Southam, L;
Gilly, A;
Suveges, D;
Farmaki, A-E;
Schwartzentruber, J;
Tachmazidou, I;
Matchan, A;
... Zeggini, E; + view all
(2017)
Whole genome sequencing and imputation in isolated populations identify genetic associations with medically-relevant complex traits.
Nature Communications
, 8
, Article 15606. 10.1038/ncomms15606.
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Abstract
Next-generation association studies can be empowered by sequence-based imputation and by studying founder populations. Here we report ∼9.5 million variants from whole-genome sequencing (WGS) of a Cretan-isolated population, and show enrichment of rare and low-frequency variants with predicted functional consequences. We use a WGS-based imputation approach utilizing 10,422 reference haplotypes to perform genome-wide association analyses and observe 17 genome-wide significant, independent signals, including replicating evidence for association at eight novel low-frequency variant signals. Two novel cardiometabolic associations are at lead variants unique to the founder population sequences: chr16:70790626 (high-density lipoprotein levels beta −1.71 (SE 0.25), P=1.57 × 10−11, effect allele frequency (EAF) 0.006); and rs145556679 (triglycerides levels beta −1.13 (SE 0.17), P=2.53 × 10−11, EAF 0.013). Our findings add empirical support to the contribution of low-frequency variants in complex traits, demonstrate the advantage of including population-specific sequences in imputation panels and exemplify the power gains afforded by population isolates.
| Type: | Article |
|---|---|
| Title: | Whole genome sequencing and imputation in isolated populations identify genetic associations with medically-relevant complex traits |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/ncomms15606 |
| Publisher version: | https://doi.org/10.1038/ncomms15606 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, WIDE ASSOCIATION, PHOSPHATIDYLINOSITOL 3,5-BISPHOSPHATE, GLYCEMIC TRAITS, RARE VARIANTS, LOCI, DISEASE, CELL, ARCHITECTURE, METAANALYSIS, HEMOGLOBIN |
| 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 |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10053193 |
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