A genetic stochastic process model for genome-wide joint analysis of biomarker dynamics and disease susceptibility with longitudinal data

摘要

Unraveling the underlying biological mechanisms or pathways behind the identified effects of genetic variations on complex diseases remains one of the major challenges in the post-GWAS era. To further explore the relationship between genetic variation, biomarkers, and diseases for elucidating underlying pathological mechanism, a huge effort has been placed on examining pleiotropic and gene-environmental interaction effects. We propose a novel genetic stochastic process model (GSPM) that can be applied to GWAS and jointly investigate the genetic effects on longitudinally-measured biomarkers and risks of diseases. This model is characterized by more profound biological interpretation and takes into account the dynamics of biomarkers during follow-up when investigating the hazards of a disease. We illustrate the rationale and evaluate the performance of the proposed model through two genome-wide association studies. One is to detect single nucleotide polymorphisms (SNPs) having interaction effects on type 2 diabetes (T2D) with body mass index (BMI) and the other is to detect SNPs affecting the optimal BMI level for protecting from T2D. We identified multiple SNPs that showed interaction effects with BMI on T2D, including a novel SNP rs11757677 in the CDKAL1 gene (p=5.77e-07). We also found a SNP rs1551133 located on 2q14.2 that reversed the effect of BMI on T2D (p=6.70e-07). In conclusion, the proposed GSPM provides a promising and useful alternative in GWAS of longitudinal data for interrogating pleiotropic and interaction effects to gain more insights into the relationship between genes, quantitative biomarkers and risks of complex diseases.