Introduction
Autosomal genetic analyses of plasma lipids have yielded key fundamental and clinical insights for the relationships between plasma lipids and coronary heart disease (CHD); however, genetic variation on the X chromosome has been understudied for plasma lipids in large sample sizes.

Hypothesis
High-coverage next-generation sequence analysis of the X chromosome will yield novel genetic associations for plasma lipids.

Methods
We aggregated plasma lipids and X chromosome sequence variation from 53,520 individuals with high-coverage (~38X) whole genome sequence (WGS) data from 21 cohorts in the NHLBI TOPMed program. We associated individual variants (minor allele count > 20) using linear mixed models and aggregated rare (minor allele frequency < 1%), predicted disruptive variants using SKAT. Significant lipid associations with were evaluated for associations with lipids and CHD in GWAS/imputed datasets from the UK Biobank (18,204 cases, 372,402 controls) and HUNT (7,710 cases, 61,881 controls).

Results
Three variants at chrXq23 in moderate linkage disequilibrium (r2 > 0.60) were significantly (P<1x10-9) associated with reduced levels of total cholesterol (-1.9 mg/dl), low-density lipoprotein cholesterol (-1.5 mg/dl), and triglycerides (-2.02%), with similar effects in males and females. These variants replicated in UK Biobank (P<1x10-29) and HUNT (P<4x10-8); other variants with P<1x10-6 in discovery did not replicate. Phenome-wide association analyses in UK Biobank data identified significant associations with these variants for reduced risk of type 2 diabetes risk, glaucoma, and hypertension, but increased body-mass index. Co-localization analyses with GTEx gene expression data implicated reduced CHRDL1 expression in subcutaneous adipose tissue with reduced lipid level. In both UK Biobank and HUNT data, the three variants were associated with 3% reduced odds of CHD (meta-analysis P<0.002). For targeted assessment of the 8 genes within +/- 1Mb of the lead single variants, rare predicted disruptive variants in CHRDL1 were significantly associated with reduced triglycerides (P=0.002).

Conclusions
ChrXq23 is a novel genetic locus for plasma lipid levels and may also associate with related cardiometabolic traits.