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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

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Harvard

Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, PG, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, KL, Mazzanti, A, Beckmann, BM, Shimamoto, K, Diamant, U-B, Wijeyeratne, YD, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, SA, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, MB, Weeke, PE, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, DJ, Bos, JM, Sarquella-Brugada, G, Campuzano, Ó, Platonov, PG, Stallmeyer, B, Zumhagen, S, Nannenberg, EA, Veldink, JH, van den Berg, LH, Al-Chalabi, A, Shaw, CE, Shaw, PJ, Morrison, KE, Andersen, PM, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, CC, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, JP, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J-J, Gourraud, J-B, Makiyama, T, Ohno, S, Itoh, H, Krahn, AD, Antzelevitch, C, Roden, DM, Saenen, J, Borggrefe, M, Odening, KE, Ellinor, PT, Tfelt-Hansen, J, Skinner, JR, van den Berg, MP, Olesen, MS, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, ER, Rydberg, A, Aiba, T, Kääb, S, Priori, SG, Guicheney, P, Tan, HL, Newton-Cheh, C, Ackerman, MJ, Schwartz, PJ, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, AA, Tanck, MWT & Bezzina, CR 2020, 'Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome', Circulation, vol. 142, no. 4, pp. 324-338. https://doi.org/10.1161/CIRCULATIONAHA.120.045956

APA

Lahrouchi, N., Tadros, R., Crotti, L., Mizusawa, Y., Postema, P. G., Beekman, L., Walsh, R., Hasegawa, K., Barc, J., Ernsting, M., Turkowski, K. L., Mazzanti, A., Beckmann, B. M., Shimamoto, K., Diamant, U-B., Wijeyeratne, Y. D., Kucho, Y., Robyns, T., Ishikawa, T., ... Bezzina, C. R. (2020). Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. Circulation, 142(4), 324-338. https://doi.org/10.1161/CIRCULATIONAHA.120.045956

CBE

Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant U-B, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott J-J, Gourraud J-B, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, Bezzina CR. 2020. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. Circulation. 142(4):324-338. https://doi.org/10.1161/CIRCULATIONAHA.120.045956

MLA

Vancouver

Author

Lahrouchi, Najim ; Tadros, Rafik ; Crotti, Lia ; Mizusawa, Yuka ; Postema, Pieter G ; Beekman, Leander ; Walsh, Roddy ; Hasegawa, Kanae ; Barc, Julien ; Ernsting, Marko ; Turkowski, Kari L ; Mazzanti, Andrea ; Beckmann, Britt M ; Shimamoto, Keiko ; Diamant, Ulla-Britt ; Wijeyeratne, Yanushi D ; Kucho, Yu ; Robyns, Tomas ; Ishikawa, Taisuke ; Arbelo, Elena ; Christiansen, Michael ; Winbo, Annika ; Jabbari, Reza ; Lubitz, Steven A ; Steinfurt, Johannes ; Rudic, Boris ; Loeys, Bart ; Shoemaker, M Ben ; Weeke, Peter E ; Pfeiffer, Ryan ; Davies, Brianna ; Andorin, Antoine ; Hofman, Nynke ; Dagradi, Federica ; Pedrazzini, Matteo ; Tester, David J ; Bos, J Martijn ; Sarquella-Brugada, Georgia ; Campuzano, Óscar ; Platonov, Pyotr G ; Stallmeyer, Birgit ; Zumhagen, Sven ; Nannenberg, Eline A ; Veldink, Jan H ; van den Berg, Leonard H ; Al-Chalabi, Ammar ; Shaw, Christopher E ; Shaw, Pamela J ; Morrison, Karen E ; Andersen, Peter M ; Müller-Nurasyid, Martina ; Cusi, Daniele ; Barlassina, Cristina ; Galan, Pilar ; Lathrop, Mark ; Munter, Markus ; Werge, Thomas ; Ribasés, Marta ; Aung, Tin ; Khor, Chiea C ; Ozaki, Mineo ; Lichtner, Peter ; Meitinger, Thomas ; van Tintelen, J Peter ; Hoedemaekers, Yvonne ; Denjoy, Isabelle ; Leenhardt, Antoine ; Napolitano, Carlo ; Shimizu, Wataru ; Schott, Jean-Jacques ; Gourraud, Jean-Baptiste ; Makiyama, Takeru ; Ohno, Seiko ; Itoh, Hideki ; Krahn, Andrew D ; Antzelevitch, Charles ; Roden, Dan M ; Saenen, Johan ; Borggrefe, Martin ; Odening, Katja E ; Ellinor, Patrick T ; Tfelt-Hansen, Jacob ; Skinner, Jonathan R ; van den Berg, Maarten P ; Olesen, Morten Salling ; Brugada, Josep ; Brugada, Ramón ; Makita, Naomasa ; Breckpot, Jeroen ; Yoshinaga, Masao ; Behr, Elijah R ; Rydberg, Annika ; Aiba, Takeshi ; Kääb, Stefan ; Priori, Silvia G ; Guicheney, Pascale ; Tan, Hanno L ; Newton-Cheh, Christopher ; Ackerman, Michael J ; Schwartz, Peter J ; Schulze-Bahr, Eric ; Probst, Vincent ; Horie, Minoru ; Wilde, Arthur A ; Tanck, Michael W T ; Bezzina, Connie R. / Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. In: Circulation. 2020 ; Vol. 142, No. 4. pp. 324-338.

