Background.
Elevated blood lipids are heritable risk factors and major modifiable cause of cardiovascular disease. While long non-coding RNAs (lncRNAs) have important regulatory functions for lipid metabolism in model systems, the relationship between genetic variation in lncRNAs and blood lipid levels in humans is not well understood. We now utilize large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests to assess the association between lncRNAs across the genome and plasma lipid traits.

Methods.
We analyzed 66,329 individuals with TOPMed freeze8 WGS data and lipid levels (LDL-C, HDL-C, TC and TG). We defined lncRNA testing units by integrating annotations from four different genome annotation projects: GENCODE (v38), FANTOM CAT(robust), NONCODE (v6), and lncRNAKB (v7). We aggregated rare (MAF < 1%) variants for each lncRNA based on the lncRNA genomic locations and conducted the rare variants aggregate test using the STAAR framework incorporating multiple functional annotations. We further performed conditional analyses adjusting for previously reported common variants that associated with lipids. Since there are overlapping regions between the lncRNAs, we estimated the effective number of aggregate-based tests (Meff) for multiple testing correction.

Results.
In total, we conducted RV aggregate tests in 166k lncRNA regions with 113,587 effective number of aggregate-based tests. We identified 40, 31, 30, and 30 genome-wide significant (p < 0.05/111550 =4.5e-07) lncRNAs with LDL, HDL, TC and TG, respectively, in 16 loci. After conditioning on known lipid-associated variants, 21, 15, 16, and 11 associations remained significant. Of the significant lncRNAs in the conditional analysis, 16, 11, 14, and 10 associations were near at least a known lipid mendelian gene, including ENSG00000233271.1 near PCSK9 associated with LDL-C, NONHSAG026009.2 near APOE associated with TC, NONHSAG108446.1 near CETP associated with HDL-C, and NONHSAG009700.3 near APOA5 associated with TG. The remaining associations were all in lipid GWAS regions, except ENSG00000260441.5, which is an antisense to PLA2G15 that is associated with HDL-C.

Conclusions.
We discovered several associations between lncRNAs and plasma lipid traits, which provide insights into potential lipid regulatory mechanisms of GWAS loci. We will further seek replications in UK Biobank WGS and investigate the effects of lncRNAs on gene expression.