Genome-wide association meta-analysis of human olfactory identification discovers sex-specific and sex-differential genetic variants

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 o...

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Published in:	Nature communications Vol. 16; no. 1; pp. 5434 - 15
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01.07.2025 Nature Publishing Group Nature Portfolio
Subjects:	45/43 631/208/205/2138 692/4017 Alzheimer Disease - genetics Alzheimer's disease Amygdala Chemosensory perception Clusters Disease Female Females Genes Genetic diversity Genetic variance Genetic Variation Genetics Genome-Wide Association Study Genomes Genomic analysis Health risks Hormones Humanities and Social Sciences Humans Identification Male Males Mendelian Randomization Analysis Meta-analysis multidisciplinary Neurodegenerative diseases Odorant receptors Odorants - analysis Odors Olfactory discrimination Olfactory perception Olfactory Perception - genetics Parkinson's disease Perception Polymorphism, Single Nucleotide Receptor density Receptors Receptors, Odorant - genetics Regulatory sequences Science Science (multidisciplinary) Sex Characteristics Sex hormones Sexual dimorphism Smell - genetics White People - genetics
ISSN:	2041-1723, 2041-1723
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Abstract	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 −8 ) 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 − 9 ). 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. Olfactory perception shows marked sexual dimorphism, yet its genetic basis remains underexplored. Here, the authors show sex-specific and shared genetic loci for odour identification, implicating olfactory receptor clusters and links to Alzheimer’s disease risk.
AbstractList	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 × 10−8) involving five odours. Seven of these loci, including four novel ones, are also significant using a stricter study-wide significance threshold (p < 3.85 × 10−9). 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.Olfactory perception shows marked sexual dimorphism, yet its genetic basis remains underexplored. Here, the authors show sex-specific and shared genetic loci for odour identification, implicating olfactory receptor clusters and links to Alzheimer’s disease risk. 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 × 10-8) involving five odours. Seven of these loci, including four novel ones, are also significant using a stricter study-wide significance threshold (p < 3.85 × 10-9). 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.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 × 10-8) involving five odours. Seven of these loci, including four novel ones, are also significant using a stricter study-wide significance threshold (p < 3.85 × 10-9). 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. 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 −8 ) 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 − 9 ). 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. Abstract 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 × 10−8) 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− 9). 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. 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. 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 −8 ) 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 − 9 ). 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. Olfactory perception shows marked sexual dimorphism, yet its genetic basis remains underexplored. Here, the authors show sex-specific and shared genetic loci for odour identification, implicating olfactory receptor clusters and links to Alzheimer’s disease risk.
ArticleNumber	5434
Author	Melas, Konstantinos Talevi, Valentina Aziz, N. Ahmad Engel, Christoph Pramstaller, Peter Shrestha, Srishti Scholz, Markus Frasnelli, Johannes Breteler, Monique M. B. Horn, Katrin Förster, Franz Gögele, Martin Pott, Janne Mosley, Thomas H. Filosi, Michele Löffler, Markus Wirkner, Kerstin Pattaro, Cristian Emmert, David Fornage, Myriam Imtiaz, Mohammed Aslam Chen, Honglei Fuchsberger, Christian
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Ahmad orcidid: 0000-0001-6184-458X surname: Aziz fullname: Aziz, N. Ahmad organization: German Centre for Neurodegenerative Diseases (DZNE), Population Health Sciences, Department of Neurology, Faculty of Medicine, University of Bonn – sequence: 20 givenname: Monique M. B. orcidid: 0000-0002-0626-9305 surname: Breteler fullname: Breteler, Monique M. 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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/40593737$$D View this record in MEDLINE/PubMed
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Snippet	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... Abstract Smelling is a human sense, expressing strong sexual dimorphisms. We aim to improve the knowledge of the genetics of human olfactory perception by...
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SubjectTerms	45/43 631/208/205/2138 692/4017 Alzheimer Disease - genetics Alzheimer's disease Amygdala Chemosensory perception Clusters Disease Female Females Genes Genetic diversity Genetic variance Genetic Variation Genetics Genome-Wide Association Study Genomes Genomic analysis Health risks Hormones Humanities and Social Sciences Humans Identification Male Males Mendelian Randomization Analysis Meta-analysis multidisciplinary Neurodegenerative diseases Odorant receptors Odorants - analysis Odors Olfactory discrimination Olfactory perception Olfactory Perception - genetics Parkinson's disease Perception Polymorphism, Single Nucleotide Receptor density Receptors Receptors, Odorant - genetics Regulatory sequences Science Science (multidisciplinary) Sex Characteristics Sex hormones Sexual dimorphism Smell - genetics White People - genetics
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Title	Genome-wide association meta-analysis of human olfactory identification discovers sex-specific and sex-differential genetic variants
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