Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank

Harrison, Sean; Davies, Neil M; Howe, Laura D; Hughes, Amanda

doi:10.1126/sciadv.abf8257

Cited by 20 publications

(16 citation statements)

References 61 publications

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“…Two Sample MR analyses: MR is a novel statistical approach that assesses the random combination of genes from parent to offspring during gamete formation and conception and provides a method of determining whether there is a causal nature for certain environmental exposures [12,31]. In this method, genetic variables are considered instrumental variables (IVs) and utilized to make causal inferences from data [32].…”

Section: Statistical Analysesmentioning

confidence: 99%

Sleep duration, genetic susceptibility, and Alzheimer's disease: a longitudinal UK Biobank-based study

Yuan

Yang

et al. 2022

BMC Geriatr

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Background Alzheimer's disease (AD) is the most frequently occurring type of dementia. Concurrently, inadequate sleep has been recognized as a public health epidemic. Notably, genetic and environmental factors are now considered contributors to AD progression. Objective To assess the association between sleep duration, genetic susceptibility, and AD. Methods and results Based on 483,507 participants from the UK Biobank (UKB) with an average follow-up of 11.3 years, there was a non-linear relationship between AD incidence and sleep duration (P for non-linear < 0.001) by restricted cubic splines (RCS). Sleep duration was categorized into short sleep duration (< 6 h/night), normal sleep duration (6–9 h/night), and long sleep duration (> 9 h/night). No statistically significant interaction was identified between sleep duration and the AD-GRS (Alzheimer's disease genetic risk score, P for interaction = 0.45) using Cox proportional risk model. Compared with the participants who had a low AD-GRS and normal sleep duration, there was associated with a higher risk of AD in participants with a low AD-GRS and long sleep duration (HR = 3.4806; 95% CI 2.0011–6.054, p < 0.001), participants with an intermediate AD-GRS and long sleep duration (HR = 2.0485; 95% CI 1.3491–3.1105, p < 0.001), participants with a high AD-GRS and normal sleep duration (HR = 1.9272; 95% CI 1.5361–2.4176, p < 0.001), and participants with a high AD-GRS and long sleep duration (HR = 5.4548; 95% CI 3.1367–9.4863, p < 0.001).In addition, there was no causal association between AD and sleep duration using Two Sample Mendelian randomization (MR). Conclusion In the UKB population, though there was no causal association between AD and sleep duration analyzed using Two Sample MR, long sleep duration (> 9 h/night) was significantly associated with a higher risk of AD, regardless of high, intermediate or low AD-GRS. Prolonged sleep duration may be one of the clinical predictors of a higher risk of AD.

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Section: Statistical Analysesmentioning

confidence: 99%

Sleep duration, genetic susceptibility, and Alzheimer's disease: a longitudinal UK Biobank-based study

Yuan

Yang

et al. 2022

BMC Geriatr

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“…Interestingly, as shown in Fig. 2B, there was no significant association between BMI and AD risk in the 37 non-linear = 0.717). However, as shown in Fig.…”

Section: The Association Between Bmi and The Risk Of Ad Analyzed Usin...mentioning

confidence: 75%

“…The exposure and outcome data are available in the Additional file 2 : Tables S2 and S3, respectively. After harmonizing the effect allele and removing the SNPs for being palindromic with intermediate allele frequencies, the remaining 433 SNPS were further analyzed using MR. After calculating the MR results, we next conducted a sensitivity analysis [ 37 ] mainly from the following three aspects: (1) Heterogeneity test: To test for differences among IVs. As these results showed a strong heterogeneity among IVs (p < 0.05), we next used a random effects model to estimate MR effect size.…”

Section: Methodsmentioning

confidence: 99%

Body mass index, genetic susceptibility, and Alzheimer's disease: a longitudinal study based on 475,813 participants from the UK Biobank

