Genetic variants in the Fat and Obesity Associated (FTO) gene and risk of Alzheimer's disease.

Christiane Reitz,Jose A Luchsinger,Giuseppe Tosto,Richard Mayeux,Steven Estus

doi:10.1371/journal.pone.0050354

Abstract

BackgroundRecent 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).MethodsWe 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.ResultsIn 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).ConclusionsOur data support the notion that genetic variation in Introns 1 and 2 of the FTO gene may contribute to AD risk.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60–80% of cases [1]
Measures of central obesity, waist to hip ratio (WHR), seem to be better predictors of cardiovascular outcomes compared with body mass index (BMI) [11], and central obesity in middle age is related to a higher risk of dementia
For the analyses described in this study, we focused on the single nucleotide polymorphisms (SNPs) in Intron1, Exon 2 and Intron 2, ie. all SNPs in the regions previously reported to be associated with obesity measures, diabetes, brain volume and verbal fluency

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60–80% of cases [1]. As delaying symptom onset by as little as 1 year could potentially lower AD prevalence by more than 9 million cases over the 40 years [1], there has been growing interest in identification of preventive measures. While for diabetes the association with AD seems clear [3,4], the association for most other cardiovascular risk factors, including obesity, remains largely inconsistent across studies. Measures of central obesity, waist to hip ratio (WHR), seem to be better predictors of cardiovascular outcomes compared with BMI [11], and central obesity in middle age is related to a higher risk of dementia. 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)

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