Growth Differentiation Factor 15 Is Associated With Alzheimer’s Disease Risk

BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10–8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.

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Life Course Adiposity and Alzheimer’s Disease: A Mendelian Randomization Study

Journal of Alzheimer s Disease ◽

10.3233/jad-210345 ◽

2021 ◽

pp. 1-10

Author(s):

Xian Li ◽

Yan Tian ◽

Yu-Xiang Yang ◽

Ya-Hui Ma ◽

Xue-Ning Shen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Life Course ◽

Mendelian Randomization ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Fat Percentage ◽

Regression Methods ◽

Weighted Median

Background: Several studies showed that life course adiposity was associated with Alzheimer’s disease (AD). However, the underlying causality remains unclear. Objective: We aimed to examine the causal relationship between life course adiposity and AD using Mendelian randomization (MR) analysis. Methods: Instrumental variants were obtained from large genome-wide association studies (GWAS) for life course adiposity, including birth weight (BW), childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), and body fat percentage (BFP). A meta-analysis of GWAS for AD including 71,880 cases and 383,378 controls was used in this study. MR analyses were performed using inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. We calculated odds ratios (ORs) per genetically predicted standard deviation (1-SD) unit increase in each trait for AD. Results: Genetically predicted 1-SD increase in adult BMI was significantly associated with higher risk of AD (IVW: OR = 1.03, 95% confidence interval [CI] = 1.01–1.05, p = 2.7×10–3) after Bonferroni correction. The weighted median method indicated a significant association between BW and AD (OR = 0.94, 95% CI = 0.90–0.98, p = 1.8×10–3). We also found suggestive associations of AD with WC (IVW: OR = 1.03, 95% CI = 1.00–1.07, p = 0.048) and WHR (weighted median: OR = 1.04, 95% CI = 1.00–1.07, p = 0.029). No association was detected of AD with childhood BMI and BFP. Conclusion: Our study demonstrated that lower BW and higher adult BMI had causal effects on increased AD risk.

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Causal association of adipokines with osteoarthritis: a Mendelian randomization study

Rheumatology ◽

10.1093/rheumatology/keaa719 ◽

2020 ◽

Author(s):

Jiayao Fan ◽

Jiahao Zhu ◽

Lingling Sun ◽

Yasong Li ◽

Tianle Wang ◽

...

Keyword(s):

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Knee Oa ◽

Genome Wide ◽

A Genome ◽

Weighted Median

Abstract Objective This two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA. Methods Summary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results. Results The positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13–5.09] and weighted median (OR: 2.94, 95% CI: 1.23–6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01–1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18–10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03–1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis. Conclusions An association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

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Herpesvirus Infections and Alzheimer’s Disease: A Mendelian Randomization Study

10.21203/rs.3.rs-323013/v1 ◽

2021 ◽

Author(s):

Shu-Yi Huang ◽

Yu-Xiang Yang ◽

Kevin Kuo ◽

Hong-Qi Li ◽

Xue-Ning Shen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Family History ◽

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association Studies ◽

Summary Statistics ◽

Primary Analysis ◽

Varicella Zoster ◽

History Of

Abstract BackgroundObservational studies have suggested that herpesvirus infection increased the risk of Alzheimer’s disease (AD), but it is unclear whether the association is causal. The aim of the present study is to evaluate the causal relationship between four herpesvirus infections and AD. MethodsWe performed a two-sample Mendelian randomization analysis to investigate association of four active herpesvirus infections with AD using summary statistics from genome-wide association studies. The four herpesvirus infections (i.e., chickenpox, shingles, cold sores, mononucleosis) are caused by varicella-zoster virus, herpes simplex virus type 1, and Epstein-Barr virus (EBV), respectively. A large summary statistics data from International Genomics of Alzheimer’s Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was further performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD and 272,244 controls).ResultsWe found evidence of a suggestive association between mononucleosis (caused by EBV) and risk of AD (odds ratio [OR] = 1.634, 95% confidence interval [CI] = 1.092-2.446, P = 0.017) after Bonferroni correction. It has been verified in validation analysis that mononucleosis is also associated with family history of AD (OR [95% CI] = 1.392 [1.061, 1.826], P=0.017). Genetically predicted shingles were associated with AD risk (OR [95% CI] = 0.867 [0.784, 0.958], P = 0.005). While genetically predicted chickenpox was suggestively associated with increased family history of AD (OR [95% CI] = 1.147 [1.007, 1.307], P = 0.039).ConclusionsOur findings provided evidence supporting a positive relationship between mononucleosis and AD, indicating a causal link between EBV infection and AD. Further elucidations of this association and underlying mechanisms are likely to identify feasible interventions to promote AD prevention.

