Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.
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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); 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. |
Year of Publication | 2018
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Journal | Nat Genet
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Volume | 50
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Issue | 4
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Pages | 559-571
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Date Published | 2018 04
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ISSN | 1546-1718
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DOI | 10.1038/s41588-018-0084-1
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PubMed ID | 29632382
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PubMed Central ID | PMC5898373
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Grant list | G0601463 / MRC_ / Medical Research Council / United Kingdom
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
U01 DK085545 / DK / NIDDK NIH HHS / United States
R01 DK098032 / DK / NIDDK NIH HHS / United States
R35 HL135824 / HL / NHLBI NIH HHS / United States
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
P30 DK116074 / DK / NIDDK NIH HHS / United States
U54 GM115428 / GM / NIGMS NIH HHS / United States
R01 DK093757 / DK / NIDDK NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
U01 HL130114 / HL / NHLBI NIH HHS / United States
MR/K023241/1 / MRC_ / Medical Research Council / United Kingdom
MR/L020149/1 / MRC_ / Medical Research Council / United Kingdom
R01 DK072193 / DK / NIDDK NIH HHS / United States
R00 HL130580 / HL / NHLBI NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL119443 / HL / NHLBI NIH HHS / United States
R01 DK062370 / DK / NIDDK NIH HHS / United States
U01 DK105535 / DK / NIDDK NIH HHS / United States
MR/S003746/1 / MRC_ / Medical Research Council / United Kingdom
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
P30 DK020572 / DK / NIDDK NIH HHS / United States
RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom
MR/K007017/1 / MRC_ / Medical Research Council / United Kingdom
P20 GM121334 / GM / NIGMS NIH HHS / United States
MC_PC_13040 / MRC_ / Medical Research Council / United Kingdom
UL1 TR001881 / TR / NCATS NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
G0601261 / MRC_ / Medical Research Council / United Kingdom
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