Genetic Variants in the Fat and Obesity Associated (FTO) Gene and Risk of Alzheimer's Disease

The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
PLoS ONE (Impact Factor: 3.23). 12/2012; 7(12):e50354. DOI: 10.1371/journal.pone.0050354
Source: PubMed


Recent studies showed that polymorphisms in the Fat and Obesity-Associated (FTO) gene have robust effects on obesity, obesity-related traits and endophenotypes associated with Alzheimer's disease (AD).

We used 1,877 Caucasian cases and controls from the NIA-LOAD study and 1,093 Caribbean Hispanics to further explore the association of FTO with AD. Using logistic regression, we assessed 42 SNPs in introns 1 and 2, the region previously reported to be associated with AD endophenotypes, which had been derived by genome-wide screenings. In addition, we performed gene expression analyses of neuropathologically confirmed AD cases and controls of two independent datasets (19 AD cases, 10 controls; 176 AD cases, 188 controls) using within- and between-group factors ANOVA of log10 transformed rank invariant normalized expression data.

In the NIALOAD study, one SNP was significantly associated with AD and three additional markers were close to significance (rs6499640, rs10852521, rs16945088, rs8044769, FDR p-value: 0.05<p<0.09). Two of the SNPs are in strong LD (D′>0.9) with the previously reported SNPs. In the Caribbean Hispanic dataset, we identified three SNPs (rs17219084, rs11075996, rs11075997, FDR p-value: 0.009<p<0.01) that were associated with AD. These results were confirmed by haplotype analyses and in a metaanalysis in which we included the ADNI dataset. FTO had a significantly lower expresssion in AD cases compared to controls in two independent datasets derived from human cortex and amygdala tissue, respectively (p = 2.18×10−5 and p<0.0001).

Our data support the notion that genetic variation in Introns 1 and 2 of the FTO gene may contribute to AD risk.

Download full-text


Available from: Christiane Reitz, Jul 01, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Late-onset Alzheimer's disease (LOAD), which is characterized by progressive deterioration in cognition, function, and behavior, is the most common cause of dementia and the sixth leading cause of all deaths, placing a considerable burden on Western societies. Most studies aiming to identify genetic susceptibility factors for LOAD have focused on non-Hispanic white populations. This is, in part related to differences in linkage disequilibrium and allele frequencies between ethnic groups that could lead to confounding. However, in addition, non-Hispanic white populations are simply more widely studied. As a consequence, minorities are genetically underrepresented despite the fact that in several minority populations living in the same community as whites (including African American and Caribbean Hispanics), LOAD incidence is higher. This review summarizes the current knowledge on genetic risk factors associated with LOAD risk in Caribbean Hispanics and African Americans and provides suggestions for future research. We focus on Caribbean Hispanics and African Americans because they have a high LOAD incidence and a body of genetic studies on LOAD that is based on samples with genome-wide association studies data and reasonably large effect sizes to yield generalizable results.
    Biological psychiatry 07/2013; 75(7). DOI:10.1016/j.biopsych.2013.06.003 · 10.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies have revealed that single-nucleotide polymorphisms in the first intron of the gene encoding fat mass and obesity-associated protein (FTO) are robustly associated with BMI and obesity. Subsequently, this association with body weight, which is replicable across multiple populations and different age groups, has been unequivocally linked to increased food intake. Although evidence from a number of animal models with perturbed FTO expression indicates a role for FTO in energy homeostasis, to date, no conclusive link has been made between the risk alleles and FTO expression or its physiological role. FTO is a nucleic acid demethylase, and a deficiency in FTO leads to a complex phenotype highlighted by postnatal growth retardation, pointing to some fundamental developmental role. Recent emerging data now points to a role for FTO in the sensing of nutrients and the regulation of translation and growth. In this review, we explore the in vivo and in vitro evidence detailing the complex biology of FTO and discuss how these might link to the regulation of body weight.
    Diabetologia 07/2013; 56(10). DOI:10.1007/s00125-013-2999-5 · 6.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Though a great deal is known of the pathophysiology of phenylketonuria (PKU), Parkinson's disease (PD) and Alzheimer's disease (AD) very little is known regarding possible chemical species responsible for initiating the cascade of events that ultimately cause cognitive dysfunction. Can these be viewed as inborn errors in metabolism, occurring at various stages in the life cycle, analogous to adult onset diabetes? One major deficiency in understanding such conditions is the paucity of information regarding the total metabolic pathway for various amino acids that may be implicated in their causation. For example in PKU, its etiology was reported in 1934 and dietary restriction of phenylalanine proved effective for individuals with unsatisfactory metabolism of phenylalanine. Yet, current phenylalanine metabolism does not take into account fully the multiple biochemical pathways operating whose role is preventing burdensome accumulations of intermediates that can contribute to morbidity and toxicity. The same may apply for metabolism of tyrosine in PD and methionine in AD. Especially important, are the presence of labile and reactive chemical species which may be causative agents in protein alteration, misfolding and the creation of prions in neurodegenerative diseases, thereby preventing normal protein catabolism and excretion. Though genetic or epigenetic factors must be responsible, the question remains how are these translated into the chemical structures responsible for disease initiation? The purpose of this presentation is to explore potential labile metabolites in those biochemical pathways, which may be contributing factors. Finally it is worth noting, that drug development has been increasingly designed based upon targeting genetic deficiencies. The effectiveness of this approach for the treatment of these neurodegenerative illnesses will be determined in the future.
    Medical Hypotheses 08/2013; 81(4). DOI:10.1016/j.mehy.2013.07.028 · 1.07 Impact Factor
Show more