Abstract
IMPORTANCE
Olfactory dysfunction is among the earliest signs of many age-related neurodegenerative
diseases and has been associated with increased mortality in older adults; however, its genetic
basis remains largely unknown.
OBJECTIVE
To identify the genetic loci associated with olfactory dysfunction in the general population.
DESIGN, SETTING AND PARTIICIPANTS
This genome-wide association study meta-analysis (GWMA) included participants of
European ancestry (N = 22,730) enrolled in four different large population-based studies,
followed by a multi-ancestry GWMA including participants of African ancestry (N = 1,030).
The data analysis was performed from March 2023 through June 2024.
EXPOSURES
Genome-wide single nucleotide polymorphisms.
MAIN OUTCOMES AND MEASURES
Olfactory dysfunction was the outcome and assessed using a 12-item smell identification test.
RESULTS
GWMA revealed a novel genome-wide significant locus (tagged by rs11228623 at 11q12)
associated with olfactory dysfunction. Gene-based analysis revealed a high enrichment for
olfactory receptor genes in this region. Phenome-wide association studies demonstrated
associations between genetic variants related to olfactory dysfunction and blood cell counts,
kidney function, skeletal muscle mass, cholesterol levels and cardiovascular disease. Using
individual-level data, we also confirmed and quantified the strength of these associations on a
phenotypic level. Moreover, employing two-sample Mendelian Randomization analyses, we
found evidence for causal associations between olfactory dysfunction and these phenotypes.
It is made available under a CC-BY-NC-ND 4.0 International license .
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
medRxiv preprint doi: https://doi.org/10.1101/2024.08.09.24311665; this version posted August 10, 2024. The copyright holder for this preprint
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CONCLUSIONS
These findings provide novel insights into the genetic architecture of the sense of smell and
highlight its importance for many aspects of human health.