Journal
JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION
Volume 117, Issue 537, Pages 1-11Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/01621459.2021.1906684
Keywords
Bias correction; Genome-wide association studies; Marginal screening; Polygenic risk score
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Funding
- NIH [MH086633, MH116527]
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The study investigates and addresses the bias phenomenon of cross-trait PRS in numerous GWAS applications and proposes a consistent estimator to correct the bias. Results show that the bias-corrected estimators uncover a moderate degree of genetic overlap between cognitive function and human brain structures.
Cross-trait polygenic risk score (PRS) method has gained popularity for assessing genetic correlation of complex traits using summary statistics from biobank-scale genome-wide association studies (GWAS). However, empirical evidence has shown a common bias phenomenon that highly significant cross-trait PRS can only account fora very small amount of genetic variance (R-2 can be < 1%) in independent testing GWAS. The aim of this paper is to investigate and address the bias phenomenon of cross-trait PRS in numerous GWAS applications. We show that the estimated genetic correlation can be asymptotically biased toward zero. A consistent cross-trait PRS estimator is then proposed to correct such asymptotic bias. In addition, we investigate whether or not SNP screening by GWAS p-values can lead to improved estimation and show the effect of overlapping samples among GWAS. We analyze GWAS summary statistics of reaction time and brain structural magnetic resonance imaging-based features measured in the Pediatric Imaging, Neurocognition, and Genetics study. We find that the raw cross-trait PRS estimators heavily underestimate the genetic similarity between cognitive function and human brain structures (mean R-2 = 1.32%), whereas the bias-corrected estimators uncover the moderate degree of genetic overlap between these closely related heritable traits (mean R-2 = 22.42%). Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.
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