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Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

71669
10.1038/s41598-024-71669-9
Article
Genomic study of taste perception genes in African Americans reveals SNPs linked to Alzheimer’s disease
Joseph Paule Valery 1
Abbas Malak 2
Goodney Gabriel 2
Diallo Ana 3
Gaye Amadou amadou.gaye@mmc.edu

4
1 grid.420085.b 0000 0004 0481 4802 Sensory Science and Metabolism Unit, Biobehavioral Branch, National Institute On Alcohol Abuse and Alcoholism, National Institue of Nursing Research, National Institutes of Health, Bethesda, MD USA
2 grid.280128.1 0000 0001 2233 9230 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA
3 https://ror.org/02nkdxk79 grid.224260.0 0000 0004 0458 8737 Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University, Richmond, VA USA
4 https://ror.org/00k63dq23 grid.259870.1 0000 0001 0286 752X Department of Integrative Genomics and Epidemiology, School of Graduate Studies, Meharry Medical College, Nashville, TN USA
16 9 2024
16 9 2024
2024
14 215605 3 2024
29 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
While previous research has shown the potential links between taste perception pathways and brain-related conditions, the area involving Alzheimer’s disease remains incompletely understood. Taste perception involves neurotransmitter signaling, including serotonin, glutamate, and dopamine. Disruptions in these pathways are implicated in neurodegenerative diseases. The integration of olfactory and taste signals in flavor perception may impact brain health, evident in olfactory dysfunction as an early symptom in neurodegenerative conditions. Shared immune response and inflammatory pathways may contribute to the association between altered taste perception and conditions like neurodegeneration, present in Alzheimer’s disease. This study consists of an exploration of expression-quantitative trait loci (eQTL), utilizing whole-blood transcriptome profiles, of 28 taste perception genes, from a combined cohort of 475 African American subjects. This comprehensive dataset was subsequently intersected with single-nucleotide polymorphisms (SNPs) identified in Genome-Wide Association Studies (GWAS) of Alzheimer’s Disease (AD). Finally, the investigation delved into assessing the association between eQTLs reported in GWAS of AD and the profiles of 741 proteins from the Olink Neurological Panel. The eQTL analysis unveiled 3,547 statistically significant SNP-Gene associations, involving 412 distinct SNPs that spanned all 28 taste genes. In 17 GWAS studies encompassing various traits, a total of 14 SNPs associated with 12 genes were identified, with three SNPs consistently linked to Alzheimer’s disease across four GWAS studies. All three SNPs demonstrated significant associations with the down-regulation of TAS2R41, and two of them were additionally associated with the down-regulation of TAS2R60. In the subsequent pQTL analysis, two of the SNPs linked to TAS2R41 and TAS2R60 genes (rs117771145 and rs10228407) were correlated with the upregulation of two proteins, namely EPHB6 and ADGRB3. Our investigation introduces a new perspective to the understanding of Alzheimer's disease, emphasizing the significance of bitter taste receptor genes in its pathogenesis. These discoveries set the stage for subsequent research to delve into these receptors as promising avenues for both intervention and diagnosis. Nevertheless, the translation of these genetic insights into clinical practice requires a more profound understanding of the implicated pathways and their pertinence to the disease's progression across diverse populations.

Keywords

Taste genes
GWAS
Transcriptome
Proteome
Alzheimer’s disease
African American
Subject terms

Genetics
Gene expression
Gene regulation
Genetic association study
Genome
Genomics
Neurodegenerative diseases
Alzheimer's disease
National Institute on Alcohol Abuse and Alcoholism, United Stateshttp://dx.doi.org/10.13039/100000051 National Human Genome Research Institute Virginia Commonwealth University, United StatesNational Institutes of Health (NIH)Open access funding provided by the National Institutes of Health

issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Taste perception is a complex sensory phenomenon that involves the detection and interpretation of various chemical stimuli by specialized receptors located on the tongue and oral cavity1. The human sense of taste, or gustation, is primarily categorized into five modalities: sweet, salty, sour, bitter, and umami. The intricate interplay between taste perception and the brain constitutes a process, integrating peripheral sensory signals with central neural processing. Neuroimaging studies, such as functional magnetic resonance imaging and positron emission tomography, have provided valuable insights into the neural mechanisms underlying taste perception2,3. These studies reveal the involvement of various brain regions in different aspects of taste processing, highlighting the distributed nature of the taste neural network.

There is evidence to suggest potential links between taste perception pathways and brain-related conditions4,5; however, the connections are still not fully understood. For instance, taste perception involves neurotransmitter signaling in the gustatory system, particularly through molecules such as serotonin, glutamate, and dopamine6. Disruptions in these neurotransmitter systems have been implicated in mood disorders, schizophrenia, and neurodegenerative diseases7,8. The integration of olfactory and taste signals in flavor perception may have implications for brain health. For example, olfactory dysfunction is a common early symptom in neurodegenerative conditions like Alzheimer's and Parkinson's diseases9. Futhermore, inflammation plays a role in both alterations in taste perception and neuroinflammatory conditions. Shared pathways involving immune response and inflammatory mediators may contribute to the link between altered taste perception and conditions like depression and neurodegeneration10,11.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that significantly impacts cognitive function and daily living activities. As the most common cause of dementia, AD is characterized by the accumulation of amyloid-beta plaques and tau tangles, leading to neuronal loss and a decline in cognitive abilities12. Alongside these well-documented features, AD is increasingly associated with sensory dysfunctions, including alterations in taste and smell perception9,13. These sensory changes are not just secondary symptoms but are thought to be integral to the disease process, potentially serving as early indicators of neurodegeneration9.

Taste alterations in individuals with Alzheimer's diseases have been documented in various studies13–15. Individuals with AD often experience changes in food preferences, decreased taste sensitivity or increase taste preference for sweet and salty tastes, and sometimes a complete loss of taste perception. These alterations can lead to nutritional imbalances and affect the quality of life and overall health16. The underlying mechanisms are believed to involve both central and peripheral pathways, including changes in taste bud integrity, central processing of taste information and taste receptor expression.

Genetic factors influencing taste receptor expression may have broader implications for many diseases including brain conditions17–20. Polymorphisms in taste receptor genes loci may contribute to variations in gene expression and protein levels that could be associated with neurodenerative conditions such as Alzheimer’s disease (AD)21. Functional genomics approaches, leveraging transcriptomics and proteomics can serve as valuable supplements to genetic inquiries and offer perspectives into the molecular mechanisms that link polymorphisms associated with taste perception to brain diseases. Such strategies can help decipher the complex biological pathways linked to the initiation and advancement of those diseases.

Notably, AD and associated sensory dysfunctions may vary significantly across different populations, influenced by a complex interplay of genetic, environmental, and social factors. African Americans are disproportionately affected by AD, experiencing higher incidence rates and more severe cognitive deterioration compared to other racial groups22,23. These disparities are not fully understood and are attributed to factors including genetic predisposition, health comorbidities, socioeconomic status, and access to healthcare. Understanding the specific genetic and molecular basis of taste alterations in an African American cohort can provide insights into the unique progression of AD in this population and highlight potential areas for targeted intervention and care. The objectives of this project are twofold: (1) identify expression-quantitative trait loci (eQTL) impacting the expression of taste-related genes that have been reported in genome-wide association studies (GWAS) of brain conditions, and (2) evaluate the connections between these variants and proteins involved in neurological processes relevant to neurodegenerative conditions and specifically AD.

Material and methods

Phenotype data

The GENomics, Environmental FactORs and the Social DEterminants of Cardiovascular Disease in African-Americans STudy (GENE-FORECAST) is a research platform that establishes a strategic, multi-omics systems biology approach amenable to the deep, multi-dimensional characterization of minority health and disease in AA (African American). GENE-FORECAST is designed to create a cohort based on a community-based sampling frame of U.S.- born, AA men and women (ages 21–65) recruited from the metropolitan Washington D.C. area.

