Journal
GENETIC EPIDEMIOLOGY
Volume 43, Issue 8, Pages 930-940Publisher
WILEY
DOI: 10.1002/gepi.22259
Keywords
GWAS; heritability estimation; misspecified models
Funding
- European Unions Horizon 2020 Research and Innovation Programme [754513]
- Marie Skodowska-Curie grant [75451]
- Aarhus Universitets Forskningsfond [702500094B]
- Australian Research Council [DP190103188]
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Linkage disequilibrium SCore regression (LDSC) has become a popular approach to estimate confounding bias, heritability, and genetic correlation using only genome-wide association study (GWAS) test statistics. SumHer is a newly introduced alternative with similar aims. We show using theory and simulations that both approaches fail to adequately account for confounding bias, even when the assumed heritability model is correct. Consequently, these methods may estimate heritability poorly if there was an inadequate adjustment for confounding in the original GWAS analysis. We also show that the choice of a summary statistic for use in LDSC or SumHer can have a large impact on resulting inferences. Further, covariate adjustments in the original GWAS can alter the target of heritability estimation, which can be problematic for test statistics from a meta-analysis of GWAS with different covariate adjustments.
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