Genetic and Environmental Factors Influencing the Genomic Prediction of Complex Traits

Precision medicine is an emerging field in health care which aims to synthesize therapeutics precisely targeted towards a subgroup of individuals identified to be at a higher risk of a disease. The subgroups of individuals to be targeted are identified using predictive health genomics approaches which utilize genetic, environment, lifestyle, and ancestry information for disease risk stratification. While this field has shown some success in providing personalized treatment advice for Mendelian diseases, the challenge for the future is to extend it to common diseases and complex traits, which are polygenic and influenced by multiple environmental factors. Collectively these represent the largest health and economic burden for society. Using polygenic models and integrative genomic approaches, my thesis aims to understand the genetic and environmental factors influencing the genomic prediction of complex traits, with the goal of disease risk assessment and its implication in precision medicine. Specifically, I assessed disease risk using genomic data to study three overarching questions: (1) The role of polygenic risk score-by-environment interactions and how the rapid cultural changes of the modern environment interact with genetic variation and impact disease susceptibility; (2) The role of ancestry-specific genetic effects in the estimation of disease risk; (3) The ability of integrative genomic strategies, namely integrating gene expression profiling with GWAS, to move from prediction of disease onset to prediction of disease progression within cases. By analyzing the relationship between the prevalence of disease as a function of polygenic score (PGS) for 10 complex traits and 151 environmental exposures of the UK Biobank, I sought evidence of the process of (de)canalization i.e. the modern environment plays a major role in increasing the genetic variance leading to current surge in the prevalence of common diseases. Secondly, I argued that subtle differences in effect sizes and allele frequencies at the inflammatory bowel disease risk loci between Europeans and Africans, when combined into a PGS, can have a significant impact on the estimation of disease risk. Thus, as the focus moves towards precision medicine and clinical translation, ancestry-matched genetic effects must be used for accurate polygenic risk prediction and to avoid the exacerbation of health disparities. Thirdly, I introduced a transcriptome-wide association study (TWAS) method and its further utility by developing a genetic predictor based on predicted gene expression, called predicted polygenic transcriptional risk score (PPTRS). PPTRS offered advantage over both traditional PGS and transcriptional risk score (TRS), by not only predicting disease onset but also progression to colectomy in ulcerative colitis patients, from the genotypes alone, when gene expression profiling of the relevant tissue is impractical. Although certain challenges remain to addressed, integrating genomic, environment and ancestry information enhances the resolution of disease risk stratification and can help in clinical decision making, therapeutic interventions or lifestyle modifications as we move towards precision medicine.Ph.D

Mendelian Randomization Indicates a Causal Role for Omega-3 Fatty Acids in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal system. Omega-3 (ω3) fatty acids are polyunsaturated fatty acids (PUFAs) that are largely obtained from diet and have been speculated to decrease the inflammatory response that is involved in IBD; however, the causality of this association has not been established. A two-sample Mendelian randomization (MR) was used to assess genetic associations between 249 circulating metabolites measured in the UK Biobank as exposures and IBD as the outcome. The genome-wide association study summary level data for metabolite measurements and IBD were derived from large European ancestry cohorts. We observed ω3 fatty acids as a significant protective association with IBD, with multiple modes of MR evidence replicated in three IBD summary genetic datasets. The instrumental variables that were involved in the causal association of ω3 fatty acids with IBD highlighted an intronic SNP, rs174564, in FADS2, a protein engaged in the first step of alpha-linolenic acid desaturation leading to anti-inflammatory EPA and thence DHA production. A low ratio of ω3 to ω6 fatty acids was observed to be a causal risk factor, particularly for Crohn’s disease. ω3 fatty acid supplementation may provide anti-inflammatory responses that are required to attenuate inflammation that is involved in IBD

Pervasive Modulation of Obesity Risk by the Environment and Genomic Background

The prevalence of the so-called diseases of affluence, such as type 2 diabetes or hypertension, has increased dramatically in the last two generations. Although genome-wide association studies (GWAS) have discovered hundreds of genes involved in disease etiology, the sudden increase in disease incidence suggests a major role for environmental risk factors. Obesity constitutes a case example of a modern trait shaped by contemporary environment, although with considerable debates about the extent to which gene-by-environment (G×E) interactions accentuate obesity risk in individuals following obesogenic lifestyles. Although interaction effects have been robustly confirmed at the FTO locus, accumulating evidence at the genome-wide level implicates a role for polygenic risk-by-environment interactions. Through a variety of analyses using the UK Biobank, we confirm that the genomic background plays a major role in shaping the expressivity of alleles that increase body mass index (BMI)

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease