Förster Franz, Emmert David, Horn Katrin, Pott Janne, Frasnelli Johannes, Imtiaz Mohammed Aslam, Melas Konstantinos, Talevi Valentina, Chen Honglei, Engel Christoph, Filosi Michele, Fornage Myriam, Gögele Martin, Löffler Markus, Mosley Thomas H, Pattaro Cristian, Pramstaller Peter, Shrestha Srishti, Aziz N Ahmad, Breteler Monique M B, Wirkner Kerstin, Scholz Markus, Fuchsberger Christian
Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Medical Faculty, Leipzig University, Leipzig, Germany.
Institute of Molecular Biology gGmbH (IMB), Mainz, Germany.
Nat Commun. 2025 Jul 1;16(1):5434. doi: 10.1038/s41467-025-61330-y.
Smelling is a human sense, expressing strong sexual dimorphisms. We aim to improve the knowledge of the genetics of human olfactory perception by performing an exploratory genome-wide association meta-analysis of up to 21,495 individuals of European ancestry. By sex-stratified and overall analysis of the identification of twelve odours and an identification score, we discovered ten independent loci, seven of them novel, with trait-wise genome-wide significance (p < 5 × 10) involving five odours. Seven of these loci, including four novel ones, are also significant using a stricter study-wide significance threshold (p < 3.85 × 10). Loci were predominantly located within clusters of olfactory receptors. Two loci were female-specific while one was sex-differential with respective candidate genes containing androgen response elements. Two-sample Mendelian randomization was applied to search for causal relationships between sex hormones, odour identification and neurodegenerative diseases. A causal negative effect was detected for Alzheimer's disease on the identification score. These findings deepen our understanding of the genetic basis of olfactory perception and its interaction with sex, prioritizing mechanisms for further molecular research.
嗅觉是一种人类感官，表现出强烈的性别二态性。我们旨在通过对多达21495名欧洲血统个体进行探索性全基因组关联荟萃分析，来增进对人类嗅觉感知遗传学的认识。通过对12种气味的识别和一个识别分数进行性别分层及总体分析，我们发现了10个独立位点，其中7个是新发现的，在性状层面具有全基因组显著性（p < 5 × 10），涉及5种气味。使用更严格的全研究显著性阈值（p < 3.85 × 10）时，这些位点中的7个，包括4个新位点，也具有显著性。位点主要位于嗅觉受体簇内。两个位点是女性特有的，而一个是性别差异的，各自的候选基因含有雄激素反应元件。应用两样本孟德尔随机化来寻找性激素、气味识别和神经退行性疾病之间的因果关系。检测到阿尔茨海默病对识别分数有因果负效应。这些发现加深了我们对嗅觉感知遗传基础及其与性别的相互作用的理解，为进一步的分子研究确定了优先机制。