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Novel Alzheimer’s disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers

Translational Psychiatry ◽

10.1038/s41398-021-01412-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jong-Ho Park ◽

Inho Park ◽

Emilia Moonkyung Youm ◽

Sejoon Lee ◽

June-Hee Park ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Disease Risk ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Whole Genome ◽

Ε4 Allele

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disease associated with a complex genetic etiology. Besides the apolipoprotein E ε4 (APOE ε4) allele, a few dozen other genetic loci associated with AD have been identified through genome-wide association studies (GWAS) conducted mainly in individuals of European ancestry. Recently, several GWAS performed in other ethnic groups have shown the importance of replicating studies that identify previously established risk loci and searching for novel risk loci. APOE-stratified GWAS have yielded novel AD risk loci that might be masked by, or be dependent on, APOE alleles. We performed whole-genome sequencing (WGS) on DNA from blood samples of 331 AD patients and 169 elderly controls of Korean ethnicity who were APOE ε4 carriers. Based on WGS data, we designed a customized AD chip (cAD chip) for further analysis on an independent set of 543 AD patients and 894 elderly controls of the same ethnicity, regardless of their APOE ε4 allele status. Combined analysis of WGS and cAD chip data revealed that SNPs rs1890078 (P = 6.64E−07) and rs12594991 (P = 2.03E−07) in SORCS1 and CHD2 genes, respectively, are novel genetic variants among APOE ε4 carriers in the Korean population. In addition, nine possible novel variants that were rare in individuals of European ancestry but common in East Asia were identified. This study demonstrates that APOE-stratified analysis is important for understanding the genetic background of AD in different populations.

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Is disrupted sleep a risk factor for Alzheimer’s disease? Evidence from a two-sample Mendelian randomization analysis

International Journal of Epidemiology ◽

10.1093/ije/dyaa183 ◽

2020 ◽

Author(s):

Emma L Anderson ◽

Rebecca C Richmond ◽

Samuel E Jones ◽

Gibran Hemani ◽

Kaitlin H Wade ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Daytime Sleepiness ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Self Report ◽

Genome Wide Association Studies ◽

Tentative Evidence

Abstract Background It is established that Alzheimer’s disease (AD) patients experience sleep disruption. However, it remains unknown whether disruption in the quantity, quality or timing of sleep is a risk factor for the onset of AD. Methods We used the largest published genome-wide association studies of self-reported and accelerometer-measured sleep traits (chronotype, duration, fragmentation, insomnia, daytime napping and daytime sleepiness), and AD. Mendelian randomization (MR) was used to estimate the causal effect of self-reported and accelerometer-measured sleep parameters on AD risk. Results Overall, there was little evidence to support a causal effect of sleep traits on AD risk. There was some suggestive evidence that self-reported daytime napping was associated with lower AD risk [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.50–0.99). Some other sleep traits (accelerometer-measured ‘eveningness’ and sleep duration, and self-reported daytime sleepiness) had ORs of a similar magnitude to daytime napping, but were less precisely estimated. Conclusions Overall, we found very limited evidence to support a causal effect of sleep traits on AD risk. Our findings provide tentative evidence that daytime napping may reduce AD risk. Given that this is the first MR study of multiple self-report and objective sleep traits on AD risk, findings should be replicated using independent samples when such data become available.

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Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses

BMC Medicine ◽

10.1186/s12916-021-01939-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Maxime M. Bos ◽

Neil J. Goulding ◽

Matthew A. Lee ◽

Amy Hofman ◽

Mariska Bot ◽

...

Keyword(s):

Sleep Duration ◽

Mendelian Randomization ◽

Disease Risk ◽

Association Studies ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Multivariable Regression ◽

Artery Disease ◽

Insomnia Symptoms

Abstract Background Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

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Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2009808118 ◽

2021 ◽

Vol 118 (16) ◽

pp. e2009808118

Author(s):

Jodie Lord ◽

Bradley Jermy ◽

Rebecca Green ◽

Andrew Wong ◽

Jin Xu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Bayesian Model Averaging ◽

Mendelian Randomization ◽

Association Studies ◽

Model Averaging ◽

High Density Lipoproteins ◽

Genome Wide Association Studies ◽

Causal Pathway ◽

Target Disease

There are currently no disease-modifying treatments for Alzheimer’s disease (AD), and an understanding of preclinical causal biomarkers to help target disease pathogenesis in the earliest phases remains elusive. Here, we investigated whether 19 metabolites previously associated with midlife cognition—a preclinical predictor of AD—translate to later clinical risk, using Mendelian randomization (MR) to tease out AD-specific causal relationships. Summary statistics from the largest genome-wide association studies (GWASs) for AD and metabolites were used to perform bidirectional univariable MR. Bayesian model averaging (BMA) was additionally performed to address high correlation between metabolites and identify metabolite combinations that may be on the AD causal pathway. Univariable MR indicated four extra-large high-density lipoproteins (XL.HDL) on the causal pathway to AD: free cholesterol (XL.HDL.FC: 95% CI = 0.78 to 0.94), total lipids (XL.HDL.L: 95% CI = 0.80 to 0.97), phospholipids (XL.HDL.PL: 95% CI = 0.81 to 0.97), and concentration of XL.HDL particles (95% CI = 0.79 to 0.96), significant at an adjusted P < 0.009. MR–BMA corroborated XL.HDL.FC to be among the top three causal metabolites, in addition to total cholesterol in XL.HDL (XL.HDL.C) and glycoprotein acetyls (GP). Both XL.HDL.C and GP demonstrated suggestive univariable evidence of causality (P < 0.05), and GP successfully replicated within an independent dataset. This study offers insight into the causal relationship between metabolites demonstrating association with midlife cognition and AD. It highlights GP in addition to several XL.HDLs—particularly XL.HDL.FC—as causal candidates warranting further investigation. As AD pathology is thought to develop decades prior to symptom onset, expanding on these findings could inform risk reduction strategies.

