Christiansen, Colette E;
Arathimos, Ryan;
Pain, Oliver;
Molokhia, Mariam;
Bell, Jordana T;
Lewis, Cathryn M;
(2023)
Stratified genome-wide association analysis of type 2 diabetes reveals subgroups with genetic and environmental heterogeneity.
Human Molecular Genetics
, Article ddad093. 10.1093/hmg/ddad093.
(In press).
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Abstract
Type 2 diabetes (T2D) is a heterogeneous illness caused by genetic and environmental factors. Previous genome wide association studies (GWAS) have identified many genetic variants associated with T2D and found evidence of differing genetic profiles by age-at-onset. This study seeks to explore further the genetic and environmental drivers of T2D by analysing subgroups based on age-at-onset of diabetes and body mass index (BMI). In UK Biobank, 36 494 T2D cases were stratified into 3 subgroups and GWAS performed for all T2D cases and for each subgroup relative to 421 021 controls. Altogether, 18 SNPs significantly associated genome-wide with T2D in one or more subgroups also showed evidence of heterogeneity between the subgroups, (Cochrane's Q p < 0.01) with 2 remaining significant after multiple testing (in CDKN2B and CYTIP). Combined risk scores, based on genetic profile, BMI and age, resulted in excellent diabetes prediction (AUC = 0.92). A modest improvement in prediction (AUC = 0.93) was seen when the contribution of genetic and environmental factors was evaluated separately for each subgroup. Increasing sample sizes of genetic studies enables us to stratify disease cases into subgroups which have sufficient power to highlight areas of genetic heterogeneity. Despite some evidence that optimising combined risk scores by subgroup improves prediction, larger sample sizes are likely needed for prediction when using a stratification approach.
| Type: | Article |
|---|---|
| Title: | Stratified genome-wide association analysis of type 2 diabetes reveals subgroups with genetic and environmental heterogeneity |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddad093 |
| Publisher version: | https://doi.org/10.1093/hmg/ddad093 |
| Language: | English |
| Additional information: | This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry > Epidemiology and Applied Clinical Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10174232 |
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