D'Silva Sheldon, Chakraborty Shreya, Kahali Bratati
Centre for Brain Research, Indian Institute of Science, Bangalore, 560012, India.
Interdisciplinary Mathematical Sciences, Indian Institute of Science, Bangalore, 560012, India.
Sci Rep. 2022 May 4;12(1):7306. doi: 10.1038/s41598-022-11270-0.
Genome wide association studies (GWAS) have focused on elucidating the genetic architecture of complex traits by assessing single variant effects in additive genetic models, albeit explaining a fraction of the trait heritability. Epistasis has recently emerged as one of the intrinsic mechanisms that could explain part of this missing heritability. We conducted epistasis analysis for genome-wide body mass index (BMI) associated SNPs in Alzheimer's Disease Neuroimaging Initiative (ADNI) and followed up top significant interacting SNPs for replication in the UK Biobank imputed genotype dataset. We report two pairwise epistatic interactions, between rs2177596 (RHBDD1) and rs17759796 (MAPK1), rs1121980 (FTO) and rs6567160 (MC4R), obtained from a consensus of nine different epistatic approaches. Gene interaction maps and tissue expression profiles constructed for these interacting loci highlights co-expression, co-localisation, physical interaction, genetic interaction, and shared pathways emphasising the neuronal influence in obesity and implicating concerted expression of associated genes in liver, pancreas, and adipose tissues insinuating to metabolic abnormalities characterized by obesity. Detecting epistasis could thus be a promising approach to understand the effect of simultaneously interacting multiple genetic loci in disease aetiology, beyond single locus effects.
全基因组关联研究（GWAS）一直致力于通过评估加性遗传模型中的单变异效应来阐明复杂性状的遗传结构，尽管只能解释部分性状遗传力。上位性最近已成为一种内在机制，可解释部分缺失的遗传力。我们对阿尔茨海默病神经影像倡议（ADNI）中全基因组体重指数（BMI）相关的单核苷酸多态性（SNP）进行了上位性分析，并在英国生物银行推算基因型数据集中对最显著的相互作用SNP进行了重复验证。我们报告了从九种不同上位性方法的共识中获得的两对上位性相互作用，分别是rs2177596（RHBDD1）与rs17759796（MAPK1）之间，以及rs1121980（FTO）与rs6567160（MC4R）之间。为这些相互作用位点构建的基因相互作用图谱和组织表达谱突出了共表达、共定位、物理相互作用、遗传相互作用和共享途径，强调了神经元对肥胖的影响，并暗示肝脏、胰腺和脂肪组织中相关基因的协同表达与以肥胖为特征的代谢异常有关。因此，检测上位性可能是一种有前景的方法，用于理解疾病病因中多个遗传位点同时相互作用的效应，而不仅仅是单一位点的效应。
