TY  - JOUR
AU  - Lin, Hui-Yi
AU  - Mazumder, Harun
AU  - Sarkar, Indrani
AU  - Huang, Po-Yu
AU  - Eeles, Rosalind A
AU  - Kote-Jarai, Zsofia
AU  - Muir, Kenneth R
AU  - Schleutker, Johanna
AU  - Pashayan, Nora
AU  - Batra, Jyotsna
AU  - Neal, David E
AU  - Nielsen, Sune F
AU  - Nordestgaard, Børge G
AU  - Grönberg, Henrik
AU  - Wiklund, Fredrik
AU  - MacInnis, Robert J
AU  - Haiman, Christopher A
AU  - Travis, Ruth C
AU  - Stanford, Janet L
AU  - Kibel, Adam S
AU  - Cybulski, Cezary
AU  - Khaw, Kay-Tee
AU  - Maier, Christiane
AU  - Thibodeau, Stephen N
AU  - Teixeira, Manuel R
AU  - Cannon-Albright, Lisa
AU  - Brenner, Hermann
AU  - Kaneva, Radka
AU  - Pandha, Hardev
AU  - Park, Jong Y
TI  - Cluster effect for SNP-SNP interaction pairs for predicting complex traits.
JO  - Scientific reports
VL  - 14
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DKFZ-2024-01651
SP  - 18677
PY  - 2024
AB  - Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP-SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP-SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP-SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP-SNP interaction detection accuracy.
KW  - Polymorphism, Single Nucleotide
KW  - Humans
KW  - Multifactorial Inheritance: genetics
KW  - Gene Frequency
KW  - Genome-Wide Association Study: methods
KW  - Cluster Analysis
KW  - Models, Genetic
KW  - Epistasis, Genetic
KW  - Cluster (Other)
KW  - False positivity (Other)
KW  - SNP interaction (Other)
KW  - Simulation (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39134575
DO  - DOI:10.1038/s41598-024-66311-7
UR  - https://inrepo02.dkfz.de/record/292290
ER  -