In a combined analysis of UKB and MVP with a sample size of up to 840K, we identify 108 Bonferroni-significant genes associated with lipid traits, including 41 for HDL (below), more than doubling the number of genes identified in our previous analyses.

Though we recommend using LD calculated in a relevant sample, due to the low LD among rare variants, the test remains valid even when variants are assumed to be in linkage equilibrium.

In simulations and real data, we show that COAST-SS is robust to how linkage disequilibrium (LD) is specified.

In summary, associations with ratio traits are not specific to the ratio per se. Practitioners considering GWAS on ratios should examine the motivation for forming the ratio. We provide guidance on how to approach GWAS of related pairs of traits in light of analysis objectives.

In the case where the denominator is heritable and collider bias is a concern, we propose additionally adjusting for a leave-one-chromosome-out polygenic score (LOCO-PGS) of the denominator, which we show corrects for collider bias due to genetic background.

Examining ratio traits commonly used in clinical practice and genetic association testing, such as waist-to-hip ratio and albumin-to-creatinine ratio, we find that loci detected by the ratio model are enriched for denominator signals.

Top “hits” from ratio trait GWASs can be driven entirely by the denominator. This means, for example, that attempts to find genes associated with BMI may return genes associated entirely with height (only), and not weight.