Genetically predicted body mass index and Alzheimer's disease–related phenotypes in three large samples: Mendelian randomization analyses

Investigators, Adult Changes in Thought Study; Study, Religious Orders

doi:10.1016/j.jalz.2015.05.015

Cited by 48 publications

(45 citation statements)

References 49 publications

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“…Observational evidence supports an association with adiposity and AD that varies by age [41] , so, leptin might theoretically be a mediator in the adiposity-AD pathway. However, recent Mendelian randomization analyses found no evidence of a causal association of BMI with AD [42] , and the present study found no causal association of leptin with AD, independent of BMI. Unintentional weight loss is a hallmark of AD [43] , beginning years before the onset of symptoms [44] , so measures of adiposity are expected to be confounders in observational studies examining the relationship between leptin and AD.…”

Section: Discussioncontrasting

confidence: 87%

Examining the Causal Role of Leptin in Alzheimer Disease: A Mendelian Randomization Study

Romo¹,

Schooling²

2017

Neuroendocrinology

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Background: Observational evidence regarding the role of leptin in Alzheimer disease (AD) is conflicting. We sought to determine the causal role of circulating leptin and soluble plasma leptin receptor (sOB-R) levels in AD using a separate-sample Mendelian randomization study. Methods: Single nucleotide polymorphisms (SNPs) independently and solely predictive of log-transformed leptin (rs10487505 [LEP], rs780093 [GCKR], rs900400 [CCNL1], rs6071166 [SLC32A1], and rs6738627 [COBLL1]) and of sOB-R (rs1137101 [LEPR], rs2767485 [LEPR], and rs1751492 [LEPR]) levels (ng/mL) were obtained from 2 previously reported genome-wide association studies. We obtained associations of leptin and sOB-R levels with AD using inverse variance weighting with fixed effects by combining Wald estimates for each SNP. Sensitivity analyses included using weighted median and MR-Egger methods and repeating the analyses using only SNPs of genome-wide significance. Results: Using inverse variance weighting, genetically predicted circulating leptin levels were not associated with AD, albeit with wide confidence intervals (CIs): odds ratio (OR) 0.99 per log-transformed ng/mL; 95% CI 0.55-1.78. Similarly, the association of sOB-R with AD was null using inverse variance weighting (OR 1.08 per log-transformed ng/mL; 95% CI 0.83-1.41). Results from our sensitivity analyses confirmed our findings. Conclusions: In this first Mendelian randomization study estimating the causal effect of leptin on AD, we did not find an effect of genetically predicted circulating leptin and sOB-R levels on AD. As such, this study suggests that leptin is unlikely to be a major contributor to AD, although the wide CIs preclude a definitive assessment.

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Section: Discussioncontrasting

confidence: 87%

Examining the Causal Role of Leptin in Alzheimer Disease: A Mendelian Randomization Study

Romo¹,

Schooling²

2017

Neuroendocrinology

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“…We found minimal genetic overlap between BMI and AD. Others have found strong genetic overlap between BMI and AD [53], and yet others found no casual evidence between these traits [57]. These findings suggest that the genetic relationship between AD and BMI and CAD is complex and other factors may be influencing the relationship.…”

Section: Discussionmentioning

confidence: 98%

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

et al. 2018

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Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10−9), MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10−7 and closest gene = MYBPC3, meta-p = 5.62 × 10−8). In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

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“…Unlike that study, we did not create separate polygenic risk scores from a GWAS of another phenotype, but grouped genome-wide significant predictors of T2D and associated genes into biologically functional groups that contribute to the expression of the T2D phenotype, following our prior approach with other heterogeneous phenotypes, such as body mass index. 35 The “insulin sensitivity” group in our study consists of nine SNPs presumed on the basis of physical proximity to represent genes whose functions influence insulin sensitivity. Although some of the SNPs are related to genes that were also included in Oestergard's insulin resistance polygenic score (Insulin Receptor Substrate 1 (IRS1), Peroxisome Proliferator-Activated Receptor Gamma (PPARG), they were rescaled in the current paper according to their association with T2D.…”

Section: Discussionmentioning

confidence: 99%

Diabetic Phenotypes and Late-Life Dementia Risk

Walter

Marden

Kubzansky

et al. 2016

Alzheimer Disease &Amp; Associated Disorders

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Background Mendelian Randomization (MR) studies have reported that type 2 diabetes (T2D) was not associated with Alzheimer's Disease (AD). We adopted a modified, mechanism-specific MR design to explore this surprising result. Methods Using inverse-variance weighted MR analysis, we evaluated the association between T2D and AD using data from 39 single nucleotide polymorphisms (SNPs) significantly associated to T2D in DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the corresponding associations of each SNP with AD risk obtained from the International Genomics of Alzheimer's Project (IGAP, n=17,008 AD cases and n=37,154 controls). We evaluated mechanism-specific genetic subscores, including beta-cell function, insulin sensitivity, and adiposity, and repeated analyses in 8,501 Health and Retirement Study (HRS) participants for replication and model validation. Results In IGAP, the overall T2D polygenic score did not predict AD (odds ratio (OR) for the T2D polygenic score = 1.01, 95% confidence interval (CI): 0.96, 1.06) but the insulin sensitivity polygenic score predicted higher AD risk (OR=1.17, CI: 1.02, 1.34). In HRS, polygenic scores were associated with T2D risk; the associations between insulin sensitivity genetic polygenic score and cognitive phenotypes were not statistically significant. Conclusion Evidence from polygenic scores suggests insulin sensitivity specifically may affect AD risk, more than T2D overall.

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Genetically predicted body mass index and Alzheimer's disease–related phenotypes in three large samples: Mendelian randomization analyses

Cited by 48 publications

References 49 publications

Examining the Causal Role of Leptin in Alzheimer Disease: A Mendelian Randomization Study

Examining the Causal Role of Leptin in Alzheimer Disease: A Mendelian Randomization Study

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Diabetic Phenotypes and Late-Life Dementia Risk

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