Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

Gustav Ahlberg; Lena Refsgaard; Pia R Lundegaard; Laura Andreasen; Mattis F Ranthe; Nora Linscheid; Jonas B Nielsen; Mads Melbye; Stig Haunsø; Ahmad Sajadieh; Lu Camp; Søren-Peter Olesen; Simon Rasmussen; Alicia Lundby; Patrick T Ellinor; Anders G Holst; Jesper H Svendsen; Morten S Olesen

doi:10.1038/s41467-018-06618-y

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

Gustav Ahlberg, Lena Refsgaard, Pia R Lundegaard, Laura Andreasen, Mattis F Ranthe, Nora Linscheid, Jonas B Nielsen, Mads Melbye, Stig Haunsø, Ahmad Sajadieh, Lu Camp, Søren-Peter Olesen, Simon Rasmussen, Alicia Lundby, Patrick T Ellinor, Anders G Holst, Jesper H Svendsen, Morten S Olesen

33 Citations (Scopus)

79 Downloads (Pure)

Abstract

A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

Original language	English
Article number	4316
Journal	Nature Communications
Volume	9
Issue number	1
Number of pages	11
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-06618-y
Publication status	Published - 2018

Access to Document

10.1038/s41467-018-06618-yLicence: CC BY

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillationFinal published version, 3.43 MBLicence: CC BY

Cite this

Ahlberg, G., Refsgaard, L., Lundegaard, P. R., Andreasen, L., Ranthe, M. F., Linscheid, N., Nielsen, J. B., Melbye, M., Haunsø, S., Sajadieh, A., Camp, L., Olesen, S-P., Rasmussen, S., Lundby, A., Ellinor, P. T., Holst, A. G., Svendsen, J. H., & Olesen, M. S. (2018). Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation. Nature Communications, 9(1), [4316]. https://doi.org/10.1038/s41467-018-06618-y

Ahlberg, G, Refsgaard, L, Lundegaard, PR, Andreasen, L, Ranthe, MF, Linscheid, N, Nielsen, JB, Melbye, M, Haunsø, S, Sajadieh, A, Camp, L, Olesen, S-P, Rasmussen, S, Lundby, A, Ellinor, PT, Holst, AG, Svendsen, JH & Olesen, MS 2018, 'Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation', Nature Communications, vol. 9, no. 1, 4316. https://doi.org/10.1038/s41467-018-06618-y

@article{11c0e0fb9a7c438f865096436515dccc,

title = "Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation",

abstract = "A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.",

author = "Gustav Ahlberg and Lena Refsgaard and Lundegaard, {Pia R} and Laura Andreasen and Ranthe, {Mattis F} and Nora Linscheid and Nielsen, {Jonas B} and Mads Melbye and Stig Hauns{\o} and Ahmad Sajadieh and Lu Camp and S{\o}ren-Peter Olesen and Simon Rasmussen and Alicia Lundby and Ellinor, {Patrick T} and Holst, {Anders G} and Svendsen, {Jesper H} and Olesen, {Morten S}",

year = "2018",

doi = "10.1038/s41467-018-06618-y",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

number = "1",

}

TY - JOUR

T1 - Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

AU - Ahlberg, Gustav

AU - Refsgaard, Lena

AU - Lundegaard, Pia R

AU - Andreasen, Laura

AU - Ranthe, Mattis F

AU - Linscheid, Nora

AU - Nielsen, Jonas B

AU - Melbye, Mads

AU - Haunsø, Stig

AU - Sajadieh, Ahmad

AU - Camp, Lu

AU - Olesen, Søren-Peter

AU - Rasmussen, Simon

AU - Lundby, Alicia

AU - Ellinor, Patrick T

AU - Holst, Anders G

AU - Svendsen, Jesper H

AU - Olesen, Morten S

PY - 2018

Y1 - 2018

N2 - A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

AB - A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

UR - http://www.scopus.com/inward/record.url?scp=85055120704&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06618-y

DO - 10.1038/s41467-018-06618-y

M3 - Journal article

C2 - 30333491

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4316

ER -

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

Abstract

Access to Document

Other files and links

Fingerprint

Cite this