TY - JOUR TI - GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background AU - Sinnott-Armstrong, Nasa AU - Naqvi, Sahin AU - Rivas, Manuel AU - Pritchard, Jonathan K A2 - Flint, Jonathan A2 - Wittkopp, Patricia J A2 - Lynch, Vincent J A2 - Wray, Naomi A2 - Chakravarti, Aravinda VL - 10 PY - 2021 DA - 2021/02/15 SP - e58615 C1 - eLife 2021;10:e58615 DO - 10.7554/eLife.58615 UR - https://doi.org/10.7554/eLife.58615 AB - Genome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. We describe UK Biobank GWAS results for three molecular traits—urate, IGF-1, and testosterone—with better-understood biology than most other complex traits. We find that many of the most significant hits are readily interpretable. We observe huge enrichment of associations near genes involved in the relevant biosynthesis, transport, or signaling pathways. We show how GWAS data illuminate the biology of each trait, including differences in testosterone regulation between females and males. At the same time, even these molecular traits are highly polygenic, with many thousands of variants spread across the genome contributing to trait variance. In summary, for these three molecular traits we identify strong enrichment of signal in putative core gene sets, even while most of the SNP-based heritability is driven by a massively polygenic background. KW - complex traits KW - biomarkers KW - genome-wide association study KW - testosterone KW - igf-1 KW - urate JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -