Journal Article

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

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

2017

Overview

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. Isolated populations can provide useful information on low-frequency variants for dissecting genetic architecture of complex traits. Here, Zeggini and colleagues show enrichment of rare and low-frequency variants and 8 novel low-frequency variant signals for cardiometabolic traits in two Greek isolated populations

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 45/43 / 631/208/205/2138 / 631/208/457/649/2219 / Adult / Aged / Female / Gene Frequency - genetics / Genetic Variation / Genome, Human - genetics / Genome-Wide Association Study - methods / Greece / Haplotypes / Humanities and Social Sciences / Humans / Male / Middle Aged / multidisciplinary / Phenotype / Polymorphism, Single Nucleotide / Science / Science (multidisciplinary) / White People - genetics / Whole Genome Sequencing - methods