Bibtex

@article{14cc3c748dc14e4bac9d5d33358afe6a,
title = "Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome",
abstract = "BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.",
keywords = "genome-wide association study, inheritance patterns, long QT syndrome",
author = "Najim Lahrouchi and Rafik Tadros and Lia Crotti and Yuka Mizusawa and Postema, {Pieter G} and Leander Beekman and Roddy Walsh and Kanae Hasegawa and Julien Barc and Marko Ernsting and Turkowski, {Kari L} and Andrea Mazzanti and Beckmann, {Britt M} and Keiko Shimamoto and Ulla-Britt Diamant and Wijeyeratne, {Yanushi D} and Yu Kucho and Tomas Robyns and Taisuke Ishikawa and Elena Arbelo and Michael Christiansen and Annika Winbo and Reza Jabbari and Lubitz, {Steven A} and Johannes Steinfurt and Boris Rudic and Bart Loeys and Shoemaker, {M Ben} and Weeke, {Peter E} and Ryan Pfeiffer and Brianna Davies and Antoine Andorin and Nynke Hofman and Federica Dagradi and Matteo Pedrazzini and Tester, {David J} and Bos, {J Martijn} and Georgia Sarquella-Brugada and {\'O}scar Campuzano and Platonov, {Pyotr G} and Birgit Stallmeyer and Sven Zumhagen and Nannenberg, {Eline A} and Veldink, {Jan H} and {van den Berg}, {Leonard H} and Ammar Al-Chalabi and Shaw, {Christopher E} and Shaw, {Pamela J} and Morrison, {Karen E} and Andersen, {Peter M} and Martina M{\"u}ller-Nurasyid and Daniele Cusi and Cristina Barlassina and Pilar Galan and Mark Lathrop and Markus Munter and Thomas Werge and Marta Ribas{\'e}s and Tin Aung and Khor, {Chiea C} and Mineo Ozaki and Peter Lichtner and Thomas Meitinger and {van Tintelen}, {J Peter} and Yvonne Hoedemaekers and Isabelle Denjoy and Antoine Leenhardt and Carlo Napolitano and Wataru Shimizu and Jean-Jacques Schott and Jean-Baptiste Gourraud and Takeru Makiyama and Seiko Ohno and Hideki Itoh and Krahn, {Andrew D} and Charles Antzelevitch and Roden, {Dan M} and Johan Saenen and Martin Borggrefe and Odening, {Katja E} and Ellinor, {Patrick T} and Jacob Tfelt-Hansen and Skinner, {Jonathan R} and {van den Berg}, {Maarten P} and Olesen, {Morten Salling} and Josep Brugada and Ram{\'o}n Brugada and Naomasa Makita and Jeroen Breckpot and Masao Yoshinaga and Behr, {Elijah R} and Annika Rydberg and Takeshi Aiba and Stefan K{\"a}{\"a}b and Priori, {Silvia G} and Pascale Guicheney and Tan, {Hanno L} and Christopher Newton-Cheh and Ackerman, {Michael J} and Schwartz, {Peter J} and Eric Schulze-Bahr and Vincent Probst and Minoru Horie and Wilde, {Arthur A} and Tanck, {Michael W T} and Bezzina, {Connie R}",
year = "2020",
month = jul,
day = "28",
doi = "10.1161/CIRCULATIONAHA.120.045956",
language = "English",
volume = "142",
pages = "324--338",
journal = "Circulation (Baltimore)",
issn = "0009-7322",
publisher = "Lippincott Williams & Wilkins",
number = "4",