Yuan

et al. 2022

J Transl Med

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Background The association between body mass index (BMI) and Alzheimer's disease (AD) remains controversial. Genetic and environmental factors are now considered contributors to AD risk. However, little is known about the potential interaction between genetic risk and BMI on AD risk. Objective To study the causal relationship between BMI and AD, and the potential interaction between AD genetic risk and BMI on AD risk. Methods and Results Using the UK Biobank database, 475,813 participants were selected for an average follow-up time of more than 10 years. Main findings: 1) there was a nonlinear relationship between BMI and AD risk in participants aged 60 years or older (p for non-linear < 0.001), but not in participants aged 37–59 years (p for non-linear = 0.717) using restricted cubic splines; 2) for participants aged 60 years and older, compared with the BMI (23–30 kg/m2) group, the BMI (< 23 kg/m2) group was associated with a higher AD risk (HR = 1.585; 95% CI 1.304–1.928, p < 0.001) and the BMI (> 30 kg/m2) group was associated with a lower AD risk (HR = 0.741; 95% CI 0.618–0.888, p < 0.01) analyzed using the Cox proportional risk model; 3) participants with a combination of high AD genetic risk score (AD-GRS) and BMI (< 23 kg/m2) were associated with the highest AD risk (HR = 3.034; 95% CI 2.057–4.477, p < 0.001). In addition, compared with the BMI (< 23 kg/m2), the higher BMI was associated with a lower risk of AD in participants with the same intermediate or high AD-GRS; 4) there was a reverse causality between BMI and AD when analyzed using bidirectional Mendelian randomization (MR). Conclusion There was a reverse causality between BMI and AD analyzed using MR. For participants aged 60 years and older, the higher BMI was associated with a lower risk of AD in participants with the same intermediate or high AD genetic risk. BMI (23–30 kg/m2) may be a potential intervention for AD.

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“…The most significant signal was located at 19p13.3 (chr19: 1,922,476-2,815,372, p = 2.12 Â 10 À18 ), which harbors plentiful genes including DOT1L, associated with both osteoarthritis and osteoporosis, (36,37) and THOP1, associated with SHBG. (38) Replacing SHBG with SHBGa, nine out of the 11 local signals were successfully replicated with the most significant signal located at, again, 19p13.3 ( p = 1.39 Â 10 À17 ) (Fig. 2B, Table S3).…”

Section: Global and Local Genetic Correlationsmentioning

confidence: 93%

Genetic Correlation, Shared Loci, and Causal Association Between Sex Hormone-Binding Globulin and Bone Mineral Density: Insights From a Large-Scale Genomewide Cross-Trait Analysis

Qu,

Xiao,

et al. 2023

Journal of Bone and Mineral Research

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Although the impact of sex hormones on bone metabolism is well‐documented, effect of their primary modulator, sex hormone‐binding globulin (SHBG), remains inconclusive. This study aims to elucidate the genetic overlap between SHBG and heel estimated bone mineral density (eBMD), a widely‐accepted tool for osteoporosis management and fracture risk assessment. Using summary statistics from large‐scale genome‐wide association studies conducted for SHBG (N = 370,125), SHBG adjusted for body mass index (SHBGa, N = 368,929), and eBMD (N = 426,824), a comprehensive genome‐wide cross‐trait approach was performed to quantify global and local genetic correlations, identify pleiotropic loci, and infer causal associations. A significant overall inverse genetic correlation was found for SHBG and eBMD (rg = −0.11, P = 3.34 × 10−10), which was further supported by the significant local genetic correlations observed in 11 genomic regions. Cross‐trait meta‐analysis revealed 219 shared loci, of which 7 were novel. Notably, four novel loci (rs6542680, rs8178616, rs147110934 and rs815625) were further demonstrated to colocalize. Mendelian randomization identified a robust causal effect of SHBG on eBMD (beta = −0.22, P = 3.04 × 10−13), with comparable effect sizes observed in both men (beta = −0.16, P = 1.99 × 10−6) and women (beta = −0.19, P = 2.73 × 10−9). Replacing SHBG with SHBGa, the observed genetic correlations, pleiotropic loci and causal associations did not change substantially. Our work reveals a shared genetic basis between SHBG and eBMD, substantiated by multiple pleiotropic loci and a robust causal relationship. While SHBG has been implicated in preventing and screening aging‐related diseases, our findings support its etiological role in osteoporosis.This article is protected by copyright. All rights reserved.

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Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank

Cited by 20 publications

References 61 publications

Sleep duration, genetic susceptibility, and Alzheimer's disease: a longitudinal UK Biobank-based study

Sleep duration, genetic susceptibility, and Alzheimer's disease: a longitudinal UK Biobank-based study

Body mass index, genetic susceptibility, and Alzheimer's disease: a longitudinal study based on 475,813 participants from the UK Biobank

Genetic Correlation, Shared Loci, and Causal Association Between Sex Hormone-Binding Globulin and Bone Mineral Density: Insights From a Large-Scale Genomewide Cross-Trait Analysis

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