GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

Abstract

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.

Prospective analyses of testosterone and sex hormone‐binding globulin with the risk of 19 types of cancer in men and postmenopausal women in UK Biobank

“…18,19 There are large sex differences in the regulation and quantities of serum androgens in men and postmenopausal women, therefore associations with disease risk should be assessed separately. 20 In men, testosterone is primarily synthesized by the testes and serum concentrations of free testosterone are regulated by the hypothalamic-pituitary-gonadal (HPG) axis. 21 In postmenopausal women, testosterone is primarily synthesized peripherally from androstenedione and other androgen precursors as well as by the ovaries, and the HPG axis is thought to have little direct effect in the regulation of testosterone concentrations.…”

MRLocus: Identifying causal genes mediating a trait through Bayesian estimation of allelic heterogeneity

“…Furthermore, MRLocus is designed for investigating loci with strong causal gene candidates, whereas other methods that estimate gene-to-trait effects for many genes in a locus simultaneously may have less biased estimation of the effect, when a strong gene candidate is not present. Future work on the MRLocus model may involve estimation of the mediating effect of candidate causal genes in the context of other relevant genes in a pathway and a polygenic background [75].…”

Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program

“…Given the large mean handgrip strength difference between men and women, we might expect that handgrip strength may have at least some different genetic associations in men and women. A recent GWAS of testosterone identified, for instance, extreme sex differences in testosterone genetic architecture [ 60 ].…”