR) is a new tool to address this important question. Methods: We performed regression analyses to assess associations of self-reported BW with CVD and T2D in 237,631 individuals from the UK Biobank, a large population-based cohort study aged 40-69 years recruited across UK in 2006-2010. Further, we assessed the causal relationship of such associations using the two-sample MR approach, estimating the causal effect by contrasting the SNP effects on the exposure with the SNP effects on the outcome using independent publicly available genome-wide association datasets. Results: In the observational analyses, BW showed strong inverse associations with systolic and diastolic blood pressure (β, -0.83 and -0.26; per raw unit in outcomes and SD change in BW; 95% CI, -0.90, -0.75 and -0.31, -0.22, respectively), T2D (odds ratio [OR], 0.83; 95% CI, 0.79, 0.87), lipid-lowering treatment (OR, 0.84; 95% CI, 0.81, 0.86) and CAD (hazard ratio [HR] 0.85; 95% CI, 0.78, 0.94); while the associations with adult body mass index (BMI) and body fat (β, 0.04 and 0.02; per SD change in outcomes and BW; 95% CI, 0.03, 0.04 and 0.01, 0.02, respectively) were positive. The MR analyses indicated inverse causal associations of BW with low density lipoprotein cholesterol, 2-hour glucose, CAD and T2D, and positive causal association with BMI; but no associations with blood pressure. Sensitivity analyses and robust MR methods provided consistent results and indicated no horizontal pleiotropy. Conclusion: Our study indicates that lower BW is causally and directly related with increased susceptibility to CAD and T2D in adulthood. This causal relationship is not mediated by adult obesity or hypertension.
- Downloaded 662 times
- Download rankings, all-time:
- Site-wide: 20,237 out of 84,639
- In genetics: 1,289 out of 4,444
- Year to date:
- Site-wide: 69,653 out of 84,639
- Since beginning of last month:
- Site-wide: 78,228 out of 84,639
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!