Integrative genomic dissection of cardio-kidney-metabolic syndrome reveals novel loci, causal genes, and tissue-specific pathways in European populations

Cardiovascular-kidney-metabolic (CKM) syndrome has placed a substantial burden on society both socially and economically. But currently, little is known about the genetic structure of CKM syndrome. A multivariate genome-wide association study (GWAS) of CKM syndrome (mvCKM) in Europe was performed via genomic structural equation modelling (gSEM). A subsequent series of post-GWAS analyses elucidated novel loci and functional mechanisms of mvCKM. Cell-gene-pathway-Mendelian disease analysis further revealed the enrichment status of mvCKM. We particularly focused on various genomic loci and chromosomal regions related to CKM syndrome to explore potential targets. A total of 260 novel SNPs were identified and 92 causal SNPs were estimated independent of single phenotypes. Furthermore, we employed multiple transcriptome-wide association analysis approaches to explore 10 susceptible genes. The multi-marker analysis for genome annotation at the cellular level demonstrated that mvCKM was primarily enriched in metabolic cells, organs, and associated pathways. Partitioned heritability analysis revealed that conserved regions may make substantial genomic contributions. Polygenic risk scores indicated high genetic contributions from regions on chromosomes 4, 6, 1, and 9. This study provides an essential understanding of the genetic architecture of CKM syndrome via mvCKM in Europeans, offering new viewpoints for precision medicine and public health initiatives.