The Minority Health Genomics and Translational Research Bio-Repository Database (MH-GRID) project is a study of hypertension (HTN) in AA aged 30 to 55 years. The data included in this analysis is from an MH-GRID sub-study of samples from the Morehouse School of Medicine (MSM), in Atlanta (Georgia).

Transcriptome data

The transcriptome data consisted of the mRNA sequencing data of whole blood (buffy coat). Total RNA extraction was carried out using MagMAXTM for Stabilized Blood Tubes RNA Isolation Kit as recommended by vendor (Life Technologies, Carlsbad, CA). For library preparation, total RNA samples are concentration normalized, and ribosomal RNA (rRNA) is removed. Illumina paired end sequencing was performed on HiSeq2000 analyzer (Illumina, USA) with an average sequencing depth of 50 million reads per sample. The mRNA expression was quantified using a bioinformatics pipeline developed by the Broad Institutes and used by the Genotype-Tissue Expression (GTEx). The pipeline is detailed in the GitHub software development platform24. Transcripts that did not achieve an expression of one read count per million (CPM) in at least three samples were excluded. The expression data was normalized using the Trimmed Mean of M-values (TMM), an optimal method for read count data25. Principal component analysis was conducted to identify and exclude sample and gene outliers. A set of 17,948 protein coding mRNA passed all quality control (QC) filters including a total of 28 taste perception related genes considered for this analysis. The 28 genes are listed in Supplemental Table T1A with their raw read counts reported the supplemental document named raw_count_data_for_RNA_expression and the distribution of the counts shown graphically in Supplemental Material M1. The genes consist of 22 TAS2R genes related to bitter taste perception, 3 SCNN1 genes related to salty taste perception and 3 TAS1R genes related to to umami (glutamate) perception.

Genotype data

For all the samples DNA was extracted from blood collected in PAXgene Blood DNA Tube and plated for genotyping on the Illumina Multi-Ethnic Genotyping Array (MEGA) version 2 which includes more than two million loci. The loci targeted by this Illumina product have been specified by the PAGE (Population Architecture in Genetics and Epidemiology) consortium and the ADPC (African Diaspora Power Chip) consortium. The raw intensity data were analyzed using Illumina proprietary software, the Illumina® GenomeStudio Genotyping Module™ Genotyping Module Software v2.0 and clustering for genotype assignment was of high quality (GenTrain Score > 0.9). Pre-analysis QC were carried out according to best practice. Briefly, markers with missing rate > 0.1 were exclude as well as those that failed Hardy–Weinberg Equilibrium test; principal component analysis (PCA) was conducted to identify and exclude sample outliers. Finally, samples with discordant sex information between genotype and phenotype data were also excluded. For the purpose of this work, unrelated samples that have proteome and/or transcriptome data in both cohorts were included in the analyses.

Proteome data

The ethylenediamine tetraacetic acid (EDTA) plasma samples from the GENE-FORECAST and MH-GRID cohorts were sent to the Olink Proteomics Analysis Service in Boston, USA. Proteomic analyses were conducted collectively in a single batch, and the data were delivered in November 2022. The Explore 3072 assay, utilizing eight Explore 384 Olink panels (Cardiometabolic, Cardiometabolic II, Inflammation, Inflammation II, Neurology, Neurology II, Oncology, Oncology II), was run to assess the relative expression of a total of 2,947 proteins. Proximity Extension Assay (PEA) technology was conducted according to the Olink AB manufacturer procedures by the certified laboratory. Briefly, the technique relies on the use of antibodies labelled with unique DNA oligonucleotides that bind to their target protein present in the sample. The DNA oligonucleotides, when in proximity on a target protein, undergo hybridization and act as a template for DNA polymerase-dependent extension, forming a unique double-stranded DNA barcode proportionate to the initial protein concentration. Quantification of resulting DNA amplicons is accomplished through high-throughput DNA sequencing, generating a digital signal reflective of the number of DNA hybridization events corresponding to the protein concentration in the original sample. The measurement of protein levels is based on Normalized Protein eXpression (NPX) values, serving as a relative protein quantification unit. This quantification is normalized to account for systematic noise arising from sample processing and technical variation, leveraging internal controls and sample controls. NPX units are on a log2 scale, where a one NPX unit increase indicates a two-fold rise in the concentration of amplicons representing the target protein compared to the internal control. A total of 2,941 passed QC filtering and a subset of 741 of those from the neurological panel were included in the protein quantitative trait loci (pQTL) analysis with 585 samples (458 from GENE-FORECAST and 127 from MH-GRID) which have genotype and proteome data available.

Statistical analyses

eQTL analysis

The analysis included all bi-allelic single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) ≥ 0.01 within the combined GENE-FROECAST and MH-GRID dataset (n = 475). Only SNPs within the cis-region (within one megabase) of the 28 taste perception genes in the transcriptome data were considered. The decision to focus on bi-allelic SNPs in the analyses is informed by various considerations, such as the superior accuracy and reliability associated with genotyping techniques for bi-allelic SNPs when compared to multi-allelic SNPs. This enhanced precision contributes to the robustness of the eQTL findings. Moreover, the emphasis on bi-allelic SNPs is strategically guided by their binary allele composition, which facilitates the interpretation of genetic effects and simplifies the identification and characterization of associations between specific alleles and mRNA and protein levels. A SNP was designated as an eQTL if the false-discovery rate (FDR) adjusted p-value of the association with a gene was ≤ 0.05.

eQTL overlap with variants reported in GWAS studies of AD

The summary statistics of 4 recent large studies of AD outlined in Table 1 were downloaded from the the GWAS Catalogue26 (version of November 2023). SNPs identified as eQTL in our analysis and reported in the GWAS with a p-value ≤ 0.0001 (GWAS follow up threshold) were identified.Table 1 Four recent large GWAS studies of AD with summary statistics available for download from the GWAS catalogue.

GWAS Catalogue Study Accession	PubMed ID	Publication Date (Author)	Study Title	Sample Size	
GCST9002715	35,379,992	2022–04-04 (Bellenguez et al.)	New insights into the genetic etiology of Alzheimer's disease and related dementias	111,326 cases 677,663 controls	
GCST013196	34,493,870	2021–09-07 (Wightman et al.)	A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease	90,338 cases 1,036,225 controls	
GCST007320	30,617,256	2019–01-07 (Jansen et al.)	Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk	71,880 cases 383,378 controls	
GCST005922	29,777,097	2018–05-18 (Marioni et al.)	GWAS on family history of Alzheimer's disease	39,918 cases 101,742 controls	

pQTL analysis

eQTLs reported in GWAS as associated with AD were tested for association with any of the 741 proteins in the Olink Neurological panel to gain functional insights by understanding the genetic basis of the regulation of proteins involved in the development or progression of AD. A SNP was designated as a pQTL when its association with a protein yielded an FDR-adjusted p-value of ≤ 0.05.

Both eQTL and pQTL analyses were conducted utilizing the MatrixEQTL27 R library. MatrixEQTL applies a regression model with mRNA/protein levels as the outcome and additive genotypes as independent variables. The regression model was adjusted for covariates, including age, sex, and principal components (PCs) 1 to 6 that explain most of the variance, to account for genetic ancestry admixture.

Results

Data description

GENE-FORECAST and MH-GRID data were combined in the eQTL and pQTL analyses to maximize the sample sizes. A description of the baseline characteristics of the 342 GENE-FOREAST and 133 MH-GRID samples included in the eQTL analysis are outlined in Table 2.Table 2 Baseline characteristics of GENE-FORECAST and MH-GRID samples included in.

