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

Research output: Contribution to journalJournal articleResearchpeer-review

Anubha Mahajan, Jennifer Wessel, Sara M Willems, Wei Zhao, Neil R Robertson, Audrey Y Chu, Wei Gan, Hidetoshi Kitajima, Daniel Taliun, N William Rayner, Xiuqing Guo, Yingchang Lu, Man Li, Richard A Jensen, Yao Hu, Shaofeng Huo, Kurt K Lohman, Weihua Zhang, James P Cook, Bram Peter Prins & 31 more Jason Flannick, Niels Grarup, Vassily Vladimirovich Trubetskoy, Jasmina Kravic, Young Jin Kim, Denis V Rybin, Hanieh Yaghootkar, Martina Müller-Nurasyid, Karina Meidtner, Ruifang Li-Gao, Tibor V Varga, Jonathan Marten, Jin Li, Shoaib Afzal, Jette Bork-Jensen, Anne Tybjærg-Hansen, Marit E Jørgensen, Torben Jørgensen, Peter Kovacs, Allan Linneberg, Jun Liu, Sune F Nielsen, Line Rode, Daniel R Witte, Torben Hansen, Fredrik Karpe, Lars Lind, Ruth J F Loos, Børge G Nordestgaard, Oluf Pedersen, ExomeBP Consortium

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.

Original languageEnglish
JournalNature Genetics
Volume50
Issue number4
Pages (from-to)559-571
Number of pages13
ISSN1061-4036
DOIs
Publication statusPublished - Apr 2018

ID: 199333913