title: Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation.
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 × 10-11) and a second loss of function mutation, rs138326449 (β = -1.17,σ = 0.188, P = 1.14 × 10-9). 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 × 10-31, n = 13 480).
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Gilly
authors.affiliation: 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.
authors.forename: Graham Rs
authors.initials: GR
authors.lastname: Ritchie
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Southam
authors.affiliation: Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens 17671, Greece.
authors.forename: Aliki-Eleni
authors.initials: AE
authors.lastname: Farmaki
authors.affiliation: Anogia Medical Centre, Anogia 740 51, Greece.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Tsafantakis
authors.affiliation: Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens 17671, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Dedoussis
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK eleftheria@sanger.ac.uk.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
mesh_terms: D000483:Alleles; D053305:Apolipoprotein C-III / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D018703:Founder Effect; D005828:Genetics, Population; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006115:Greece; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D053305:Apolipoprotein C-III; D014280:Triglycerides