| Title: | Reverse gene-environment interaction approach to identify variants influencing body-mass index in humans |
| Journal: | Nature Metabolism |
| Published: | 14 Jun 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31538139/ |
| DOI: | https://doi.org/10.1038/s42255-019-0071-6 |
| URL: | https://europepmc.org/articles/pmc6752726?pdf=render |
Publication 5678
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Abstract
Identifying gene-environment (G×E) interactions contributing to human cardiometabolic disorders is challenging. Here we apply a reverse G×E candidate search by deriving candidate variants from promoter-enhancer interactions that respond to dietary fatty acid challenge through altered chromatin accessibility in primary human adipocytes. We then test all variants residing in lipid-responsive open chromatin sites in adipocyte promoter-enhancer contacts for interaction effects between genotype and dietary saturated fat intake on body-mass index (BMI) in the UK Biobank. We discover 14 new G×E variants in 12 lipid-responsive promoters, including in well-known lipid-related genes (LIPE, CARM1 and PLIN2) and newly associated genes, such as LDB3, for which we provide further functional and integrative genomic evidence. We further identify 24 G×E variants in enhancers, for a total of 38 new G×E variants for BMI in the UK Biobank, demonstrating that molecular genomics data produced in physiologically relevant contexts can be applied to discover new functional G×E mechanisms in humans.</p>
15 Authors
- Kristina M. Garske
- David Z. Pan
- Zong Miao
- Yash V. Bhagat
- Caroline Comenho
- Christopher R. Robles
- Jihane N. Benhammou
- Marcus Alvarez
- Arthur Ko
- Chun Jimmie Ye
- Joseph R. Pisegna
- Karen L. Mohlke
- Janet S. Sinsheimer
- Markku Laakso
- Päivi Pajukanta
Enabling scientific discoveries that improve human health