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It is important to study the genetics of complex traits in diverse populations. Here, we introduce covariate-adjusted linkage disequilibrium (LD) score regression (cov-LDSC), a method to estimate SNP-heritability (  ${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}})$   and its enrichment in homogenous and admixed populations with summary statistics and in-sample LD estimates. In-sample LD can be estimated from a subset of the genome-wide association studies samples, allowing our method to be applied efficiently to very large cohorts. In simulations, we show that unadjusted LDSC underestimates   ${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}}$   by 10–60% in admixed populations; in contrast, cov-LDSC is robustly accurate. We apply cov-LDSC to genotyping data from 8124 individuals, mostly of admixed ancestry, from the Slim Initiative in Genomic Medicine for the Americas study, and to approximately 161 000 Latino-ancestry individuals, 47 000 African American-ancestry individuals and 135 000 European-ancestry individuals, as classified by 23andMe. We estimate   ${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}}$   and detect heritability enrichment in three quantitative and five dichotomous phenotypes, making this, to our knowledge, the most comprehensive heritability-based analysis of admixed individuals to date. Most traits have high concordance of   ${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}}$   and consistent tissue-specific heritability enrichment among different populations. However, for age at menarche, we observe population-specific heritability estimates of   ${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}}$  . We observe consistent patterns of tissue-specific heritability enrichment across populations; for example, in the limbic system for BMI, the per-standardized-annotation effect size   $ \tau $   *  is 0.16 ± 0.04, 0.28 ± 0.11 and 0.18 ± 0.03 in the Latino-, African American- and European-ancestry populations, respectively. Our approach is a powerful way to analyze genetic data for complex traits from admixed populations.

Estimating heritability and its enrichment in tissue-specific gene sets in admixed populations