Whole genome sequencing and imputation in isolated populations identify genetic associations with medically-relevant complex traits
| Autor: | George Dedoussis, Eleftheria Zeggini, Arthur Gilly, Jeremy Schwartzentruber, Emmanouil Tsafantakis, Ioanna Tachmazidou, Aliki-Eleni Farmaki, Lorraine Southam, Maria Karaleftheri, Yali Xue, Nigel W. Rayner, Angela Matchan, Daniel Suveges |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Science Population General Physics and Astronomy Biology Polymorphism Single Nucleotide Article White People General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Gene Frequency Humans education Allele frequency Aged Genetic association Whole genome sequencing Genetics education.field_of_study Multidisciplinary Greece Whole Genome Sequencing Genome Human Haplotype Genetic Variation General Chemistry Middle Aged Phenotype 030104 developmental biology Haplotypes Female Imputation (genetics) Genome-Wide Association Study Founder effect |
| Zdroj: | Nature Communications, Vol 8, Iss 1, Pp 1-11 (2017) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms15606 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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