# A genome-wide association meta-analysis of cholesterol synthesis intermediates identifies three associations for lanosterol

## TL;DR

This study identifies new genetic links to cholesterol precursors, showing lanosterol's indirect role in heart disease.

## Contribution

The study reports four new genome-wide significant associations for cholesterol synthesis intermediates, including two novel loci.

## Key findings

- Four genome-wide significant associations were found, including two novel loci for lanosterol and free cholesterol.
- Lanosterol showed significant total and indirect effects on coronary artery disease, but no direct effect.
- Eight previously reported cholesterol-related loci were replicated in this analysis.

## Abstract

Cholesterol is a main contributor to coronary artery disease (CAD). Although the genetic basis of blood cholesterol concentration is well studied, there is currently a lack of studies investigating the genetics of its precursors from de novo biosynthesis.

We conducted a genome-wide association meta-analysis, combining data from KORA, LIFE-Heart, LIFE-Adult, LURIC, the Sorbs study, and YFS, resulting in up to 10,519 individuals. We investigated 14 traits related to serum concentrations of lanosterol, desmosterol, and cholesterol. Direct and indirect effects of lanosterol on CAD were investigated with a Mendelian randomisation mediation analysis.

Our analysis revealed four genome-wide significant (p < 5 × 10−8) associations not previously reported in the GWAS catalogue. These include two loci without prior connection to cholesterol, associated with lanosterol (7q21.2, CYP51A1) and free cholesterol (11q14.1), and two associations with lanosterol at loci previously reported for cholesterol (5q13.3, HMGCR; 11q23.3, APO cluster). We also replicated eight loci previously reported for associations with cholesterol-related traits. Lanosterol exhibited significant total and indirect effects on CAD, but its direct effect was not significant.

We demonstrate that the investigation of intermediate phenotypes can help to functionally fine map previously reported associations for cholesterol, improving our understanding of genetic regulation of cholesterol concentrations. Further, the effect of lanosterol on CAD is probably fully mediated by total cholesterol.

This investigation was primarily funded by the ministry for science and health of the Rhineland-Palatinate through the CoAGE graduate programme. A complete list of funding organisations is provided in the acknowledgements.