Genetic interactions and pleiotropy in metabolic diseases: Insights from a comprehensive GWAS analysis

Abstract This study offers insights into the genetic and biological connections between nine common metabolic diseases using data from genome‐wide association studies. Our goal is to unravel the genetic interactions and biological pathways of these complex diseases, enhancing our understanding of their genetic architecture. We employed a range of advanced analytical techniques to explore the genetic correlations and shared genetic variants of these diseases. These methods include Linked Disequilibrium Score Regression, High‐Definition Likelihood (HDL), genetic analysis combining multiplicity and annotation (GPA), two‐sample Mendelian randomization analyses, analysis under the multiplicity‐complex null hypothesis (PLACO), and Functional mapping and annotation of genetic associations (FUMA). Additionally, Bayesian co‐localization analyses were used to examine associations of specific loci across traits. Our study discovered significant genomic correlations and shared loci, indicating complex genetic interactions among these metabolic diseases. We found several shared single nucleotide variants and risk loci, notably highlighting the role of the immune system and endocrine pathways in these diseases. Particularly, rs2476601 and its associated gene PTPN22 appear to play a crucial role in the connection between type 2 diabetes mellitus, hypothyroidism/mucous oedema and hypoglycaemia. These findings enhance our understanding of the genetic underpinnings of these diseases and open new potential avenues for targeted therapeutic and preventive strategies. The results underscore the importance of considering pleiotropic effects in deciphering the genetic architecture of complex diseases, especially metabolic ones.