Characteristics	GENE-FORECAST (n = 342) Mean or Count SD or Proportion	MH-GRID (n = 133) Mean or Count SD or Proportion	
Age (years)	48	12	45	7	
Sex	
 Female	235	69%	45	34%	
 Male	107	31%	88	66%	
Systolic Blood Pressure, SBP (mmHg)	154	38	120	16	
Diastolic Blood Pressure, DBP(mmHg)	76	10	77	11	
Body Mass Index, BMI (kg/m2)	32	7	31	9	
Low Density Lipoprotein, LDL (mg/dL)	112	39	109	32	
Fasting Blood Glucose, FBG (mg/dL)	103	35	90	9	
Current Smoker	
 No	399	87%	68	51%	
 Yes	58	13%	62	47%	

Principal component analysis

Because the analysis combined two datasets, principal component analysis (PCA) was undertaken to ensure the two datasets are homogeneous across the transcriptome and proteome data analyzed and the ensuing eQTL and pQTL results are not due to batch effects. The plots in Fig. 1 indicate that the two datasets cluster together across the 28 taste perception-related mRNAs and the 741 proteins in the Olink’s neurological panel.Fig. 1 PCA results indicate that the two datasets combined in this analysis cluster well together across PC1 which explains most the variance within the data.

eQTL analysis and overlap with GWAS findings

A comprehensive total of 3,547 SNP-mRNA associations were statiscally significant after adjustment for multiple testing. These associations comprised of 412 distinct SNPs and encompassed all 28 taste genes. Details of all the eQTL associations and the number of eQTL associated with each gene are outlined respectively in Supplemental Tables T1B and T1C.

A set of 11 eQTLs associated with 16 mRNAs, in the eQTL analysis, were reported in 17 independent GWAS studies of a dozen traits. The intersection with GWAS, succinctly presented in Table 3, includes three SNPs (rs11771145, rs11762262, rs10228407) consistently associated with AD across multiple studies listed in Table 4. The comprehensive information of SNP, mRNA and GWAS is provided in Supplemental Tables T1D.Table 3 GWAS studies reporting associations with SNPs revealed as eQTL linked to taste genes in our analysis.

GWAS Trait/disease	PubMed IDs	SNPs	
Bitter taste perception (multivariate analysis)	30,223,776	rs10772420, rs10261515	
Bitter taste perception	23,966,204, 30,223,776	rs1031391, rs10772420	
Idiopathic intracranial hypertension	29,608,535	rs200288366	
Height	18,391,951, 25,282,103, 20,881,960, 23,563,607	rs2187642, rs2856321	
Alzheimer's disease	35,379,992, 31,473,137, 34,493,870	rs11771145, rs11762262, rs10228407	
Alzheimer's disease (late onset)	24,162,737, 30,617,256	rs11771145, rs11762262, rs10228407	
Alzheimer's disease or family history of Alzheimer's disease	29,777,097, 30,617,256	rs11771145, rs11762262, rs10228407	
Body size at age 10	32,376,654	rs2187642	
Tea with sugar liking	35,585,065	rs10772380	
Gamma glutamyl transferase levels	33,462,484	rs11978404	
Bitter taste perception (phenylthiocarbamide) in obesity with metabolic syndrome	31,005,965	rs13231650	
Type 2 diabetes	35,893,037	rs4920461	

Table 4 Effect allele, effect size and p-values reported by the 4 GWAS studies of AD for the 3 SNPs identified as eQTLs associated with TAS2R41 and TAS2R60. Two of the SNPs are not reported by Marioni et al.

GWAS study	GWAS stats/info	rs11762262	rs11771145	rs10228407	
Wightman et al. PMID 34,493,870	log Odds	− 0.07	− 0.05	0.06	
P-Value	9.80e-08	3.81e-07	2.71e-08	
Mapped Gene (location)	EPHA1-AS1 (intron)	EPHA1-AS1 (intron)	EPHA1-AS1 (intron)	
Effect allele reported	T	A	T	
Marioni et al. PMID 29,777,097	log Odds	Not reported	Not reported	0.05	
P-Value	Not reported	Not reported	1.28e-09	
Mapped Gene (location)	Not reported	Not reported	EPHA1-AS1 (intron)	
Effect allele reported	Not reported	Not reported	T	
Bellenguez et al. PMID 35,379,992	Odds-Ratio	0.94	0.94	1.05	
P-Value	6.35e-10	1.29e-12	1.24e-10	
Mapped Gene (location)	EPHA1-AS1 (intron)	EPHA1-AS1 (intron)	EPHA1-AS1 (intron)	
Effect allele reported	T	A	T	
Jansen et al. PMID 30,617,256	log Odds	-0.016	-0.011	-0.01	
P-Value	5.22e-09	8.84e-07	9.33e-06	
Mapped Gene (location)	EPHA1-AS1 (intron)	EPHA1-AS1 (intron)	EPHA1-AS1 (intron)	
Effect allele reported	T	A	G	

In our eQTL analysis all three SNPs exhibit significant association with a down-regulation of TAS2R41 and two of them (rs11771145, rs10228407) are additionally associated with the down-regulation of TAS2R60, reported in Table 5 and Fig. 2. The three SNPs have a common frequency in the analysis datasets; they are all upstream of TAS2R41 and TAS2R60 and are not in significant linkage disequilibrium (LD), in the analysis dataset. The LD values measured as r2 are respectively 0.58 (between rs11771145 and rs10228407), 0.06 (between and rs11771145 and rs10228407) and 0.10 (between and rs11771145 and rs11762262).Table 5 eQTL analysis results for the 3 SNPs associated with AD in multiple GWAS studies.

SNP/eQTL	Chr	Position (GRCh38)	Location	mRNA	Beta	P-Value (raw)	P-Value (adjusted)	Allele tested (Minor Allele)	MAF	
rs11762262	7	143,410,783	67.1 kb upstream	TAS2R41	-0.07	9.45e-04	1.99e-02	A	0.21	
rs11771145	7	143,413,669	64.2 kb upstream	TAS2R41	-0.15	2.58e-21	3.39e-19	G	0.43	
rs11771145	7	143,413,669	29.8 kb upstream	TAS2R60	-0.33	3.26e-27	5.77e-25	G	0.43	
rs10228407	7	143,430,678	12.8 kb upstream	TAS2R60	-0.31	7.40e-24	1.05e-21	A	0.46	
rs10228407	7	143,430,678	47.2 kb upstream	TAS2R41	-0.15	5.11e-20	6.40E-18	A	0.46	

Fig. 2 mRNA expression and protein level by rs11771145 and rs10228407 genotypes. The beta and FDR adjusted p-value of each association is provided in the legend.

pQTL analysis of the 3 SNPs reported in GWAS of AD

The association between all 741 proteins in the Olink’s neurological panel and the 3 SNPs was evaluated. A set of three proteins (EPHB6, ARHGEF5, KEL) are encoded by genes in the vicinity (cis) of the three SNPs and the remaining 738 proteins are encoded by genes further away or in another chromosome (trans). The pQTL analysis revealed that rs11771145 was associated with an upregulation of one cis protein (EPHB6, beta = 0.8, p-value = 0.0002, FDR adjusted p-value = 0.0006) and one trans protein (ADGRB3, 0.09, p-value = 0.00002, FDR adjusted p-value = 0.014) whilst rs10228407 was associated with an upregulation of cis EPHB6 (beta = 0.08 and p-value = 0.0001, FDR adjusted p-value = 0.0004) and associated with trans ADGRB3 (beta = 0.08 and p-value = 0.00009, FDR adjusted p-value = 0.069). These results are depicted graphically in Fig. 2.

Discussion

The detection of bitter taste receptors such as TAS2R41 and TAS2R60 beyond the oral cavity has substantially broadened the scope of research revealing their multifaceted biological functions28. Originally evolved to discern noxious compounds, these receptors are now recognized as integral contributors to immunological defense mechanisms29. Notably, their localization within the cerebral cortex and choroid plexus represents a seminal expansion of their previously ascribed functional roles, implying a plausible engagement in metabolic and immune processes within the brain30.

