The FAS gene, brain volume, and disease progression in Alzheimer's disease

Abstract

OBJECTIVE To identify single nucleotide polymorphisms (SNPs) that are associated with Alzheimer’s disease (AD) progression and brain volume. METHODS Ninety-seven SNPs were genotyped in 243 subjects from a longitudinal study of healthy aging. Subjects who carried a diagnosis of cognitive impairment (CI) at any study visit (prior to their last visit) and had DNA in the study DNA bank were included. AD progression was defined as the duration from onset of CI to diagnosis of AD. Association of each of the 97 SNPs with AD progression was tested via Cox model. SNPs meeting a nominal significance criterion (p < 0.05) for association with AD progression were reassessed to account for multiple testing by repeating the marker selection process in 10,000 random permutations. Next, the association between the one SNP that survived the multiple-testing adjustment and brain volume was determined by multiple regression analysis in a subgroup of subjects for whom MRI derived brain volume data were available. Brain volumes were adjusted for age at MRI, gender and time from MRI to onset of CI. RESULTS The minor allele of rs1468063 in FAS, member 6 of the tumor necrosis factor receptor superfamily, was significantly associated with faster AD progression after adjustment for multiple testing (Ppermutation=0.049). The same allele in rs1468063 was associated with smaller brain, and larger ventricular volumes (p = 0.02 and 0.04 respectively) CONCLUSION FAS, which plays a role in apoptosis, may be associated with AD by modulating apoptosis and neuronal loss secondary to AD neuropathology.

Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

“…Some of these genes were previously reported as susceptible loci for brain or neuro-related traits. For instance, FAS gene was reported to be associated with neurotic degeneration in brain volume of Alzheimer’s patients (Erten-Lyons et al, 2009). STAMBPL1 g ene regulates Tax trafficking and NF-κB activation in neuroinflammation process (Lavorgna and Harhaj, 2012).…”

Neuropathologic Basis of Age-Associated Brain Atrophy

“…There likely are other factors not measured in this study that may be mediating the degree of brain atrophy in the presence of similar neuropathologic burden. For example, functional polymorphisms in genes in the apoptotic pathway or environmental influences on neurotrophins may mediate the degree of cell loss and in turn brain atrophy in the context of AD neuropathology 34,35 . Alternatively, timing of the MRI observations in relation to cognitive evaluations may have contributed to this observation.…”

Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder

“…28 The FAS gene, which plays a role in apoptosis, may be associated with Alzheimer disease by modulating the apoptosis and neuronal loss secondary to Alzheimer disease neuropathology. 29 However, no significant differences in allelic and genotypic distributions were found between cases and controls, or patients with late-and early-onset Alzheimer disease, thus suggesting that these polymorphisms did not represent a risk factor for Alzheimer disease in the Italian population. 30 Furthermore, PDLIM1 at position 10q22 might play a role in Alzheimer disease, 31,32 serving as a scaffold to form a multiprotein complex that regulates actin cytoskeleton dynamics and playing a role in controlling neurite outgrowth.…”