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Genetic variants can alter response to drugs and other therapeutic interventions. The study of this phenomenon, called pharmacogenomics, is similar in many ways to other types of genetic studies but has distinct methodological and statistical considerations. Genetic variants involved in the processing of exogenous compounds exhibit great diversity and complexity, and the phenotypes studied in pharmacogenomics are also more complex than typical genetic studies. In this chapter, we review basic concepts in pharmacogenomic study designs, data generation techniques, statistical analysis approaches, and commonly used methods and briefly discuss the ultimate translation of findings to clinical care., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Obesity is a highly heritable condition that affects increasing numbers of adults and, concerningly, of children. However, only a small fraction of its heritability has been attributed to specific genetic variants. These variants are traditionally ascertained from genome-wide association studies (GWAS), which utilize samples with tens or hundreds of thousands of individuals for whom a single summary measurement (e.g., BMI) is collected. An alternative approach is to focus on a smaller, more deeply characterized sample in conjunction with advanced statistical models that leverage longitudinal phenotypes. Novel functional data analysis (FDA) techniques are used to capitalize on longitudinal growth information from a cohort of children between birth and three years of age. In an ultra-high dimensional setting, hundreds of thousands of single nucleotide polymorphisms (SNPs) are screened, and selected SNPs are used to construct two polygenic risk scores (PRS) for childhood obesity using a weighting approach that incorporates the dynamic and joint nature of SNP effects. These scores are significantly higher in children with (vs. without) rapid infant weight gain-a predictor of obesity later in life. Using two independent cohorts, it is shown that the genetic variants identified in very young children are also informative in older children and in adults, consistent with early childhood obesity being predictive of obesity later in life. In contrast, PRSs based on SNPs identified by adult obesity GWAS are not predictive of weight gain in the cohort of young children. This provides an example of a successful application of FDA to GWAS. This application is complemented with simulations establishing that a deeply characterized sample can be just as, if not more, effective than a comparable study with a cross-sectional response. Overall, it is demonstrated that a deep, statistically sophisticated characterization of a longitudinal phenotype can provide increased statistical power to studies with relatively small sample sizes; and shows how FDA approaches can be used as an alternative to the traditional GWAS., Competing Interests: Declarations of interest none

The metabolic activities of microbial communities play a defining role in the evolution and persistence of life on Earth, driving redox reactions that give rise to global biogeochemical cycles. Community metabolism emerges from a hierarchy of processes, including gene expression, ecological interactions, and environmental factors. In wild communities, gene content is correlated with environmental context, but predicting metabolite dynamics from genomes remains elusive. Here, we show, for the process of denitrification, that metabolite dynamics of a community are predictable from the genes each member of the community possesses. A simple linear regression reveals a sparse and generalizable mapping from gene content to metabolite dynamics for genomically diverse bacteria. A consumer-resource model correctly predicts community metabolite dynamics from single-strain phenotypes. Our results demonstrate that the conserved impacts of metabolic genes can predict community metabolite dynamics, enabling the prediction of metabolite dynamics from metagenomes, designing denitrifying communities, and discovering how genome evolution impacts metabolism. [Display omitted] • Metabolite fluxes in microbial communities are predictable from individual genotypes • A diverse collection of 79 bacterial isolates was sequenced and phenotyped • Gene presence and absence predict metabolic phenotypes of isolates via regression • A consumer-resource model predicts community metabolite fluxes from phenotypes The presence or absence of specific genes within communities of wild bacterial isolates is sufficient to predict community-level metabolite dynamics without detailed knowledge of pathway regulation or complex ecological processes. [ABSTRACT FROM AUTHOR]