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Abstract
Nutrigenetics and precision nutrition provide the means to create targeted dietary therapy for disease treatment and prevention, based on an individual’s unique genetic composition. Genome-wide association and interaction studies (GWAS and GWIS) are statistical techniques that can help identify nutrigenetic variants of interest; three of these studies are collected herein. In Chapter 2, we performed a GWIS for interactions of genotype with fish oil on blood lipids. We found that rs112803755 had significant interaction with triglycerides (P = 5.65e−10), in a meta-analysis of UK Biobank (UKB) and Atherosclerosis Risk in Communities (ARIC) cohorts. Specifically, there was a triglyceride-lowering effect of fish oil supplementation on rs112803755 heterozygotes. This locus was significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. In Chapter 3, we performed a GWAS to identify variants associated with circulating polyunsaturated and monounsaturated fatty acid (PUFA and MUFA) levels, which have strong heritable components. We meta-analyzed GWAS from three European studies, UKB, FinMetSeq, and Kettunnen et al., and identified 87 novel loci, 51 of which were replicated. Functional analyses enabled selection of candidate genes for these loci. In Chapter 4, we performed traditional and genetic epidemiology analysis on the effects of vegetarianism. We designed a rigorous definition of vegetarianism using data from two surveys in the UK Biobank to identify a cohort of “reliable” vegetarians. Significant effects of vegetarianism were found in 15 of 30 serum biomarkers; all cholesterol measures plus Vitamin D were significantly lower in vegetarians, while triglycerides were higher. GWIS detected evidence of gene-vegetarianism interaction with one genome-wide significant variant at rs72952628 (P = 4.47e-08) on calcium. rs72952628 is located in MMAA, which is part of the B12 metabolism pathway; B12 has a high deficiency potential in vegetarians. Gene-based aggregation of interaction P-values revealed two additional significant genes, RNF168 in testosterone (P = 1.45e-06), and DOCK4 in eGFR (P = 6.76e-07), which have previously been associated with testicular and renal traits, respectively. These studies illustrate nutrigenetic variants are being rapidly discovered, and underscore the need for personalized nutrition.