AUTHOR=Jiao Hongxiao , Zang Yong , Zhang Miaomiao , Zhang Yuan , Wang Yaogang , Wang Kai , Price R. Arlen , Li Wei-Dong 

TITLE=Genome-Wide Interaction and Pathway Association Studies for Body Mass Index

JOURNAL=Frontiers in Genetics

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00404

DOI=10.3389/fgene.2019.00404

ISSN=1664-8021

ABSTRACT=<p><bold>Objective:</bold> We investigated gene interactions (epistasis) for body mass index (BMI) in a European-American adult female cohort via genome-wide interaction analyses (GWIA) and pathway association analyses.</p><p><bold>Methods:</bold> Genome-wide pairwise interaction analyses were carried out for BMI in 493 extremely obese cases (BMI &gt; 35 kg/m<sup>2</sup>) and 537 never-overweight controls (BMI &lt; 25 kg/m<sup>2</sup>). To further validate the results, specific SNPs were selected based on the GWIA results for haplotype-based association studies. Pathway-based association analyses were performed using a modified Gene Set Enrichment Algorithm (GSEA) (GenGen program) to further explore BMI-related pathways using our genome wide association study (GWAS) data set, GIANT, ENGAGE, and DIAGRAM Consortia.</p><p><bold>Results:</bold> The <italic>EXOC4</italic>-1q23.1 interaction was associated with BMI, with the most significant epistasis between rs7800006 and rs10797020 (<italic>P</italic> = 2.63 × 10<sup>-11</sup>). In the pathway-based association analysis, Tob1 pathway showed the most significant association with BMI (empirical <italic>P</italic> &lt; 0.001, FDR = 0.044, FWER = 0.040). These findings were further validated in different populations.</p><p><bold>Conclusion:</bold> Genome-wide pairwise SNP-SNP interaction and pathway analyses suggest that EXOC4 and TOB1-related pathways may contribute to the development of obesity.</p>