Neurological implications

Recent investigations have unveiled the prospect that bitter taste receptors may exert their influence on neurological pathways implicated in neurodegenerative conditions, such as AD31. Traditionally acknowledged as chemical sentinels and more recently recognized as immune modulators32, these receptors offer novel insights into the mechanisms governing the pathophysiology of neurodegenerative diseases33. Their involvement in the immune and metabolic regulation within the brain not only broadens our understanding but also prompts the consideration of these receptors as potential therapeutic targets or early-stage biomarkers for neurodegenerative disorders34.

Genetic associations reported

Our research has brought to light noteworthy genetic associations linked to the TAS2R41 and TAS2R60 genes-associations extending beyond taste perception to intersect with AD. Specifically, the SNPs rs11771145 and rs10228407 located upstream of these genes, emerge as potential critical influencers of their expression. While the primary function of TAS2R41 and TAS2R60 is rooted in gustatory detection35, the association between these SNPs and AD is consistently reported in large GWAS investigations which beckons further explorations into the broader implications of genetic variants. Studies suggest that TAS2Rs might have broader implications for health and disease, including their expression in the brain and potential roles in neuronal signaling and disease pathology36. The association of TAS2Rs SNPs and their potential modulation during AD could shed light on the mechanisms of taste alterations and offer new perspectives on how sensory changes are linked to neurodegenerative processes.

Immunomodulation, neuroinflammation and alzheimer’s disease

Previous investigations have highlighted the role of the family of TAS2R genes in modulating immune cell activity, specifically in the regulation of antimicrobial peptides and inflammatory responses37. If these receptors extend a similar influence within the central nervous system, they could potentially modify microglial activity, thereby impacting neuroinflammatory pathways. The crucial function of bitter taste receptors in attenuating neuroinflammatory responses under normal physiological conditions is now well-established38. Conversely, a reduction in the expression of pivotal components within the taste receptor signaling pathway may escalate oxidative stress and activate the inflammasome, ultimately leading to neuroinflammation39.

Neuroinflammation, a shared characteristic among various neurodegenerative diseases, including AD, is now acknowledged as central to their pathophysiology40. The involvement of TAS2R bitter taste receptors in inflammatory responses underscores their significance beyond the realm of taste perception41. Pioneering work by Du et al. in 2018 unveiled that the loss of α-gustducin, a G-protein subunit integral to taste signal transduction, resulted in inflammatory responses and tissue damage42. This underscores the pro-inflammatory potential associated with disruptions in taste receptor signaling, specifically through the NF-κB signaling pathway and the NLRP3 inflammasome43.

Genetic variations and alzheimer's pathology

The identification of significant SNP-Gene associations across all 28 taste genes, particularly those leading to the down-regulation of TAS2R41 and TAS2R60, presents a notable link to Alzheimer's disease within the African American cohort studied. The location of rs117771145 and rs10228407 within the regulatory regions of TAS2R41 and TAS2R60, coupled with their association with AD, in GWAS, fortifies the proposition that bitter taste receptors may be involved in the pathological processes of AD. Variations in expression mediated by these SNPs have the potential to modulate receptor activation thresholds, thereby influencing cellular processes pivotal to neuroprotection, management of neuroinflammatory responses, and clearance of amyloid-beta44. Consequently, such variations may exacerbate neuronal susceptibility to the characteristic pathologies of AD.

Proteomic insights

To gain further functional insights, we conducted a comprehensive pQTL analysis targeting three SNPs, revealed as eQTL associated with TAS2R45 and TAS2R60 in our analysis, and previously identified in GWAS of AD45. This exploration unveiled compelling associations, elucidating proteins subject to modulation by these specific SNPs. Particularly noteworthy was the observation that rs11771145 exhibited a pronounced upregulation of EPHB6 (Ephrin type-B receptor 6), a protein encoded by a gene within the cis-region of the SNP involved in many developmental processes including neuronal development, angiogenesis, and cell migration46. This observation posits a compelling inference of direct regulatory influence. In the context of AD, EPHB6 assumes prominence owing to its extensive relavance in synaptic plasticity47, neuroprotection, and neuroinflammation48,49. Its regulatory role in fundamental processes positions EphB receptors as potential modulators of AD pathophysiology50.

Moreover, rs11771145 manifested an intriguing association with a protein, encoded by a gene, ADGRB3 (Adhesion G Protein-Coupled Receptor B3, also known as BAI3), located on a another chromosome. This finding implies the potential for long-range interactions that exert influence over protein expression levels. These associations collectively suggest that the implicated SNPs not only correlate with alterations in gene expression but also wield downstream effects on protein levels. ADGRB3 has been implicated in synaptic regulation and may influence neural circuit formation and plasticity. Alterations in ADGRB3 expression or function have been linked to various neurological conditions, suggesting that it plays a role in maintaining normal cognitive and neural functions51. The brain-specific angiogenesis inhibitor 1 (BAI1), also known as Adhesion G protein-coupled receptor B1 (ADGRB1), emerges as a pivotal regulator of synaptic plasticity52, particularly in the hippocampus. Its involvement in learning and memory processes underscores its significance53. Furthermore, ADGRB1 has been implicated in neuroprotection, mitigating toxin-induced neuronal cell death, and has known associations with dopaminergic neuronal loss in Parkinson's disease54,55. Concurrently, ADGRB3, enriched in post-synaptic density and cerebellar Purkinje cells56, orchestrates synaptic connections, particularly within the cerebellum57. Genetic variations in ADGRB3, encompassing SNPs and gene amplifications, have been linked to familial schizophrenia and other psychiatric conditions, including bipolar disorder58,59.

The association of the identified SNPs with upregulation of EPHB6 and ADGRB3 proteins suggests potential pathways through which genetic variations may contribute to the unique progression of AD in African Americans. As noted EPHB6 and ADGRB3 are involved in neuronal function and development, and their dysregulation could have significant implications for neurodegeneration. In both cases, the specific mechanisms by which TAS2R41 and TAS2R60 influence the expression or function of EPHB6 and ADGRB3 in the context of Alzheimer's disease remain to be fully elucidated. It is possible that changes in TAS2R expression alter signaling cascades or cellular environments in ways that impact these proteins, which in turn could affect neuronal health and function. Further research is needed to understand these relationships and their implications for AD and sensory health.

Integrated perspective and potential therapeutic implications

This integrative perspective, elucidating the interplay between SNPs, taste receptor genes and AD through pQTL analysis, offers profound insights into the intricacies of AD's etiology. Beyond merely illuminating potential mechanistic pathways, it underscores the multifaceted nature of neurodegenerative diseases. This holistic approach encourages nuanced research strategies for the refinement of therapeutic interventions and the development of preventive strategies.

Furthermore, the neuroprotective and anti-inflammatory attributes associated with bitter compounds, known to interact with TAS2Rs, substantiate the hypothesis that these receptors could potentially modulate the pathophysiological conditions of AD60. Compounds like flavonoids and polyphenols, which engage with TAS2Rs, have exhibited promise in enhancing cognitive function and mitigating markers of neurodegeneration in disease models61. The exploration of TAS2Rs in orchestrating the therapeutic effects of these compounds represents an intriguing avenue for further investigation62.

Limitations

Our study, elucidating novel insights into the genetic foundations of taste perception genes and their correlation with AD in an African American cohort, is constrained by several limitations. AD was not assessed in this cohort and it was hence not possible to directly link the mRNA and protein changes to AD.

Whole-blood transcriptome may imperfectly reflect brain gene expression, the primary site of AD pathology.

An additional limitation is our reliance on GWAS data predominantly derived from European populations. This underrepresentation of African American and other non-European populations in genetic research can limit the generalizability of our findings. The genetic architecture of AD may vary across different ancestries, and findings from European cohorts may not fully capture the genetic risk factors pertinent to populations of African ancestry. However, the main variants we reported are all common, suggesting they are not ancestry-specific and that our findings might be transferable across populations. Future studies should prioritize the inclusion of diverse populations to enhance the applicability of genetic research across different ethnic groups and to address health disparities in the understanding and treatment of AD.