}

RIS

TY - JOUR

T1 - Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

AU - Lahrouchi, Najim

AU - Tadros, Rafik

AU - Crotti, Lia

AU - Mizusawa, Yuka

AU - Postema, Pieter G

AU - Beekman, Leander

AU - Walsh, Roddy

AU - Hasegawa, Kanae

AU - Barc, Julien

AU - Ernsting, Marko

AU - Turkowski, Kari L

AU - Mazzanti, Andrea

AU - Beckmann, Britt M

AU - Shimamoto, Keiko

AU - Diamant, Ulla-Britt

AU - Wijeyeratne, Yanushi D

AU - Kucho, Yu

AU - Robyns, Tomas

AU - Ishikawa, Taisuke

AU - Arbelo, Elena

AU - Christiansen, Michael

AU - Winbo, Annika

AU - Jabbari, Reza

AU - Lubitz, Steven A

AU - Steinfurt, Johannes

AU - Rudic, Boris

AU - Loeys, Bart

AU - Shoemaker, M Ben

AU - Weeke, Peter E

AU - Pfeiffer, Ryan

AU - Davies, Brianna

AU - Andorin, Antoine

AU - Hofman, Nynke

AU - Dagradi, Federica

AU - Pedrazzini, Matteo

AU - Tester, David J

AU - Bos, J Martijn

AU - Sarquella-Brugada, Georgia

AU - Campuzano, Óscar

AU - Platonov, Pyotr G

AU - Stallmeyer, Birgit

AU - Zumhagen, Sven

AU - Nannenberg, Eline A

AU - Veldink, Jan H

AU - van den Berg, Leonard H

AU - Al-Chalabi, Ammar

AU - Shaw, Christopher E

AU - Shaw, Pamela J

AU - Morrison, Karen E

AU - Andersen, Peter M

AU - Müller-Nurasyid, Martina

AU - Cusi, Daniele

AU - Barlassina, Cristina

AU - Galan, Pilar

AU - Lathrop, Mark

AU - Munter, Markus

AU - Werge, Thomas

AU - Ribasés, Marta

AU - Aung, Tin

AU - Khor, Chiea C

AU - Ozaki, Mineo

AU - Lichtner, Peter

AU - Meitinger, Thomas

AU - van Tintelen, J Peter

AU - Hoedemaekers, Yvonne

AU - Denjoy, Isabelle

AU - Leenhardt, Antoine

AU - Napolitano, Carlo

AU - Shimizu, Wataru

AU - Schott, Jean-Jacques

AU - Gourraud, Jean-Baptiste

AU - Makiyama, Takeru

AU - Ohno, Seiko

AU - Itoh, Hideki

AU - Krahn, Andrew D

AU - Antzelevitch, Charles

AU - Roden, Dan M

AU - Saenen, Johan

AU - Borggrefe, Martin

AU - Odening, Katja E

AU - Ellinor, Patrick T

AU - Tfelt-Hansen, Jacob

AU - Skinner, Jonathan R

AU - van den Berg, Maarten P

AU - Olesen, Morten Salling

AU - Brugada, Josep

AU - Brugada, Ramón

AU - Makita, Naomasa

AU - Breckpot, Jeroen

AU - Yoshinaga, Masao

AU - Behr, Elijah R

AU - Rydberg, Annika

AU - Aiba, Takeshi

AU - Kääb, Stefan

AU - Priori, Silvia G

AU - Guicheney, Pascale

AU - Tan, Hanno L

AU - Newton-Cheh, Christopher

AU - Ackerman, Michael J

AU - Schwartz, Peter J

AU - Schulze-Bahr, Eric

AU - Probst, Vincent

AU - Horie, Minoru

AU - Wilde, Arthur A

AU - Tanck, Michael W T

AU - Bezzina, Connie R

PY - 2020/7/28

Y1 - 2020/7/28

N2 - BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

AB - BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

KW - genome-wide association study

KW - inheritance patterns

KW - long QT syndrome

UR - http://www.scopus.com/inward/record.url?scp=85088849122&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.120.045956

DO - 10.1161/CIRCULATIONAHA.120.045956

M3 - Journal article

C2 - 32429735

VL - 142

SP - 324

EP - 338

JO - Circulation (Baltimore)

JF - Circulation (Baltimore)

SN - 0009-7322

IS - 4

ER -

ID: 60075200