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Quantitative trait loci, G×E and G×G for glycemic traits : response to metformin and placebo in the Diabetes Prevention Program (DPP)

Maxwell, Taylor J. ; Franks, Paul W. LU ; Kahn, Steven E. ; Knowler, William C. ; Mather, Kieren J. ; Florez, Jose C. and Jablonski, Kathleen A. (2022) In Journal of Human Genetics 67(8). p.465-473
Abstract

The complex genetic architecture of type-2-diabetes (T2D) includes gene-by-environment (G×E) and gene-by-gene (G×G) interactions. To identify G×E and G×G, we screened markers for patterns indicative of interactions (relationship loci [rQTL] and variance heterogeneity loci [vQTL]). rQTL exist when the correlation between multiple traits varies by genotype and vQTL occur when the variance of a trait differs by genotype (potentially flagging G×G and G×E). In the metformin and placebo arms of the DPP (n = 1762) we screened 280,965 exomic and intergenic SNPs, for rQTL and vQTL patterns in association with year one changes from baseline in glycemia and related traits (insulinogenic index [IGI], insulin sensitivity index [ISI], fasting glucose... (More)

The complex genetic architecture of type-2-diabetes (T2D) includes gene-by-environment (G×E) and gene-by-gene (G×G) interactions. To identify G×E and G×G, we screened markers for patterns indicative of interactions (relationship loci [rQTL] and variance heterogeneity loci [vQTL]). rQTL exist when the correlation between multiple traits varies by genotype and vQTL occur when the variance of a trait differs by genotype (potentially flagging G×G and G×E). In the metformin and placebo arms of the DPP (n = 1762) we screened 280,965 exomic and intergenic SNPs, for rQTL and vQTL patterns in association with year one changes from baseline in glycemia and related traits (insulinogenic index [IGI], insulin sensitivity index [ISI], fasting glucose and fasting insulin). Significant (p < 1.8 × 10−7) rQTL and vQTL generated a priori hypotheses of individual G×E tests for a SNP × metformin treatment interaction and secondarily for G×G screens. Several rQTL and vQTL identified led to 6 nominally significant (p < 0.05) metformin treatment × SNP interactions (4 for IGI, one insulin, and one glucose) and 12G×G interactions (all IGI) that exceeded experiment-wide significance (p < 4.1 × 10−9). Some loci are directly associated with incident diabetes, and others are rQTL and modify a trait’s relationship with diabetes (2 diabetes/glucose, 2 diabetes/insulin, 1 diabetes/IGI). rs3197999, an ISI/insulin rQTL, is a possible gene damaging missense mutation in MST1, a gene affecting β-cell apoptosis and insulin secretion. This rQTL may link MST1 with insulin sensitivity where ISI and insulin responses differentially vary by genotype. This study demonstrates evidence for context-dependent effects (G×G & G×E) and the complexity of these T2D-related traits.

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author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Human Genetics
volume
67
issue
8
pages
465 - 473
publisher
Springer
external identifiers
  • pmid:35260800
  • scopus:85126064571
ISSN
1434-5161
DOI
10.1038/s10038-022-01027-y
language
English
LU publication?
yes
id
e505f9f8-1303-4b6f-88e9-abaca5de3bd4
date added to LUP
2022-04-22 13:18:27
date last changed
2024-04-11 10:57:13
@article{e505f9f8-1303-4b6f-88e9-abaca5de3bd4,
  abstract     = {{<p>The complex genetic architecture of type-2-diabetes (T2D) includes gene-by-environment (G×E) and gene-by-gene (G×G) interactions. To identify G×E and G×G, we screened markers for patterns indicative of interactions (relationship loci [rQTL] and variance heterogeneity loci [vQTL]). rQTL exist when the correlation between multiple traits varies by genotype and vQTL occur when the variance of a trait differs by genotype (potentially flagging G×G and G×E). In the metformin and placebo arms of the DPP (n = 1762) we screened 280,965 exomic and intergenic SNPs, for rQTL and vQTL patterns in association with year one changes from baseline in glycemia and related traits (insulinogenic index [IGI], insulin sensitivity index [ISI], fasting glucose and fasting insulin). Significant (p &lt; 1.8 × 10<sup>−7</sup>) rQTL and vQTL generated a priori hypotheses of individual G×E tests for a SNP × metformin treatment interaction and secondarily for G×G screens. Several rQTL and vQTL identified led to 6 nominally significant (p &lt; 0.05) metformin treatment × SNP interactions (4 for IGI, one insulin, and one glucose) and 12G×G interactions (all IGI) that exceeded experiment-wide significance (p &lt; 4.1 × 10<sup>−9</sup>). Some loci are directly associated with incident diabetes, and others are rQTL and modify a trait’s relationship with diabetes (2 diabetes/glucose, 2 diabetes/insulin, 1 diabetes/IGI). rs3197999, an ISI/insulin rQTL, is a possible gene damaging missense mutation in MST1, a gene affecting β-cell apoptosis and insulin secretion. This rQTL may link MST1 with insulin sensitivity where ISI and insulin responses differentially vary by genotype. This study demonstrates evidence for context-dependent effects (G×G &amp; G×E) and the complexity of these T2D-related traits.</p>}},
  author       = {{Maxwell, Taylor J. and Franks, Paul W. and Kahn, Steven E. and Knowler, William C. and Mather, Kieren J. and Florez, Jose C. and Jablonski, Kathleen A.}},
  issn         = {{1434-5161}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{465--473}},
  publisher    = {{Springer}},
  series       = {{Journal of Human Genetics}},
  title        = {{Quantitative trait loci, G×E and G×G for glycemic traits : response to metformin and placebo in the Diabetes Prevention Program (DPP)}},
  url          = {{http://dx.doi.org/10.1038/s10038-022-01027-y}},
  doi          = {{10.1038/s10038-022-01027-y}},
  volume       = {{67}},
  year         = {{2022}},
}