Genome-Wide Search for SNP Interactions in GWAS Data: Algorithm, Feasibility, Replication Using Schizophrenia Datasets

Kwan-Yeung Lee; Kwong-Sak Leung; Suk Ling Ma; Hon Cheong So; Dan Huang; Nelson Leung-Sang Tang; Man-Hon Wong

doi:10.3389/fgene.2020.01003

Genome-Wide Search for SNP Interactions in GWAS Data: Algorithm, Feasibility, Replication Using Schizophrenia Datasets

Front Genet. 2020 Aug 28:11:1003. doi: 10.3389/fgene.2020.01003. eCollection 2020.

Authors

Kwan-Yeung Lee¹, Kwong-Sak Leung¹, Suk Ling Ma², Hon Cheong So^{2

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4

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8}, Dan Huang⁹, Nelson Leung-Sang Tang^{4

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11}, Man-Hon Wong¹

Affiliations

¹ Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, China.
² Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong, China.
³ School of Biomedical Science, The Chinese University of Hong Kong, Hong Kong, China.
⁴ Hong Kong Branch of CAS Center for Excellence in Animal Evolution and Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
⁵ KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology, The Chinese University of Hong Kong, Hong Kong, China.
⁶ Margaret K.L. Cheung Research Centre for Management of Parkinsonism, The Chinese University of Hong Kong, Hong Kong, China.
⁷ Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
⁸ Brain and Mind Institute, The Chinese University of Hong Kong, Hong Kong, China.
⁹ Cytomics Ltd, Shatin, Hong Kong.
¹⁰ Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
¹¹ Functional Genomics and Biostatistical Computing Laboratory, CUHK Shenzhen Research Institute, Shenzhen, China.

Abstract

In this study, we looked for potential gene-gene interaction in susceptibility to schizophrenia by an exhaustive searching for SNP-SNP interactions in 3 GWAS datasets (phs000021:phg000013, phs000021:phg000014, phs000167) using our recently published algorithm. The search space for SNP-SNP interaction was confined to 8 biologically plausible ways of interaction under dominant-dominant or recessive-recessive modes. First, we performed our search of all pair-wise combination of 729,454 SNPs after filtering by SNP genotype quality. All possible pairwise interactions of any 2 SNPs (5 × 10¹¹) were exhausted to search for significant interaction which was defined by p-value of chi-square tests. Nine out the top 10 interactions, protein coding genes were partnered with non-coding RNA (ncRNA) which suggested a new alternative insight into interaction biology other than the frequently sought-after protein-protein interaction. Therefore, we extended to look for replication among the top 10,000 interaction SNP pairs and high proportion of concurrent genes forming the interaction pairs were found. The results indicated that an enrichment of signals over noise was present in the top 10,000 interactions. Then, replications of SNP-SNP interaction were confirmed for 14 SNPs-pairs in both replication datasets. Biological insight was highlighted by a potential binding between FHIT (protein coding gene) and LINC00969 (lncRNA) which showed a replicable interaction between their SNPs. Both of them were reported to have expression in brain. Our study represented an early attempt of exhaustive interaction analysis of GWAS data which also yield replicated interaction and new insight into understanding of genetic interaction in schizophrenia.

Keywords: GWAS; exhaustive search; gene–lncRNA interactions; schizophrenia; second order SNP–SNP interaction.

Abstract

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