The cross-sectional design hampers capturing the dynamic nature of gene expression changes over the disease course. Unaccounted environmental and lifestyle factors may confound genetic associations. Lack of direct correlation between genetic variations and clinical manifestations of AD, absence of detailed pathway analysis for SNP-gene and SNP-protein associations, and omission of microRNA exploration further limit our study. Notably, functional consequences of identified expression and protein QTLs lack experimental validation. Future research necessitates in vitro studies to discern genetic variant impact on gene expression and protein levels and function. Subsequent in vivo studies are vital for establishing their role in disease processes, fostering a comprehensive understanding of these associations in AD context.

Conclusions

Our investigation has unveiled novel insights into the genetic determinants implicated in AD, underscoring the potential important role of bitter taste receptor genes in its pathophysiological mechanisms. The identification of SNPs exhibiting robust associations with both taste perception genes and AD provides evidence for the plausible involvement of these genes in the intricate pathways of neurodegenerative diseases63. These findings posit genetic variations influencing taste receptor expression as potential contributors to brain health, positioning these receptors as plausible biomarkers for AD64.

The implications of our study for unraveling the genetic architecture of Alzheimer's disease have valuable significance, offering prospects for the development of targeted interventions aimed at modulating the pathways identified. Our findings also raise new questions and avenues for future research. Subsequent investigations should prioritize the validation of these associations within broader and more genetically diverse cohorts to ascertain the generalizability of our observations. Furthermore, longitudinal studies are warranted to elucidate the causal relationships between these genetic variations, gene expression regulation, and the progression of AD.

Our study highlights a significant step towards understanding the complex interplay of genetics, sensory function, and neurodegeneration in Alzheimer's disease within an African American cohort. Critical to the translation of genetic insights into therapeutic strategies, future research endeavors should delve into the direct impact of these SNPs on the neural circuitry and cognitive functions affected by AD. Such investigations will be instrumental in advancing our understanding and, consequently, facilitating the development of precise therapeutic interventions.

Supplementary Information

Supplementary Information.

Supplementary Tables.

Abbreviations

eQTL Expression-quantitative trait loci

pQTL Protein-quantitative trait loci

GWAS Genome-wide association study

SNP Single-nucleotide polymorphisms

AD Alzheimer’s disease

GENE-FORECAST GENomics, environmental factors and the social determinants of cardiovascular disease in african-americans study

MH-GRID Minority health genomics and translational research bio-repository database

MSM Morehouse school of medicine

PCA Principal component analysis

LD Linkage disequilibrium

SBP Systolic blood pressure

DBP Diastolic blood pressure

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-024-71669-9.

Acknowledgements

PVJ is supported by National Institute of Alcohol Abuse and Alcoholism under award number, Z01AA000135, the National Institute of Nursing Research and the Rockefeller University Heilbrunn Nurse Scholar Award. PVJ is supported by the Office of Workforce Diversity, and the Office of Workforce Diversity, National Institutes of Health Distinguished Scholar Program. We are grateful to Dr Gary H. Gibbons, the initial PI of the GENE-FORECAST study.

Author contributions

AG and PVJ designed the analysis. GG processed and conducted quality controls of the transcriptome, proteome and phenotype data. AG conducted the statistical analyses. AG, PVJ and MA interpreted the results. AG, PVJ, MA, GG and AD drafted and edited the manuscript. All authors reviewed and approved the final version of the manuscript.

Funding

Open access funding provided by the National Institutes of Health. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health.

Data availability

The datasets presented in this article cannot be publicly shared due to privacy restrictions. Requests to access the datasets should be directed to the corresponding author.

Competing interests

The authors declare no competing interests.

