Direct effect of genetic ancestry on complex traits in a Mexican population

Human populations differ in disease prevalences and in average values of phenotypes, but the extent to which differences are caused by genetic or environmental factors is unknown for most complex traits. Comparing phenotypic means across populations is confounded by environmental differences and comparisons based on polygenic predictors can lead to biased inference1,2. Family-based analyses of genetically admixed individuals offer a powerful framework for disentangling the direct and associated effects of genetic ancestry on phenotypes. Here, we leverage genetic data from admixed adults in the Mexico City Prospective Study (MCPS)3,4 to estimate within-family ancestry effects5. We quantified associations between genetic ancestry and 15 complex traits among 52,583 unrelated individuals and in 39,714 relatives across 17,627 families. At the population level, relative to a European ancestry baseline, we estimate an effect of Indigenous American (IAM) ancestry of -1.98 standard deviations (P < 2x10-16) for height and a natural log-odds ratio (lnOR) of 1.73 (95% confidence interval [CI] 1.54-1.92) for type 2 diabetes (T2D, P < 2x10-16), and multiple associations with other traits and ancestries. We estimated a within-family direct effect of IAM of -1.51 standard deviations (P = 1.02x10-8) for height and lnOR of 5.13 (95% CI 2.48-7.78, P = 1.51x10-4) for risk of T2D. These direct effects are supported by between-ancestry differences in polygenic burden and evidence of selection at trait-associated loci. In contrast, we found no evidence for a direct effect of ancestry on educational attainment or other study traits despite large and significant associations at the population level, implying environmental causes or confounding. Overall, this study provides an experimental design to study between-ancestry genetic effects for complex traits and reports significant ancestry differences for height, T2D, and metabolic-related traits in a genetically diverse population from Mexico City.