Genetic Predisposition to Low-Density Lipoprotein Cholesterol May Increase Risks of Both Individual and Familial Alzheimer's Disease

Tan, Jiang-Shan; Hu, Mengjin; Yang, Yanmin; Yang, Yuejin

doi:10.3389/fmed.2021.798334

Cited by 14 publications

(14 citation statements)

References 61 publications

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“…While the association between the LDL-PGS and the risk for Alzheimer’s disease was slightly attenuated after removing the ApoE locus (OR = 1.23 vs. 1.36 per SD PGS increase), the association remained significant ( p -value = 2.51 × 10 −21 ). Recent Mendelian randomization studies also provide evidence for the causal effect of lipids on risk for dementia [ 44 ] and Alzheimer’s disease [ 45 ]. The LDL-C and TC PGSs were also associated with increased aspartate aminotransferase levels (a liver enzyme), in accordance with other studies [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

et al. 2022

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Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

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Section: Resultsmentioning

confidence: 99%

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

et al. 2022

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“…First, these data adopted to infer the correlation between obesity and HDP risk factors came mainly from European ancestry, therefore, subsequent studies need to test other regions and races to determine whether the correlation is consistent in other populations ( 24 ). Second, we are not able to further explore subgroup analysis on the interest covariates because we just adopted the summary data rather than individual patient data ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Genetically Predicted Obesity Causally Increased the Risk of Hypertension Disorders in Pregnancy

Wang

Tan

Liu

et al. 2022

Front. Cardiovasc. Med.

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AimsThis study aimed to evaluate the causal association between obesity and hypertension disorders in pregnancy.MethodsTwo-sample Mendelian randomization (MR) study was conducted based on the data obtained from the GIANT (n = 98,697 participants) consortium and FinnGen (n = 96,449 participants) consortium to determine the causal effect of obesity on the risk of hypertension disorders in pregnancy. Based on a genome-wide significance, 14 single-nucleotide polymorphisms (SNPs) associated with obesity-related databases were used as instrumental variables. The random-effects inverse-variance weighted (IVW) method was adopted as the main analysis with a supplemented sensitive analysis of the MR-Egger and weighted median approaches.ResultsAll three MR methods showed that genetically predicted obesity causally increased the risk of hypertension disorders in pregnancy. IVW analysis provided obesity as a risk factor for hypertension disorders in pregnancy with an odds ratio (OR) of 1.39 [95% confidence interval (CI) 1.21–1.59; P = 2.46 × 10−6]. Weighted median and MR Egger regression also showed directionally similar results [weighted median OR = 1.49 (95% CI, 1.24–1.79), P = 2.45 × 10−5; MR-Egger OR = 1.95 (95% CI, 1.35–2.82), P = 3.84 × 10−3]. No directional pleiotropic effects were found between obesity and hypertension disorders in pregnancy with both MR-Egger intercepts and funnel plots.ConclusionsOur findings provided directed evidence that obesity was causally associated with a higher risk of hypertension disorders in pregnancy. Taking measures to reduce the proportion of obesity may help reduce the incidence of hypertension disorders in pregnancy.

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“…A cohort study also demonstrated that total cholesterol levels decreased in AD patients but remained stable in healthy people (Toro et al., 2014). Studies have also shown that high levels of low‐density lipoprotein cholesterol (LDL‐C) could increase the risk of individual and familial AD (Tan et al., 2021). Hence, it is still worth studying whether a maternal history of AD can affect the cholesterol metabolism of offspring.…”

Section: Introductionmentioning

confidence: 99%

Maternal history of Alzheimer's disease predisposes to altered serum cholesterol levels in adult offspring

Liang,

Deng,

Jian

et al. 2024

Journal of Neurochemistry

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Controversial findings regarding the association between serum cholesterol levels and Alzheimer's disease (AD) have been identified through observational studies. The genetic basis shared by both factors and the causality between them remain largely unknown. The objective of this study is to examine the causal impact of maternal history of AD on changes in serum cholesterol levels in adult offspring. By retrieving genetic variants from summary statistics of large‐scale genome‐wide association study of maternal history of AD (European‐based: Ncase = 27 696, Ncontrol = 260 980). The causal association between genetically predicted maternal history of AD and changes in serum cholesterol levels in adult offspring was examined using the two‐sample Mendelian randomization (MR) method. Causal impact estimates were calculated using single‐nucleotide polymorphisms in both univariable MR (UMR) and multivariable MR (MVMR) analyses. Additionally, other approaches, such as Cochran's Q test and leave‐one‐out variant analysis, were employed to correct for potential biases. The results of UMR presented that genetically predicted maternal history of AD was positively associated with hypercholesterolemia (OR = 1.014; 95% CI: 1.009–1.018; p < 0.001), total cholesterol (OR = 1.29; 95% CI: 1.134–1.466; p < 0.001) and low‐density lipoprotein (OR = 1.525; 95% CI: 1.272–1.828; p < 0.001) among adult offspring. Genetic predisposition for maternal history of AD to be negatively associated with high‐density lipoprotein (OR = 0.889; 95% CI: 0.861–0.917; p < 0.001). The MVMR analysis remained robust and significant after adjusting for diabetes and obesity in offspring. Sufficient evidence was provided in this study to support the putative causal impact of maternal history of AD on the change of serum cholesterol profile in adult offspring. In clinical practice, priority should be given to the detection and monitoring of cholesterol levels in individuals with a maternal history of AD, particularly in the early stages.

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Genetic Predisposition to Low-Density Lipoprotein Cholesterol May Increase Risks of Both Individual and Familial Alzheimer's Disease

Cited by 14 publications

References 61 publications

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Genetically Predicted Obesity Causally Increased the Risk of Hypertension Disorders in Pregnancy

Maternal history of Alzheimer's disease predisposes to altered serum cholesterol levels in adult offspring

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