Ethics approval and consent to particpate

This study was approved by National Institutes of Health Institutional Review Board (IRB). The study was conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Chandrashekar J Hoon MA Ryba NJ Zuker CS The receptors and cells for mammalian taste Nature 2006 444 7117 288 294 10.1038/nature05401 17108952
Chandrashekar, J., Hoon, M. A., Ryba, N. J. & Zuker, C. S. The receptors and cells for mammalian taste. Nature 444(7117), 288–294. 10.1038/nature05401 (2006).17108952 10.1038/nature05401
2. Small DM Prescott J Odor/taste integration and the perception of flavor Exp. Brain Res. 2005 166 3–4 345 357 10.1007/s00221-005-2376-9 16028032
Small, D. M. & Prescott, J. Odor/taste integration and the perception of flavor. Exp. Brain Res. 166(3–4), 345–357. 10.1007/s00221-005-2376-9 (2005).16028032 10.1007/s00221-005-2376-9
3. Kure Liu C Joseph PV Feldman DE Brain imaging of taste perception in obesity: A review Curr. Nutr. Rep. 2019 8 2 108 119 10.1007/s13668-019-0269-y 30945140
Kure Liu, C. et al. Brain imaging of taste perception in obesity: A review. Curr. Nutr. Rep. 8(2), 108–119. 10.1007/s13668-019-0269-y (2019).30945140 10.1007/s13668-019-0269-y
4. Heckmann JG Lang CJG Neurological causes of taste disorders Adv. Otorhinolaryngol. 2006 63 255 264 10.1159/000093764 16733343
Heckmann, J. G. & Lang, C. J. G. Neurological causes of taste disorders. Adv. Otorhinolaryngol. 63, 255–264. 10.1159/000093764 (2006).16733343 10.1159/000093764
5. Ram S, Wada T, Sahai-Srivastava S. Neurosensory Disturbances Including Smell and Taste. In: Farah CS, Balasubramaniam R, McCullough MJ, eds. Contemporary Oral Medicine: A Comprehensive Approach to Clinical Practice. Springer International Publishing, (2018)
6. Yarmolinsky DA Zuker CS Ryba NJ Common sense about taste: from mammals to insects Cell 2009 139 2 234 244 10.1016/j.cell.2009.10.001 19837029
Yarmolinsky, D. A., Zuker, C. S. & Ryba, N. J. Common sense about taste: from mammals to insects. Cell 139(2), 234–244. 10.1016/j.cell.2009.10.001 (2009).19837029 10.1016/j.cell.2009.10.001
7. Howes OD Kambeitz J Kim E The nature of dopamine dysfunction in schizophrenia and what this means for treatment Arch. Gen. Psychiatry 2012 69 8 776 786 10.1001/archgenpsychiatry.2012.169 22474070
Howes, O. D. et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch. Gen. Psychiatry 69(8), 776–786. 10.1001/archgenpsychiatry.2012.169 (2012).22474070 10.1001/archgenpsychiatry.2012.169
8. Nutt DJ Lingford-Hughes A Erritzoe D Stokes PR The dopamine theory of addiction: 40 years of highs and lows Nat. Rev. Neurosci. 2015 16 5 305 312 10.1038/nrn3939 25873042
Nutt, D. J., Lingford-Hughes, A., Erritzoe, D. & Stokes, P. R. The dopamine theory of addiction: 40 years of highs and lows. Nat. Rev. Neurosci. 16(5), 305–312. 10.1038/nrn3939 (2015).25873042 10.1038/nrn3939
9. Doty RL Olfactory dysfunction in neurodegenerative diseases: Is there a common pathological substrate? Lancet Neurol. 2017 16 6 478 488 10.1016/S1474-4422(17)30123-0 28504111
Doty, R. L. Olfactory dysfunction in neurodegenerative diseases: Is there a common pathological substrate?. Lancet Neurol. 16(6), 478–488. 10.1016/S1474-4422(17)30123-0 (2017).28504111 10.1016/S1474-4422(17)30123-0
10. Steiner JE Human facial expressions in response to taste and smell stimulation Adv. Child Dev. Behav. 1979 13 257 295 10.1016/s0065-2407(08)60349-3 484324
Steiner, J. E. Human facial expressions in response to taste and smell stimulation. Adv. Child Dev. Behav. 13, 257–295. 10.1016/s0065-2407(08)60349-3 (1979).484324 10.1016/s0065-2407(08)60349-3
11. Dantzer R O'Connor JC Freund GG Johnson RW Kelley KW From inflammation to sickness and depression: When the immune system subjugates the brain Nat. Rev. Neurosci. 2008 9 1 46 56 10.1038/nrn2297 18073775
Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: When the immune system subjugates the brain. Nat. Rev. Neurosci. 9(1), 46–56. 10.1038/nrn2297 (2008).18073775 10.1038/nrn2297
12. Medeiros R Baglietto-Vargas D LaFerla FM The role of tau in Alzheimer's disease and related disorders CNS Neurosci. Ther. 2011 17 5 514 524 10.1111/j.1755-5949.2010.00177.x 20553310
Medeiros, R., Baglietto-Vargas, D. & LaFerla, F. M. The role of tau in Alzheimer’s disease and related disorders. CNS Neurosci. Ther. 17(5), 514–524. 10.1111/j.1755-5949.2010.00177.x (2011).20553310 10.1111/j.1755-5949.2010.00177.x
13. Sakai M Kazui H Shigenobu K Komori K Ikeda M Nishikawa T Gustatory Dysfunction as an Early Symptom of Semantic Dementia Dement. Geriatr. Cogn. Dis. Extra. 2017 7 3 395 405 10.1159/000481854 29430242
Sakai, M. et al. Gustatory Dysfunction as an Early Symptom of Semantic Dementia. Dement. Geriatr. Cogn. Dis. Extra. 7(3), 395–405. 10.1159/000481854 (2017).29430242 10.1159/000481854
14. Sakai M Ikeda M Kazui H Shigenobu K Nishikawa T Decline of gustatory sensitivity with the progression of Alzheimer's disease Int. Psychogeriatr. 2016 28 3 511 517 10.1017/s1041610215001337 26423603
Sakai, M., Ikeda, M., Kazui, H., Shigenobu, K. & Nishikawa, T. Decline of gustatory sensitivity with the progression of Alzheimer’s disease. Int. Psychogeriatr. 28(3), 511–517. 10.1017/s1041610215001337 (2016).26423603 10.1017/s1041610215001337
15. Schiffman SS Graham BG Sattely-Miller EA Zervakis J Welsh-Bohmer K Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer’s disease Neurobiol. Aging 2002 10.1016/S0197-4580(01)00337-2 11959402
Schiffman, S. S., Graham, B. G., Sattely-Miller, E. A., Zervakis, J. & Welsh-Bohmer, K. Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer’s disease. Neurobiol. Aging10.1016/S0197-4580(01)00337-2 (2002).11959402 10.1016/S0197-4580(01)00337-2
16. Steinbach S Hundt W Vaitl A Taste in mild cognitive impairment and Alzheimer's disease J. Neurol. 2010 257 2 238 246 10.1007/s00415-009-5300-6 19727902
Steinbach, S. et al. Taste in mild cognitive impairment and Alzheimer’s disease. J. Neurol. 257(2), 238–246. 10.1007/s00415-009-5300-6 (2010).19727902 10.1007/s00415-009-5300-6
17. Lambert JC Ibrahim-Verbaas CA Harold D Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease Nat. Genet. 2013 45 12 1452 1458 10.1038/ng.2802 24162737
Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45(12), 1452–1458. 10.1038/ng.2802 (2013).24162737 10.1038/ng.2802
18. Marioni RE Harris SE Zhang Q GWAS on family history of Alzheimer's disease Transl. Psychiatry 2018 10.1038/s41398-018-0150-6 29777097
Marioni, R. E. et al. GWAS on family history of Alzheimer’s disease. Transl. Psychiatry10.1038/s41398-018-0150-6 (2018).29777097 10.1038/s41398-018-0150-6
19. Moreno-Grau S de Rojas I Hernandez I Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project Alzheimers Dement. 2019 15 10 1333 1347 10.1016/j.jalz.2019.06.4950 31473137
Moreno-Grau, S. et al. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks: The GR@ACE project. Alzheimers Dement. 15(10), 1333–1347. 10.1016/j.jalz.2019.06.4950 (2019).31473137 10.1016/j.jalz.2019.06.4950
20. Bellenguez C Kucukali F Jansen IE New insights into the genetic etiology of Alzheimer's disease and related dementias Nat Genet. 2022 54 4 412 436 10.1038/s41588-022-01024-z 35379992
Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 54(4), 412–436. 10.1038/s41588-022-01024-z (2022).35379992 10.1038/s41588-022-01024-z
21. Jansen IE Savage JE Watanabe K Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk Nat Genet. 2019 51 3 404 413 10.1038/s41588-018-0311-9 30617256
Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 51(3), 404–413. 10.1038/s41588-018-0311-9 (2019).30617256 10.1038/s41588-018-0311-9
22. Lennon JC Aita SL Bene VAD Black and White individuals differ in dementia prevalence, risk factors, and symptomatic presentation Alzheimers Dement. 2022 18 8 1461 1471 10.1002/alz.12509 34854531
