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

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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.

Originalsprog	Engelsk
Artikelnummer	4316
Tidsskrift	Nature Communications
Vol/bind	9
Udgave nummer	1
Antal sider	11
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-018-06618-y
Status	Udgivet - 2018

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

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillationForlagets udgivne version, 3,43 MBLicens: CC BY

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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), Artikel 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, bind 9, nr. 1, 4316. https://doi.org/10.1038/s41467-018-06618-y

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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.",

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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

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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.

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

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