Estimating heritability and its enrichment in tissue-specific gene sets in admixed populations. Issue 16 (13th May 2021)

• Record Type: Journal Article
• Authors: Luo, Yang; Li, Xinyi; Wang, Xin; Gazal, Steven; Mercader, Josep Maria; Neale, Benjamin M; Florez, Jose C; Auton, Adam; Price, Alkes L; Finucane, Hilary K; Raychaudhuri, Soumya
• Is Part Of: Human molecular genetics. Volume 30:Issue 16(2021)
• Page Start: 1521
• Page End: 1534
• Publication Date: 2021-05-13
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddab130
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: 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.