Whole genome sequencing and imputation in isolated populations identify genetic associations with medically-relevant complex traits

Lorraine Southam, Arthur Gilly, Daniel Süveges, Aliki Eleni Farmaki, Jeremy Schwartzentruber, Ioanna Tachmazidou, Angela Matchan, Nigel W. Rayner, Emmanouil Tsafantakis, Maria Karaleftheri, Yali Xue, George Dedoussis, Eleftheria Zeggini

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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.

Original languageEnglish
Article number15606
JournalNature Communications
Volume8
DOIs
StatePublished - 26 May 2017
Externally publishedYes

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