Genome-Wide Association Study Meta-Analysis Uncovers Novel Genetic Variants Associated with Olfactory Dysfunction.

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.

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.