Journal Article

DZNE-2020-02844

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Integrated genome-wide pathway association analysis with INTERSNP.

Herold, C. ; Mattheisen, M. ; Lacour, A. ; Vaitsiakhovich, T. ; Angisch, M. ; Drichel, D. ; Becker, T. (Last author)DZNE*

2012
Karger Basel

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Please use a persistent id in citations: doi:10.1159/000336196

Abstract: Pathway association analysis (PAA) tests for an excess of moderately significant SNPs in genes from a common pathway.We present a Monte-Carlo simulation framework that allows to formulate the main ideas of existing PAA approaches using a self-contained rather than a competitive null hypothesis. A stand-alone implementation in INTERSNP makes time-consuming communication with standard GWAS software redundant. By additional parallelization with the OpenMP API, we achieve a reduction in running time for PAA by orders of magnitude, making a power simulation study for PAA feasible. Our approach properly accounts for linkage disequilibrium and is robust with respect to residual λ inflation.We demonstrate that under simple, realistic disease models, PAA can actually strongly outperform the GWAS single-marker approach. PAA methods that make use of the strength of the SNP association (GenGen, Fisher's combination test), in general, perform better than ratio-based methods (ALIGATOR, SNP ratio), whereas the relative performance of gene-based scoring (ALIGATOR, GenGen) and pathway-based scoring (SNP ratio, Fisher's combination test) depends on the architecture of the assumed disease model. Finally, we present a new PAA score that models independent signals from the same gene in a regression framework and show that it is a reasonable compromise that combines the advantages of existing ideas.

Keyword(s): Genome-Wide Association Study: methods (MeSH) ; Humans (MeSH) ; Monte Carlo Method (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Software (MeSH)

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Contributing Institute(s):

1. GenomMathematik in der Neuroepidemiologie (AG Becker)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2012

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Database coverage:
; Allianz-Lizenz ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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