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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 (? = -1.09,? = 0.163, P = 8.2 × 10-11) and a second loss of function mutation, rs138326449 (? = -1.17,? = 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).

SUBMITTER: Gilly A

PROVIDER: S-EPMC5081052 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Gilly Arthur A Ritchie Graham Rs GR Southam Lorraine L Farmaki Aliki-Eleni AE Tsafantakis Emmanouil E Dedoussis George G Zeggini Eleftheria E

Human molecular genetics 20160504 11

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<sup>-11</sup>) and a seco ...[more]

PMID: 27146844

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Dataset Information

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

Publications

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

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