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Physical activity and risk of Alzheimer’s disease: a two-sample Mendelian randomization study

10.1101/819821 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sebastian E Baumeister ◽

André Karch ◽

Martin Bahls ◽

Alexander Teumer ◽

Michael F Leitzmann ◽

...

Keyword(s):

Physical Activity ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Observational Studies ◽

Protective Factor ◽

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Inverse Variance

ABSTRACTIntroductionEvidence from observational studies for the effect of physical activity on the risk of Alzheimer’s disease (AD) is inconclusive. We performed Mendelian randomization analysis to examine whether physical activity is a protective factor for AD.MethodsSummary data of genome-wide association studies on physical activity and AD were identified using PubMed and the GWAS catalog. The study population included 21,982 AD cases and 41,944 cognitively normal controls. Eight single nucleotide polymorphisms (SNP) known at P < 5×10−8 to be associated with accelerometer-assessed physical activity served as instrumental variables.ResultsGenetically predicted accelerometer-assessed physical activity had no effect on the risk of AD (inverse variance weighted odds ratio [OR] per standard deviation (SD) increment: 1.03, 95% confidence interval: 0.97-1.10, P=0.332).DiscussionThe present study does not support a relationship between physical activity and risk of AD, and suggests that previous observational studies might have been biased.

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Investigating the relationships between unfavorable sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses

10.1101/2020.08.27.20173518 ◽

2020 ◽

Author(s):

Maxime M Bos ◽

Neil J Goulding ◽

Matthew A Lee ◽

Amy Hofman ◽

Mariska Bot ◽

...

Keyword(s):

Sleep Duration ◽

Mendelian Randomization ◽

Disease Risk ◽

Association Studies ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Multivariable Regression ◽

Artery Disease ◽

Insomnia Symptoms

Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods: We used AMV (N=17,370) combined with two-sample MR (N=38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (-0.08 standard deviation (SD)[95% confidence interval (CI): -0.12, -0.03] in AMV and -0.03SD [-0.07, -0.003] in MR), higher glycoprotein acetyls (0.08SD [95%CI: 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (-0.04SD [-0.08, 0.00] in AMV and -0.05SD [-0.09, -0.02] in MR) and lower phospholipids in very large HDL particles (-0.04SD [-0.08, 0.002] in AMV and -0.05SD [-0.08, -0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1-hour [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

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The relationship between cognitive function, Alzheimer's disease and sleep duration: A Mendelian randomisation study

10.1101/2020.09.08.20190611 ◽

2020 ◽

Author(s):

Antoine Salzmann ◽

Nishi Chaturvedi ◽

Victoria Garfield

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Reaction Time ◽

Cognitive Function ◽

Sleep Duration ◽

Association Studies ◽

Sensitivity Analyses ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

The Relationship

Objective: Sleep duration is associated with cognitive function and dementia. MR evidence to date, points towards a causal relationship in this direction. However, whether cognitive function or dementia may also cause problematic sleep duration remains unclear. Methods: We conducted summary-level Mendelian Randomisation (MR) analyses to estimate the causal association between general cognitive function, 'g' (177 SNPs), reaction time (44 SNPs), Alzheimer's disease (AD) (29 SNPs), and self-reported and objective sleep duration. Sensitivity analyses included: MR-Egger, Weighted median estimator and leave-one-out analyses. We used data from recently published cognitive function, AD and sleep duration genome wide association studies. Results: MR results showed that AD was associated with longer, (Beta=0.14, 95% CI=0.04;0.24), whilst 'g', and reaction time were associated with shorter (Beta=-0.06, 95% CI=-0.11;-0.01 and Beta=-0.15, 95% CI=-0.29;-0.01, respectively), objective sleep duration. No association was observed between our exposures and self-reported sleep duration. Interpretation: These results suggest a causative relationship between AD, 'g', reaction time and objective sleep duration, where AD is associated with longer sleep duration and 'g' and reaction time are associated with shorter sleep. This study furthers our understanding of the relationship between brain health and sleep duration and sheds light on the causal nature of these associations.

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