Lennon, J. C. et al. Black and White individuals differ in dementia prevalence, risk factors, and symptomatic presentation. Alzheimers Dement. 18(8), 1461–1471. 10.1002/alz.12509 (2022).34854531 10.1002/alz.12509
23. Association As. Black Americans and alzheimer's. https://www.alz.org/help-support/resources/black-americans-and-alzheimers, (Accessed 02 May 2024).
24. Institute B. broadinstitute/gtex-pipeline. https://github.com/broadinstitute/gtex-pipeline
25. Robinson MD Oshlack A A scaling normalization method for differential expression analysis of RNA-seq data Genome Biol. 2010 11 3 R25 10.1186/gb-2010-11-3-r25 20196867
Robinson, M. D. & Oshlack, A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 11(3), R25. 10.1186/gb-2010-11-3-r25 (2010).20196867 10.1186/gb-2010-11-3-r25
26. Sollis E Mosaku A Abid A The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource Nucleic Acids Res. 2023 51 D1 D977 D985 10.1093/nar/gkac1010 36350656
Sollis, E. et al. The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource. Nucleic Acids Res. 51(D1), D977–D985. 10.1093/nar/gkac1010 (2023).36350656 10.1093/nar/gkac1010
27. Shabalin AA Matrix eQTL: Ultra fast eQTL analysis via large matrix operations Bioinformatics 2012 28 10 1353 1358 10.1093/bioinformatics/bts163 22492648
Shabalin, A. A. Matrix eQTL: Ultra fast eQTL analysis via large matrix operations. Bioinformatics 28(10), 1353–1358. 10.1093/bioinformatics/bts163 (2012).22492648 10.1093/bioinformatics/bts163
28. Avau B Depoortere I The bitter truth about bitter taste receptors: beyond sensing bitter in the oral cavity Acta Physiol. (Oxf). 2016 216 4 407 420 10.1111/apha.12621 26493384
Avau, B. & Depoortere, I. The bitter truth about bitter taste receptors: beyond sensing bitter in the oral cavity. Acta Physiol. (Oxf). 216(4), 407–420. 10.1111/apha.12621 (2016).26493384 10.1111/apha.12621
29. Carey RM Lee RJ Taste receptors in upper airway innate immunity Nutrients 2019 10.3390/nu11092017 31487854
Carey, R. M. & Lee, R. J. Taste receptors in upper airway innate immunity. Nutrients10.3390/nu11092017 (2019).31487854 10.3390/nu11092017
30. Duarte AC Santos J Costa AR Bitter taste receptors profiling in the human blood-cerebrospinal fluid-barrier Biochem. Pharmacol. 2020 10.1016/j.bcp.2020.113954 32272108
Duarte, A. C. et al. Bitter taste receptors profiling in the human blood-cerebrospinal fluid-barrier. Biochem. Pharmacol.10.1016/j.bcp.2020.113954 (2020).32272108 10.1016/j.bcp.2020.113954
31. Duarte AC Costa AR Goncalves I Quintela T Preissner R Santos CRA The druggability of bitter taste receptors for the treatment of neurodegenerative disorders Biochem. Pharmacol. 2022 10.1016/j.bcp.2022.114915 35182520
Duarte, A. C. et al. The druggability of bitter taste receptors for the treatment of neurodegenerative disorders. Biochem. Pharmacol.10.1016/j.bcp.2022.114915 (2022).35182520 10.1016/j.bcp.2022.114915
32. Lu P Zhang CH Lifshitz LM ZhuGe R Extraoral bitter taste receptors in health and disease J. Gen. Physiol. 2017 149 2 181 197 10.1085/jgp.201611637 28053191
Lu, P., Zhang, C. H., Lifshitz, L. M. & ZhuGe, R. Extraoral bitter taste receptors in health and disease. J. Gen. Physiol. 149(2), 181–197. 10.1085/jgp.201611637 (2017).28053191 10.1085/jgp.201611637
33. de Jesus VC Mittermuller BA Hu P Schroth RJ Chelikani P Association between downstream taste signaling genes, oral microbiome, and severe early childhood caries Int. J. Mol. Sci. 2022 10.3390/ijms24010081 36613519
de Jesus, V. C., Mittermuller, B. A., Hu, P., Schroth, R. J. & Chelikani, P. Association between downstream taste signaling genes, oral microbiome, and severe early childhood caries. Int. J. Mol. Sci.10.3390/ijms24010081 (2022).36613519 10.3390/ijms24010081
34. Harmon CP Deng D Breslin PAS Bitter taste receptors (T2Rs) are sentinels that coordinate metabolic and immunological defense responses Curr. Opin. Physiol. 2021 20 70 76 10.1016/j.cophys.2021.01.006 33738371
Harmon, C. P., Deng, D. & Breslin, P. A. S. Bitter taste receptors (T2Rs) are sentinels that coordinate metabolic and immunological defense responses. Curr. Opin. Physiol. 20, 70–76. 10.1016/j.cophys.2021.01.006 (2021).33738371 10.1016/j.cophys.2021.01.006
35. da Silva EC de Jager N Burgos-Paz W Reverter A Perez-Enciso M Roura E Characterization of the porcine nutrient and taste receptor gene repertoire in domestic and wild populations across the globe BMC Genomics. 2014 10.1186/1471-2164-15-1057 25573652
da Silva, E. C. et al. Characterization of the porcine nutrient and taste receptor gene repertoire in domestic and wild populations across the globe. BMC Genomics.10.1186/1471-2164-15-1057 (2014).25573652 10.1186/1471-2164-15-1057
36. Behrens M Meyerhof W Gustatory and extragustatory functions of mammalian taste receptors Physiol. Behav. 2011 105 1 4 13 10.1016/j.physbeh.2011.02.010 21324331
Behrens, M. & Meyerhof, W. Gustatory and extragustatory functions of mammalian taste receptors. Physiol. Behav. 105(1), 4–13. 10.1016/j.physbeh.2011.02.010 (2011).21324331 10.1016/j.physbeh.2011.02.010
37. Xi R Zheng X Tizzano M Role of taste receptors in innate immunity and oral health J. Dent. Res. 2022 101 7 759 768 10.1177/00220345221077989 35191336
Xi, R., Zheng, X. & Tizzano, M. Role of taste receptors in innate immunity and oral health. J. Dent. Res. 101(7), 759–768. 10.1177/00220345221077989 (2022).35191336 10.1177/00220345221077989
38. Welcome MO Dogo D Nikos EM Cellular mechanisms and molecular pathways linking bitter taste receptor signalling to cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases Inflammopharmacology 2023 31 1 89 117 10.1007/s10787-022-01086-9 36471190
Welcome, M. O., Dogo, D. & Nikos, E. M. Cellular mechanisms and molecular pathways linking bitter taste receptor signalling to cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases. Inflammopharmacology 31(1), 89–117. 10.1007/s10787-022-01086-9 (2023).36471190 10.1007/s10787-022-01086-9
39. Welcome MO Mastorakis NE The taste of neuroinflammation: Molecular mechanisms linking taste sensing to neuroinflammatory responses Pharmacol. Res. 2021 10.1016/j.phrs.2021.105557 33737243
Welcome, M. O. & Mastorakis, N. E. The taste of neuroinflammation: Molecular mechanisms linking taste sensing to neuroinflammatory responses. Pharmacol. Res.10.1016/j.phrs.2021.105557 (2021).33737243 10.1016/j.phrs.2021.105557
40. Guzman-Martinez L Maccioni RB Andrade V Navarrete LP Pastor MG Ramos-Escobar N Neuroinflammation as a Common Feature of Neurodegenerative Disorders Front. Pharmacol. 2019 10 1008 10.3389/fphar.2019.01008 31572186
Guzman-Martinez, L. et al. Neuroinflammation as a Common Feature of Neurodegenerative Disorders. Front. Pharmacol. 10, 1008. 10.3389/fphar.2019.01008 (2019).31572186 10.3389/fphar.2019.01008
41. Tuzim K Korolczuk A An update on extra-oral bitter taste receptors J. Transl. Med. 2021 10.1186/s12967-021-03067-y 34836552
Tuzim, K. & Korolczuk, A. An update on extra-oral bitter taste receptors. J. Transl. Med.10.1186/s12967-021-03067-y (2021).34836552 10.1186/s12967-021-03067-y
42. Dong G Boothe K He L Shi Y McCluskey LP Altered peripheral taste function in a mouse model of inflammatory bowel disease Res. Sq. 2023 10.21203/rs.3.rs-3304297/v1 38196646
Dong, G., Boothe, K., He, L., Shi, Y. & McCluskey, L. P. Altered peripheral taste function in a mouse model of inflammatory bowel disease. Res. Sq.10.21203/rs.3.rs-3304297/v1 (2023).38196646 10.21203/rs.3.rs-3304297/v1
43. Liu T Zhang L Joo D Sun SC NF-kappaB signaling in inflammation Signal Transduct. Target Ther. 2017 10.1038/sigtrans.2017.23 29266131
Liu, T., Zhang, L., Joo, D. & Sun, S. C. NF-kappaB signaling in inflammation. Signal Transduct. Target Ther.10.1038/sigtrans.2017.23 (2017).29266131 10.1038/sigtrans.2017.23
44. Kinney JW Bemiller SM Murtishaw AS Leisgang AM Salazar AM Lamb BT Inflammation as a central mechanism in Alzheimer's disease Alzheimers Dement (N Y). 2018 4 575 590 10.1016/j.trci.2018.06.014 30406177
