Objective: To determine whether 4 genetic variants in the fat mass and obesity associated gene (FTO) identified in genome-wide association studies of diabetes and obesity are associated with cognitive change in midlife in the Atherosclerosis Risk in Communities (ARIC) Study. Methods: ARIC is a prospective cohort study of the development of atherosclerosis in 15,792 individuals aged 45 to 64 years at baseline from 1986 to 1989. FTO is highly expressed in human fetal and adult brain, and a single nucleotide polymorphism in FTO has previously been associated with reduced brain volume in cognitively normal subjects. Since a relationship between brain atrophy and diminished cognitive function has been demonstrated in ARIC participants, general linear models were used to evaluate the association between 6-year change in scores on 3 neuropsychological tests and FTO genotype. Results: In a sample of 8,364 white and 2,083 African American men and women with no clinical history of stroke, significantly greater mean change in performance on the DelayedWord Recall Test was associated with 2 of 4 FTO single nucleotide polymorphisms examined (rs9939609, rs805136, rs17817449, and rs1421085) in whites but not in African Americans (p ≤ 0.002). The association of the FTO polymorphismswith cognitive change was independent of potential confounding clinical and demographic variables including age, gender, education, diabetes, hypertension, and body mass index. Conclusions: Further studies will be needed to clarify the biological mechanisms and genetic pathways through which variants in FTO can increase susceptibility to decline in verbal memory detectable in middle-aged, community-dwelling adults.
Bibliographical noteFunding Information:
The Atherosclerosis Risk in Communities Study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C) .
J. Bressler and M. Fornage receive research support from the NIH. E. Demerath received an honorarium for speaking at the Pennington Biomedical Research Center; is an investigator of a study sponsored by COSMED, Inc.; and receives research support from the NIH. D.S. Knopman serves as Deputy Editor for Neurology®; serves on a Data Safety Monitoring Board for Lilly Pharmaceuticals; is an investigator in clinical trials sponsored by Baxter, Elan Pharmaceuticals, and Forest Pharmaceuticals; and receives research support from the NIH. K. Monda received travel expenses from Amgen Inc. to attend a conference and is currently employed by Amgen Inc. K. North receives research support from the NIH. A. Penman receives research support from Pfizer Inc., the NIH, and from Friends of the Massachusetts Eye and Ear Infirmary. T. Mosley and E. Boerwinkle receive research support from the NIH. Go to Neurology.org for full disclosures.