Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Arthur Gilly; Daniel Suveges; Karoline Kuchenbaecker; Martin Pollard; Lorraine Southam; Konstantinos Hatzikotoulas; Aliki Eleni Farmaki; Thea Bjornland; Ryan Waples; Emil V.R. Appel; Elisabetta Casalone; Giorgio Melloni; Britt Kilian; Nigel W. Rayner; Ioanna Ntalla; Kousik Kundu; Klaudia Walter; John Danesh; Adam Butterworth; Inês Barroso; Emmanouil Tsafantakis; George Dedoussis; Ida Moltke; Eleftheria Zeggini

doi:10.1038/s41467-018-07070-8

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Arthur Gilly, Daniel Suveges, Karoline Kuchenbaecker, Martin Pollard, Lorraine Southam, Konstantinos Hatzikotoulas, Aliki Eleni Farmaki, Thea Bjornland, Ryan Waples, Emil V.R. Appel, Elisabetta Casalone, Giorgio Melloni, Britt Kilian, Nigel W. Rayner, Ioanna Ntalla, Kousik Kundu, Klaudia Walter, John Danesh, Adam Butterworth, Inês BarrosoEmmanouil Tsafantakis, George Dedoussis, Ida Moltke, Eleftheria Zeggini

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24 Scopus citations

Abstract

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10 ⁻⁸ ; APOC3 and triglyceride levels, P = 1.5 × 10 ⁻²⁶ ), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10 ⁻⁸ ), indicating a role for this gene in lipid metabolism.

Original language	English
Article number	4674
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07070-8
State	Published - 1 Dec 2018
Externally published	Yes

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Gilly, A., Suveges, D., Kuchenbaecker, K., Pollard, M., Southam, L., Hatzikotoulas, K., Farmaki, A. E., Bjornland, T., Waples, R., Appel, E. V. R., Casalone, E., Melloni, G., Kilian, B., Rayner, N. W., Ntalla, I., Kundu, K., Walter, K., Danesh, J., Butterworth, A., ... Zeggini, E. (2018). Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits. Nature Communications, 9(1), Article 4674. https://doi.org/10.1038/s41467-018-07070-8

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title = "Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits",

abstract = " The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10 −8 ; APOC3 and triglyceride levels, P = 1.5 × 10 −26 ), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10 −8 ), indicating a role for this gene in lipid metabolism.",

author = "Arthur Gilly and Daniel Suveges and Karoline Kuchenbaecker and Martin Pollard and Lorraine Southam and Konstantinos Hatzikotoulas and Farmaki, {Aliki Eleni} and Thea Bjornland and Ryan Waples and Appel, {Emil V.R.} and Elisabetta Casalone and Giorgio Melloni and Britt Kilian and Rayner, {Nigel W.} and Ioanna Ntalla and Kousik Kundu and Klaudia Walter and John Danesh and Adam Butterworth and In{\^e}s Barroso and Emmanouil Tsafantakis and George Dedoussis and Ida Moltke and Eleftheria Zeggini",

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Gilly, A, Suveges, D, Kuchenbaecker, K, Pollard, M, Southam, L, Hatzikotoulas, K, Farmaki, AE, Bjornland, T, Waples, R, Appel, EVR, Casalone, E, Melloni, G, Kilian, B, Rayner, NW, Ntalla, I, Kundu, K, Walter, K, Danesh, J, Butterworth, A, Barroso, I, Tsafantakis, E, Dedoussis, G, Moltke, I & Zeggini, E 2018, 'Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits', Nature Communications, vol. 9, no. 1, 4674. https://doi.org/10.1038/s41467-018-07070-8

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T1 - Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

AU - Gilly, Arthur

AU - Suveges, Daniel

AU - Kuchenbaecker, Karoline

AU - Pollard, Martin

AU - Southam, Lorraine

AU - Hatzikotoulas, Konstantinos

AU - Farmaki, Aliki Eleni

AU - Bjornland, Thea

AU - Waples, Ryan

AU - Appel, Emil V.R.

AU - Casalone, Elisabetta

AU - Melloni, Giorgio

AU - Kilian, Britt

AU - Rayner, Nigel W.

AU - Ntalla, Ioanna

AU - Kundu, Kousik

AU - Walter, Klaudia

AU - Danesh, John

AU - Butterworth, Adam

AU - Barroso, Inês

AU - Tsafantakis, Emmanouil

AU - Dedoussis, George

AU - Moltke, Ida

AU - Zeggini, Eleftheria

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AB - The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10 −8 ; APOC3 and triglyceride levels, P = 1.5 × 10 −26 ), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10 −8 ), indicating a role for this gene in lipid metabolism.

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Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

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