Journal Article

Causal effects on complex traits are similar for common variants across segments of different continental ancestries within admixed individuals

Rasmussen-Torvik, Laura J., Pasaniuc, Bogdan, Bhattacharya, Arjun, Buyske, Steve, Wojcik, Genevieve L., Conti, David V., Wu, Yue, Fornage, Myriam, Peters, Ulrike, Xu, Ziqi, Darst, Burcu F., Haiman, Christopher, Guo, Xiuqing, Mester, Rachel, Gignoux, Chris, Kim, Michelle, Kooperberg, Charles, Rotter, Jerome I., Belbin, Gillian M., North, Kari E., Wheeler, Heather E., Zhou, Ying, Lange, Leslie, Manichaikul, Ani, Ding, Yi, Rich, Stephen S., Hou, Kangcheng, Kenny, Eimear E., Sankararaman, Sriram

2023

Overview

Individuals of admixed ancestries (for example, African Americans) inherit a mosaic of ancestry segments (local ancestry) originating from multiple continental ancestral populations. This offers the unique opportunity of investigating the similarity of genetic effects on traits across ancestries within the same population. Here we introduce an approach to estimate correlation of causal genetic effects ( r admix ) across local ancestries and analyze 38 complex traits in African-European admixed individuals ( N  = 53,001) to observe very high correlations (meta-analysis r admix  = 0.95, 95% credible interval 0.93–0.97), much higher than correlation of causal effects across continental ancestries. We replicate our results using regression-based methods from marginal genome-wide association study summary statistics. We also report realistic scenarios where regression-based methods yield inflated heterogeneity-by-ancestry due to ancestry-specific tagging of causal effects, and/or polygenicity. Our results motivate genetic analyses that assume minimal heterogeneity in causal effects by ancestry, with implications for the inclusion of ancestry-diverse individuals in studies. This analysis of individuals of admixed genetic ancestries suggests that complex trait causal variant effect sizes are, by and large, similar across ancestries, and discusses the implications for the study of these and other diverse populations.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/114 / 631/208/205/2138 / 631/208/457 / Agriculture / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Black or African American - genetics / Cancer Research / Gene Function / Genetic analysis / Genetic effects / Genetics, Population / Genome-wide association studies / Genome-Wide Association Study - methods / Genomes / Genotype & phenotype / Heterogeneity / Human Genetics / Humans / Hypothesis testing / Meta-analysis / Multifactorial Inheritance - genetics / Polymorphism, Single Nucleotide - genetics / Racial Groups - genetics / Random variables / Segments / Statistical analysis