Kinney, J. W. et al. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y). 4, 575–590. 10.1016/j.trci.2018.06.014 (2018).30406177 10.1016/j.trci.2018.06.014
45. Wooding SP Ramirez VA Global population genetics and diversity in the TAS2R bitter taste receptor family Front. Genet. 2022 10.3389/fgene.2022.952299 36303543
Wooding, S. P. & Ramirez, V. A. Global population genetics and diversity in the TAS2R bitter taste receptor family. Front. Genet.10.3389/fgene.2022.952299 (2022).36303543 10.3389/fgene.2022.952299
46. Kania A Klein R Mechanisms of ephrin-Eph signalling in development, physiology and disease Nat. Rev. Mol. Cell Biol. 2016 17 4 240 256 10.1038/nrm.2015.16 26790531
Kania, A. & Klein, R. Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nat. Rev. Mol. Cell Biol. 17(4), 240–256. 10.1038/nrm.2015.16 (2016).26790531 10.1038/nrm.2015.16
47. Sloniowski S Ethell IM Looking forward to EphB signaling in synapses Semin Cell Dev. Biol. 2012 23 1 75 82 10.1016/j.semcdb.2011.10.020 22040917
Sloniowski, S. & Ethell, I. M. Looking forward to EphB signaling in synapses. Semin Cell Dev. Biol. 23(1), 75–82. 10.1016/j.semcdb.2011.10.020 (2012).22040917 10.1016/j.semcdb.2011.10.020
48. He CH Song NN Xie PX Overexpression of EphB6 and EphrinB2 controls soma spacing of cortical neurons in a mutual inhibitory way Cell Death Dis. 2023 10.1038/s41419-023-05825-w 38129399
He, C. H. et al. Overexpression of EphB6 and EphrinB2 controls soma spacing of cortical neurons in a mutual inhibitory way. Cell Death Dis.10.1038/s41419-023-05825-w (2023).38129399 10.1038/s41419-023-05825-w
49. Darling TK Lamb TJ Emerging roles for eph receptors and ephrin ligands in immunity Front Immunol. 2019 10 1473 10.3389/fimmu.2019.01473 31333644
Darling, T. K. & Lamb, T. J. Emerging roles for eph receptors and ephrin ligands in immunity. Front Immunol. 10, 1473. 10.3389/fimmu.2019.01473 (2019).31333644 10.3389/fimmu.2019.01473
50. Dal Pra I Armato U Chiarini A Family C G-protein-coupled receptors in Alzheimer's disease and therapeutic implications Front Pharmacol. 2019 10 1282 10.3389/fphar.2019.01282 31719824
Dal Pra, I., Armato, U. & Chiarini, A. Family C G-protein-coupled receptors in Alzheimer’s disease and therapeutic implications. Front Pharmacol. 10, 1282. 10.3389/fphar.2019.01282 (2019).31719824 10.3389/fphar.2019.01282
51. Lanoue V Usardi A Sigoillot SM The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons Mol. Psychiatry 2013 10.1038/mp.2013.46 23628982
Lanoue, V. et al. The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons. Mol. Psychiatry10.1038/mp.2013.46 (2013).23628982 10.1038/mp.2013.46
52. Stephenson JR Paavola KJ Schaefer SA Kaur B Van Meir EG Hall RA Brain-specific angiogenesis inhibitor-1 signaling, regulation, and enrichment in the postsynaptic density J. Biol. Chem. 2013 288 31 22248 22256 10.1074/jbc.M113.489757 23782696
Stephenson, J. R. et al. Brain-specific angiogenesis inhibitor-1 signaling, regulation, and enrichment in the postsynaptic density. J. Biol. Chem. 288(31), 22248–22256. 10.1074/jbc.M113.489757 (2013).23782696 10.1074/jbc.M113.489757
53. Shiu FH Wong JC Yamamoto T Mice lacking full length Adgrb1 (Bai1) exhibit social deficits, increased seizure susceptibility, and altered brain development Exp. Neurol. 2022 351 113994 10.1016/j.expneurol.2022.113994 35114205
Shiu, F. H. et al. Mice lacking full length Adgrb1 (Bai1) exhibit social deficits, increased seizure susceptibility, and altered brain development. Exp. Neurol. 351, 113994. 10.1016/j.expneurol.2022.113994 (2022).35114205 10.1016/j.expneurol.2022.113994
54. Choi JS Bae WY Nam S Jeong JW New targets for Parkinson's disease: Adhesion G protein-coupled receptor B1 is downregulated by AMP-activated protein kinase activation OMICS 2018 22 7 493 501 10.1089/omi.2018.0047 30004846
Choi, J. S., Bae, W. Y., Nam, S. & Jeong, J. W. New targets for Parkinson’s disease: Adhesion G protein-coupled receptor B1 is downregulated by AMP-activated protein kinase activation. OMICS 22(7), 493–501. 10.1089/omi.2018.0047 (2018).30004846 10.1089/omi.2018.0047
55. Choi JS Park C Jeong JW AMP-activated protein kinase is activated in Parkinson's disease models mediated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Biochem. Biophys. Res. Commun. 2010 391 1 147 151 10.1016/j.bbrc.2009.11.022 19903456
Choi, J. S., Park, C. & Jeong, J. W. AMP-activated protein kinase is activated in Parkinson’s disease models mediated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Biochem. Biophys. Res. Commun. 391(1), 147–151. 10.1016/j.bbrc.2009.11.022 (2010).19903456 10.1016/j.bbrc.2009.11.022
56. Purcell RH Hall RA Adhesion G protein-coupled receptors as drug targets Annu. Rev. Pharmacol. Toxicol. 2018 58 429 449 10.1146/annurev-pharmtox-010617-052933 28968187
Purcell, R. H. & Hall, R. A. Adhesion G protein-coupled receptors as drug targets. Annu. Rev. Pharmacol. Toxicol. 58, 429–449. 10.1146/annurev-pharmtox-010617-052933 (2018).28968187 10.1146/annurev-pharmtox-010617-052933
57. Lala T Hall RA Adhesion G protein-coupled receptors: Structure, signaling, physiology, and pathophysiology Physiol. Rev. 2022 102 4 1587 1624 10.1152/physrev.00027.2021 35468004
Lala, T. & Hall, R. A. Adhesion G protein-coupled receptors: Structure, signaling, physiology, and pathophysiology. Physiol. Rev. 102(4), 1587–1624. 10.1152/physrev.00027.2021 (2022).35468004 10.1152/physrev.00027.2021
58. Scuderi C Saccuzzo L Vinci M Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder Eur. J. Hum. Genet. 2019 27 4 594 602 10.1038/s41431-018-0321-1 30659260
Scuderi, C. et al. Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder. Eur. J. Hum. Genet. 27(4), 594–602. 10.1038/s41431-018-0321-1 (2019).30659260 10.1038/s41431-018-0321-1
59. Bipolar D, Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address drve, Bipolar D, Schizophrenia Working Group of the Psychiatric Genomics C. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes. Cell. 10.1016/j.cell.2018.05.046, (2018).
60. Zehentner S, Reiner AT, Grimm C, Somoza V. The Role of Bitter Taste Receptors in Cancer: A Systematic Review. Cancers (Basel). Nov 23 2021;13(23)10.3390/cancers13235891
61. Minocha T Birla H Obaid AA Flavonoids as promising neuroprotectants and their therapeutic potential against Alzheimer's disease Oxid. Med. Cell. Longev. 2022 2022 6038996 10.1155/2022/6038996 36071869
Minocha, T. et al. Flavonoids as promising neuroprotectants and their therapeutic potential against Alzheimer’s disease. Oxid. Med. Cell. Longev. 2022, 6038996. 10.1155/2022/6038996 (2022).36071869 10.1155/2022/6038996
62. Nayak AP Villalba D Deshpande DA Bitter taste receptors: An answer to comprehensive asthma control? Curr. Allergy Asthma. Rep. 2019 10.1007/s11882-019-0876-0 31486942
Nayak, A. P., Villalba, D. & Deshpande, D. A. Bitter taste receptors: An answer to comprehensive asthma control?. Curr. Allergy Asthma. Rep.10.1007/s11882-019-0876-0 (2019).31486942 10.1007/s11882-019-0876-0
63. Oatman SR Reddy JS Quicksall Z Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's disease related proteins Mol. Neurodegener. 2023 10.1186/s13024-022-00592-2 36609403
Oatman, S. R. et al. Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s disease related proteins. Mol. Neurodegener.10.1186/s13024-022-00592-2 (2023).36609403 10.1186/s13024-022-00592-2
64. Romano RR 3rd Carter MA Monroe TB Narrative review of sensory changes as a biomarker for Alzheimer's disease Biol Res Nurs. 2021 23 2 223 230 10.1177/1099800420947176 32799655
Romano, R. R. 3rd., Carter, M. A. & Monroe, T. B. Narrative review of sensory changes as a biomarker for Alzheimer’s disease. Biol Res Nurs. 23(2), 223–230. 10.1177/1099800420947176 (2021).32799655 10.1177/1099800420947176
