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Individual Differences in Taste and Their Association with Genes, Dietary Behaviour, and Brain Structure

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Individual Differences in Taste and Their Association with Genes, Dietary Behaviour, and Brain Structure Individual differences in taste and their association with genes, dietary behaviour, and brain structure Liang-Dar (Daniel) Hwang B.Sc. (Biochemistry), M.B. (Biotechnology), M.Sc. (Nutritional Sciences) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2018 Faculty of Medicine Abstract Taste perception plays a key role influencing human dietary behaviour and further health consequences. It has been shown that genetic and neurological factors contribute to variation in taste, but their underlying mechanisms remain largely underexplored. For example, it is unclear how much of the variance in sweet taste is due to genetics, whether the association between sweet and bitter tastes is due to genetic covariance, and whether variation in brain structure is associated with taste. The goal of this work is to extend current knowledge in individual differences in human taste perception of sweetness and bitterness by showing their relationships with genes, dietary behaviour, and brain morphology. We perform quantitative and statistical genetic analyses using an extensively phenotyped and genotyped twin sample of Australian adolescents (n = 1999), with replication and extension making use of two publically available datasets from the Human Connectome Project (HCP; n = 1101) and the UK Biobank (N = 438,870). In Chapter 1, we employed structural equation modelling (variance components analysis) to provide the first evidence that approximately 30% of variation in the perceived intensity of sweet compounds, including sugars (i.e. glucose and fructose) and high-potency sweeteners (i.e. aspartame and neohesperidin dihydrochalcone) is due to genetics. Furthermore, we identified a common genetic factor accounting for more than 75% of the genetic variance in the perception for each of these sweet compounds, suggesting that the perception of both sugars and high-potency sweeteners was regulated by a common set of genes. In Chapter 2, we demonstrated that a quarter of the genetic variance in perceived sweetness (i.e. a weighted mean score of the four sweet tastes from Chapter 1) is shared with at least half of the genetic variance in the perceived bitterness of quinine, sucrose octaacetate (SOA), and caffeine. The genetic association between sweetness and the bitterness of propylthiouracil (PROP) becomes evident after adjusting for the TAS2R38 genotype. These results reveal shared genetic pathways for the human perception of sweetness and bitterness. To pinpoint the source of genetic variation in bitter taste, in Chapter 3, we performed a genome-wide association analysis (GWAS). As previous work was underpowered to detect variants with small effects, we used a bivariate approach to boost power. We identified two putative novel variants with small effects (< 2%) on 2 chromosomes 7 and 12 for the perceived intensity of denatonium benzoate (DB) and SOA, respectively. We provided the first independent replication for the caffeine bitterness on chromosome 12 and confirmed the previously identified variants on chromosomes 7 and 12 for PROP and quinine, respectively. Building on the common source of genetic variances identified in Chapter 2, we showed evidence for pleiotropy that each of the three variants (for quinine, caffeine, and SOA) on chromosome 12 is associated with more than one of the bitter tastes (quinine, SOA, caffeine, and DB). These findings offer a useful starting point for determining the biological pathways linking perception of bitter substances. We investigated the effect of taste perception on diet-related outcomes. Although previous findings of the association between bitter taste perception and bitter beverage intake were inconsistent, we used two-sample Mendelian randomization (Chapter 4) to demonstrate a causal relationship between the perceived bitterness of PROP, quinine, and caffeine and the consumption of coffee, tea, and alcohol among UK Biobank participants. In Chapter 5, our longitudinal analyses showed that the perceived sweetness in adolescence is a predictor for body mass index (BMI) in early adulthood. We also showed that this association is partly due to genetics using structural equation modelling and polygenic risk prediction approaches. In Chapter 6, we conducted an exploratory analysis to examine the associations between the volumes of 84 brain regions of interest (ROI) and the perceived sweetness and bitterness (PROP, quinine, caffeine). The volumes of 5 ROIs (right cuneus gyrus, right inferior temporal gyrus, left transverse temporal gyrus, and left and right caudates) were nominally associated with both sweet and bitter tastes. Additionally, we replicated an association between quinine bitterness and the volume of left entorhinal gyrus using data from HCP. This study provides the first evidence for an association between brain morphology and taste intensity ratings. In conclusion, we used structural equation modelling to show that sweet taste is heritable and the association between sweet and bitter tastes is largely due to genetic covariance. Additionally, bivariate GWAS identified variants with small effects on bitter tastes and revealed their pleiotropy. Furthermore, results from Mendelian randomization and longitudinal analyses evidence the potential causal impact of taste on dietary behaviour and BMI. These findings enhance our understanding in the genetic architecture of taste and shed light on the personalized 3 nutrition and medicine. Lastly, we showed that the volume of specific brain regions is associated with taste perception, which provides new insights into the gustatory network and suggests a potential role of brain structure in taste. 4 Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. 5 Publications during candidature Peer-reviewed papers Hwang LD, Zhu G, Breslin PAS, Reed DR, Wright MJ, and Martin NG (2015). A common genetic influence on human intensity ratings of sugars and high-potency sweeteners, Twin Res. Hum. Genet., 18(4):361-7. Hwang LD, Breslin PAS, Reed DR, Zhu G, Martin NG, and Wright MJ (2016). Is the association between sweet and bitter perception due to genetic variation? Chem. Senses, 41(9): 737-744. Hwang LD, Cuellar-Partida G, Ong JS, Breslin PAS, Reed DR, MacGregor S, Gharahkani P, Martin NG, and Renteria ME (2016). Sweet taste perception is associated with body mass Index at the phenotypic and genetic level, Twin Res. Hum. Genet., 19(5):465-71. Ong JS, Hwang LD, Cuellar-Partida G, Martin NG, Chenevix-Trench G, Quinn MCJ, Cornelis MC, Gharahkani P, Webb PM, MacGregor, Ovarian Cancer Association Consortium (2017). Assessment of moderate coffee consumption on risk of epithelial ovarian cancer: a Mendelian randomization study, Int. J. Epidemiol., dyx236 Conference abstracts Hwang LD, Zhu G, Wright MJ, Martin NG, Reed RD, Breslin PAS. Genetic modeling of human intensity ratings of four sweeteners, Australasian Association for ChemoSensory Sciences, Brisbane, Australia, December 2014. Hwang LD, Breslin PAS, Reed DR, Zhu G, Martin NG, and Wright MJ. Is the Association between Sweet and Bitter Perception due to Genetic Variation? International Congress of Human Genetics, Kyoto, Japan, April 2016. Hwang LD, Cuellar-Partida G, Breslin PAS, Reed DR, MacGregor S, Gharahkani P, Martin NG, and Renteria ME. Sweet Taste Perception is Associated to Body Mass Index at the Phenotypic and Genetic Level, International Society of Twin Studies, Brisbane, Australia, June 2016. 6 Hwang LD, Breslin PAS, Reed DR, Zhu G, Martin NG, and Wright MJ. GWAS of Bitter Taste Perception in Australian Adolescents, Behavior Genetics Association, Brisbane, Australia, June 2016. Hwang LD, Gharahkhani P, Breslin PAS, Gordon SD, Zhu G, Martin NG, Reed DR, and Wright MJ. Replication and discovery of genetic variants influencing human bitter taste perception, Association for Chemoreception Sciences, Fort Myers, FL, USA, April 2017 7 Publications included in this thesis Hwang LD, Zhu G, Breslin PAS, Reed DR, Wright MJ, and Martin NG (2015). A common genetic influence on human intensity
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