Abstract
Genetic predisposition for complex traits often acts through multiple tissues at different time points during development. As a simple example, the genetic predisposition for obesity could be manifested either through inherited variants that control metabolism through regulation of genes expressed in the brain, or that control fat storage through dysregulation of genes expressed in adipose tissue, or both. Here we describe a statistical approach that leverages tissue-specific expression quantitative trait loci (eQTLs) corresponding to tissue-specific genes to prioritize a relevant tissue underlying the genetic predisposition of a given individual for a complex trait. Unlike existing approaches that prioritize relevant tissues for the trait in the population, our approach probabilistically quantifies the tissue-wise genetic contribution to the trait for a given individual. We hypothesize that for a subgroup of individuals the genetic contribution to the trait can be mediated primarily through a specific tissue. Through simulations using the UK Biobank, we show that our approach can predict the relevant tissue accurately and can cluster individuals according to their tissue-specific genetic architecture. We analyze body mass index (BMI) and waist to hip ratio adjusted for BMI (WHRadjBMI) in the UK Biobank to identify subgroups of individuals whose genetic predisposition act primarily through brain versus adipose tissue, and adipose versus muscle tissue, respectively. Notably, we find that these individuals have specific phenotypic features beyond BMI and WHRadjBMI that distinguish them from random individuals in the data, suggesting biological effects of tissue-specific genetic contribution for these traits.
Highlights
Multiple clinical, pathologic, and molecular lines of evidence suggest that many phenotypes and diseases show heterogeneity and can be viewed as a collection of multiple traits in the population [1,2,3,4,5]
Other examples include adiposity traits such as body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI (WHRadjBMI), that can be subtyped based on genetic variants with distinct patterns of fat depots and metabolism [14]
The main hypothesis underlying our model is that the genetic susceptibility of a complex trait for a given individual is mediated through regulation of either gene A in tissue 1 or gene B in tissue 2 or both
Summary
Pathologic, and molecular lines of evidence suggest that many phenotypes and diseases show heterogeneity and can be viewed as a collection of multiple traits (i.e. subtypes) in the population [1,2,3,4,5]. Autism can be subtyped by grouping together individuals with recurrent mutations in the same autism-associated gene [10, 12]; type 2 diabetes can be subtyped using clusters of genetic variants previously associated with the disease [13]. Other examples include adiposity traits such as body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI (WHRadjBMI), that can be subtyped based on genetic variants with distinct patterns of fat depots and metabolism [14]. Genetic subtyping offers an advantage over phenotypic subtyping in that germline genetic characteristics are more stable than phenotypic characteristics of an individual [12, 13]
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