title: Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults.
abstract: Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 × 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 × 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 × 10). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases.
authors.affiliation: From the Epidemiology Branch (JD, ZX, SL, HC) and Biostatistics Branch (LN), National Institute of Environmental Health Sciences, Research Triangle Park, NC; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL (JY, RSW, LY, DAB); California Pacific Medical Center Research Institute, San Francisco, CA (GT, NP, SC); Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC (NF); Department of Human Genetics, University of Chicago, Chicago, IL (GA-A); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN (AA); Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX (MF); Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, PA (XH); Sticht Center on Aging (SK) and Division of Public Health Sciences (YL), Wake Forest School of Medicine, Winston-Salem, NC; Program in Translational Neuro Psychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital; Harvard Medical School; Program in Medical and Population Genetics, Broad Institute, Boston, MA (PLD); Laboratory of Neurogenetics (ABS) and Laboratory of Epidemiology, Demography, and Biometry (TH), National Institute on Aging, Bethesda, MD; Division of Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, MS (THM); Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL (JMP); Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA (JY, LY, DAB); and Departments of Neurological Sciences and Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA (RSW).
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
authors.forename: Jingyun
authors.initials: J
authors.lastname: Yang
authors.forename: Greg
authors.initials: G
authors.lastname: Tranah
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Neeta
authors.initials: N
authors.lastname: Parimi
authors.forename: Gorka
authors.initials: G
authors.lastname: Alkorta-Aranburu
authors.forename: Zongli
authors.initials: Z
authors.lastname: Xu
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alonso
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.forename: Xuemei
authors.initials: X
authors.lastname: Huang
authors.forename: Stephen
authors.initials: S
authors.lastname: Kritchevsky
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Stephanie
authors.initials: S
authors.lastname: London
authors.forename: Liang
authors.initials: L
authors.lastname: Niu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wilson
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Tamara
authors.initials: T
authors.lastname: Harris
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Mosley
authors.forename: Jayant M
authors.initials: JM
authors.lastname: Pinto
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Honglei
authors.initials: H
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012903:Smell / Q000235:genetics*; D014481:United States; D044465:White People