Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation.

Arthur Gilly, Graham Rs Ritchie, Lorraine Southam, Aliki-Eleni Farmaki, Emmanouil Tsafantakis, George Dedoussis, Eleftheria Zeggini

Journal: Human molecular genetics 2017;25(11):2360-2365

PMID: 27146844

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Abstract

Cohort-wide very low-depth whole-genome sequencing (WGS) can comprehensively capture low-frequency sequence variation for the cost of a dense genome-wide genotyping array. Here, we analyse 1x sequence data across the APOC3 gene in a founder population from the island of Crete in Greece (n = 1239) and find significant evidence for association with blood triglyceride levels with the previously reported R19X cardioprotective null mutation (β = -1.09,σ = 0.163, P = 8.2 × 10) and a second loss of function mutation, rs138326449 (β = -1.17,σ = 0.188, P = 1.14 × 10). The signal cannot be recapitulated by imputing genome-wide genotype data on a large reference panel of 5122 individuals including 249 with 4x WGS data from the same population. Gene-level meta-analysis with other studies reporting burden signals at APOC3 provides robust evidence for a replicable cardioprotective rare variant aggregation (P = 3.2 × 10, n = 13 480).

Address: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.; Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens 17671, Greece.; Anogia Medical Centre, Anogia 740 51, Greece.; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK [email protected].

DOI: 10.1093/hmg/ddw088

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MeSH Terms: Alleles, Apolipoprotein C-III, Cardiovascular Diseases, Female, Founder Effect, Genetics, Population, Genome, Human, Genome-Wide Association Study, Genotype, Greece, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Polymorphism, Single Nucleotide, Triglycerides, White People