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

PLoS One. 2012;7(12):e50354. doi: 10.1371/journal.pone.0050354. Epub 2012 Dec 12.

Abstract

Background: 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).

Methods: 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 log(10) transformed rank invariant normalized expression data.

Results: 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).

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alleles
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Alzheimer Disease / genetics*
  • Case-Control Studies
  • Endophenotypes
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotype
  • Hispanic or Latino / genetics
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Proteins / genetics*
  • Whites / genetics

Substances

  • Proteins
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human