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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Mahajan, A; Wessel, J; Willems, SM; Zhao, W; Robertson, NR; Chu, AY; Gan, W; ... McCarthy, MI; + view all (2018) Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nature Genetics , 50 (4) pp. 559-571. 10.1038/s41588-018-0084-1. Green open access

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Abstract

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

Type: Article
Title: Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41588-018-0084-1
Publisher version: https://doi.org/10.1038/s41588-018-0084-1
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
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 Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine > MRC Unit for Lifelong Hlth and Ageing
URI: https://discovery.ucl.ac.uk/id/eprint/10056104
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