Elsevier

Neurobiology of Aging

Volume 89, May 2020, Pages 142.e9-142.e12
Neurobiology of Aging

Genetic reports abstract
Negative results
Failure to detect synergy between variants in transferrin and hemochromatosis and Alzheimer's disease in large cohort

https://doi.org/10.1016/j.neurobiolaging.2020.01.013Get rights and content

Abstract

Alzheimer's disease (AD) is the most common cause of dementia and, despite decades of effort, there is no effective treatment. In the last decade, many association studies have identified genetic markers that are associated with AD status. Two of these studies suggest that an epistatic interaction between variants rs1049296 in the transferrin (TF) gene and rs1800562 in the homeostatic iron regulator (HFE) gene, commonly known as hemochromatosis, is in genetic association with AD. TF and HFE are involved in the transport and regulation of iron in the brain, and disrupting these processes exacerbates AD pathology through increased neurodegeneration and oxidative stress. However, by using a significantly larger data set from the Alzheimer's Disease Genetics Consortium, we fail to detect an association between TF rs1049296 or HFE rs1800562 with AD risk (TF rs1049296 p = 0.38 and HFE rs1800562 p = 0.40). In addition, logistic regression with an interaction term and a synergy factor analysis both failed to detect epistasis between TF rs1049296 and HFE rs1800562 (SF = 0.94; p = 0.48) in AD cases. Each of these analyses had sufficient statistical power (power > 0.99), suggesting that previously reported associations may be the result of more complex epistatic interactions, genetic heterogeneity, or false-positive associations because of limited sample sizes.

Introduction

Alzheimer's disease (AD) is the most common cause of dementia and inflicts an estimated 24 to 35 million people worldwide, with incidences predicted to increase dramatically as the population ages (Alzheimer's Association, 2018). Although decades of research have been spent investigating the causes and architecture of this neurodegenerative disease, it still inflicts an estimated 5.7 million people in the United States alone. This number is projected to increase to 13.8 million by mid-century (Alzheimer's Association, 2018). Association studies have accurately identified single-nucleotide polymorphisms (SNPs) associated with AD (Harold et al., 2009, Hollingworth et al., 2011, Lambert et al., 2009, Lambert et al., 2013, Seshadri et al., 2010, Shen et al., 2015, Shuai et al., 2015, Yan et al., 2015). However, these genetic loci account for only a fraction of AD heritability (Ridge, Mukherjee, Crane, Kauwe, & Alzheimer's Disease Genetics, 2013), suggesting that much of the unexplained genetics affecting AD etiology may be due to epistasis (Bullock et al., 2013, Combarros et al., 2009, Ebbert et al., 2014, Infante et al., 2004). Epistasis occurs when multiple genes interact to create a single phenotype (Cordell, 2002). These kinds of synergetic relationships play a critical role in the etiology of complex diseases, yet remain vastly understudied in AD pathology (Alzheimer's Association, 2018, Ebbert et al., 2015, Raghavan and Tosto, 2017).

The transferrin (TF) gene and the homeostatic iron regulator (HFE) gene, commonly known as hemochromatosis, have been reported to show epistasis and play a role in the development of AD (Robson et al., 2004, Tisato et al., 2018). TFs are a group of nonheme iron-binding glycoproteins found in fluids and cells of vertebrates. The main role of TF is to maintain iron homeostasis in the body (Gkouvatsos et al., 2012). In the brain, TF interacts with the amyloid precursor protein (Belaidi et al., 2018) and tau (Jahshan et al., 2016), 2 of the major protein families implicated in AD pathology. Because iron is essential for oxygen transport, its misregulation in the brain can lead to oxidative stress and neurodegeneration (Dias et al., 2013, Matak et al., 2016, Yarjanli et al., 2017). HFE encodes for a transmembrane glycoprotein that binds to a TF receptor, subsequently regulating iron in the cell (Bennett et al., 2000, Feder et al., 1996, Lebron et al., 1998). Mutations in HFE are associated with neurodegenerative diseases through increasing neuroinflammation and production of free radicals in the brain (Andersen et al., 2014, Lull and Block, 2010). In addition, other studies suggest that TF and HFE are involved in the transport and regulation of iron in the brain, and disrupting these processes potentially affects AD pathology through increased neurodegeneration and oxidative stress (Ali-Rahmani et al., 2014, Lehmann et al., 2006).

Robson et al. (2004) suggested that epistasis between TF variant rs1049296 and HFE variant rs1800562 is associated with AD. Although neither SNP alone was a risk factor for AD, the presence of both alleles resulted in a 5 times greater risk of developing AD (Robson et al., 2004). Because the sample size for that study was relatively small (191 cases and 269 controls), a replication of these findings on a slightly larger data set (1161 cases and 1342 controls) was conducted. A logistic regression analysis and a synergy factor analysis (SFA) corroborated a significant association with AD risk among bi-allelic carriers of rs1049296 and rs1800562 (synergy factor= 2.71; p = 0.0016) (Kauwe et al., 2010).

Our study expands on these previous studies and attempts to detect statistical epistasis between TF rs1049296 and HFE rs1800562 with respect to AD risk using 25,666 individuals (12,532 cases and 13,134 controls) from the Alzheimer's Disease Genetic Consortium (ADGC), which is an expansion of the data set used by Kauwe et al. (2010).

Section snippets

Data set and filtering

Our analysis started with genetic data from all 28,730 individuals in the Alzheimer's Disease Genetics Consortium (ADGC) data set as described by Naj et al. (2011). ADGC is a collection of 30 merged data sets spanning 1984 to 2012, and was established to help identify genetic markers of late onset AD (Boehme et al. 2014) (see Supplementary Table 1 for ADGC demographics). ADGC imputed the 30 data sets to the Haplotype Reference Consortium reference panel, which includes 64,976 haplotypes and

Results

The nonparametric logistic regression analysis using ADGC as one cohort demonstrated that when testing the main effects, neither TF rs1049296 nor HFE rs1800562 was associated with AD risk (TF rs1049296 p = 0.38; HFE rs1800562 p = 0.40). The logistic regression analyses including an interaction term for the 2 variants also failed to show significant association (p = 0.23). Similarly, the SFA analysis did not find epistasis between TF rs1049296 and HFE rs1800562 (SF = 0.94; p = 0.48).

We performed

Discussion

We failed to detect evidence that epistasis between TF rs1049296 and HFE rs1800562 increases risk for AD in the ADGC data set. These findings do not support the conclusions drawn in the previous reports by Robson et al. (2004) and Kauwe et al. (2010). The cause for this variability among studies could be a result of genetic heterogeneity, the complex nature of epistasis, or false positives in these previous studies due to limited sample size.

Although recent literature suggests that much of the

Disclosure statement

None.

Acknowledgements

This work was supported by the National Institutes of Health, National Institute on Aging (USA) grant numbers R01AG042611 and RF1AG054052. Data was supported by the ADGC. ADGC grants: ADGC U01AG032984, NIAGADS U24AG041689, NCRAD U24AG21886, and NACC U01AG016976. Acknowledgements for ADGC support can be found here: http://www.adgenetics.org/content/acknowledgements.

Authors' contributions: EV contributed to conceptualization, methodology, formal analysis, writing—original draft, writing—review

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