Background So far, more than 170 loci have been associated with circulating lipid levels through genomewide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ~60 000 individuals in the discovery stage and ~90 000 samples in the replication stage. Results Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. Conclusions This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

Additional Metadata
Persistent URL dx.doi.org/10.1136/jmedgenet-2015-103439, hdl.handle.net/1765/90797
Journal Journal of Medical Genetics
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/201413 - European Network for Genetic and Genomic Epidemiology (ENGAGE), This work was funded by the European Commission 7th Framework Programme; grant id fp7/259679 - Integrated research on DEvelopmental determinants of Aging and Longevity (IDEAL), This work was funded by the European Commission 7th Framework Programme; grant id fp7/279143 - Identification of epigenetic markers underlying increased risk of T2D in South Asians (EPI-MIGRANT)
Citation
van Leeuwen, E.M, Sabo, A, Bis, J.C, Huffman, J.E, Manichaikul, A, Smith, G.D, … van Duijn, C.M. (2016). Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels. Journal of Medical Genetics. doi:10.1136/jmedgenet-2015-103439