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A flexible and parallelizable approach to genome-wide polygenic risk scores.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Nelson, Christopher P 
Samani, Nilesh J 

Abstract

The heritability of most complex traits is driven by variants throughout the genome. Consequently, polygenic risk scores, which combine information on multiple variants genome-wide, have demonstrated improved accuracy in genetic risk prediction. We present a new two-step approach to constructing genome-wide polygenic risk scores from meta-GWAS summary statistics. Local linkage disequilibrium (LD) is adjusted for in Step 1, followed by, uniquely, long-range LD in Step 2. Our algorithm is highly parallelizable since block-wise analyses in Step 1 can be distributed across a high-performance computing cluster, and flexible, since sparsity and heritability are estimated within each block. Inference is obtained through a formal Bayesian variable selection framework, meaning final risk predictions are averaged over competing models. We compared our method to two alternative approaches: LDPred and lassosum using all seven traits in the Welcome Trust Case Control Consortium as well as meta-GWAS summaries for type 1 diabetes (T1D), coronary artery disease, and schizophrenia. Performance was generally similar across methods, although our framework provided more accurate predictions for T1D, for which there are multiple heterogeneous signals in regions of both short- and long-range LD. With sufficient compute resources, our method also allows the fastest runtimes.

Description

Keywords

Bayesian variable selection, meta-GWAS, polygenic risk scores, risk prediction, summary statistics, Area Under Curve, Case-Control Studies, Coronary Artery Disease, Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Models, Genetic, Multifactorial Inheritance, Polymorphism, Single Nucleotide, ROC Curve, Risk Factors, Schizophrenia

Journal Title

Genet Epidemiol

Conference Name

Journal ISSN

0741-0395
1098-2272

Volume Title

43

Publisher

Wiley
Sponsorship
MRC (1185)
Wellcome Trust (076113/C/04/Z)
Wellcome Trust (061858/Z/00/E)