Background:
Blood lipids and specifically low-density lipoprotein cholesterol (LDL-C) is a heritable risk factor for cardiovascular diseases, a leading cause of death. Recent genome-wide association studies (GWAS) identified numerous loci related to blood lipid levels, but the role of rare non-coding variants is less well-understood. Whole-genome sequencing (WGS) allows exploration of these variants. Our study meta-analyzed WGS data from two large datasets (TOPMed, n=72,175 and UK Biobank, n=173,982), yielding the largest WGS analysis for LDL-C.
Methods:
We ascertained deep-coverage WGS and LDL-C from UK Biobank and NHLBI freeze 10 (n=23 cohorts). We harmonized and normalized lipid measures from individual cohort and adjusted for age, sex, cohort-race, PCs and accounted for lipid-lowering medicine status. To enable efficient WGS meta-analysis across UK Biobank and TOPMed freeze 10, we implemented the MetaSTAAR workflow. In addition to single variant analyses, we performed gene-centric coding and non-coding set-based, and region-based sliding window meta-analysis of rare variants (MAF <1%) for LDL-C. Finally, we replicated our findings in All of Us WGS data.
Results:
We generated variant summary statistics and covariances matrices for UK Biobank and TOPMed, independently. We processed 571M and 660M variants from TOPMed and UKB respectively, in which 92M variants had a minor allele count >20. We then conducted the meta-analysis of both studies following the MetaSTAAR workflow. We used 5gene-centric coding variant masks and 7 non-coding variant masks and filtered genome significant aggregates based on Bonferroni-correction(0.05/(20K*masks)). Before conditional analysis we obtained 70 and 111 aggregates significantly associated with LDL-C for coding and non-coding region, respectively. After adjusting for known common variants we obtained 39 and 44 aggregates and replicated 25 and 28 coding and non-coding aggregates respectively. Many important known Mendelian lipid genes including LDLR, APOB, PCSK9 were significant and novel rare variant aggregates in ABCA6
and RELB were also significantly associated with LDL-C.
Conclusion:
In summary, we extend prior observations of rare non-coding variants near Mendelian lipid genes to now novel genes without prior known common non-coding or rare variant coding evidence.