P4411Analysis of cardiometabolic traits highlights shared biological pathways

Abstract

Abstract Genome-wide association studies (GWAS) have contributed to a major leap forward in the unravelling of the genetic basis of complex disorders, and identified over 900 genetic loci for blood pressure (BP) regulation, 160 for coronary artery disease (CAD) and 140 for type 2 diabetes (T2D). The ubiquitousness of genetic pleiotropy and the fact that cardiovascular diseases, T2D, and other metabolic disorders share a number of risk factors, suggest that these conditions may have common underlying molecular mechanisms. We aimed to dissect shared genetic factors contributing to the comorbidity of these diseases using multi-phenotype approach. Using summary statistics from published GWAS available in public domain, including those from GWAS consortia DIAGRAM/DIAMANTE (T2D), MAGIC/ENGAGE (glycaemic), ICBP (blood pressure, BP), CARDIOGRAM (cardiovascular), GLGC/ENGAGE (lipids), GIANT (obesity), we analysed 3429 single nucleotide variants (SNVs) associated with 63 cardiometabolic phenotypes (defined as related to T2D, cardiovascular and metabolic disorders). We identified 301 unique association signals, and found 426 CAD/BP SNVs overlapping with 1194 SNVs reported for other phenotypes and located within 100kb from one another. Further analysis revealed 49 linkage patterns for cardiometabolic phenotypes (D'>0.9, r2>0.8). Specifically, nine SNVs in SH2B3-ATXN2 locus are associated with CAD, systolic and diastolic BP, stroke, ICAM-1 and diabetes; three SNVs in ATP5G1- UBE2Z influence CAD risk, T2D, and anthropometric traits; nine SNVs in TCF7L2 are associated with pulse pressure (PP), body mass index (BMI), glycaemic traits and T2D risk; four SNVs in ADAMTS9 and three in BCL2 are associated with BP traits, T2D, and abdominal obesity; twelve SNVs in IRS1 gene are related to hypertension, T2D risk, glycaemic and lipid traits; ten SNVs in MTNR1B affect PP, T2D susceptibility, and glycaemic traits; six SNVs in KLF14 influence systolic BP, T2D, and high density lipoproteins (HDL) level; nine SNVs in ABO affect CAD, T2D, and stroke susceptibility, as well as lipids and ICAM-1 level; eight SNVs in CDKAL1 are associated with systolic BP, increased T2D risk, and glycaemic traits; two in SLC39A8 affect BP traits, lipid levels, and BMI. Our results highlight the pathways that influence multiple cardiometabolic phenotypes, including circadian rhythm regulation (MTNR1B), pancreatic islet function and insulin signalling (CDKAL1 and IRS1), appetite control and nutritional regulation (NUCB2 and ATXN2), immune and inflammatory signaling (SH2B3 and SLC39A8), cell cycle regulation and apoptosis (UBE2Z and BCL2), angiogenesis (ADAMTS9), suggesting that similar disease-driving biological processes are implicated in the pathogenesis of these diseases.