GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Remi Stevelink; Ciarán Campbell; Siwei Chen; Bassel Abou-Khalil; Oluyomi M. Adesoji; Zaid Afawi; Elisabetta Amadori; Alison Anderson; Joseph Anderson; Danielle M. Andrade; Grazia Annesi; Pauls Auce; Andreja Avbersek; Melanie Bahlo; Mark D. Baker; Ganna Balagura; Simona Balestrini; Carmen Barba; Karen Barboza; Fabrice Bartolomei; Thomas Bast; Larry Baum; Tobias Baumgartner; Betül Baykan; Nerses Bebek; Albert J. Becker; Felicitas Becker; Caitlin A. Bennett; Bianca Berghuis; Samuel F. Berkovic; Ahmad Beydoun; Claudia Bianchini; Francesca Bisulli; Ilan Blatt; Dheeraj R. Bobbili; Ingo Borggraefe; Christian Bosselmann; Vera Braatz; Jonathan P. Bradfield; Knut Brockmann; Lawrence C. Brody; Russell J. Buono; Robyn M. Busch; Hande Caglayan; Ellen Campbell; Laura Canafoglia; Christina Canavati; Gregory D. Cascino; Barbara Castellotti; Zied Landoulsi; International League Against Epilepsy Consortium on Complex Epilepsies

doi:10.1038/s41588-023-01485-w

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Remi Stevelink, Ciarán Campbell, Siwei Chen, Bassel Abou-Khalil, Oluyomi M. Adesoji, Zaid Afawi, Elisabetta Amadori, Alison Anderson, Joseph Anderson, Danielle M. Andrade, Grazia Annesi, Pauls Auce, Andreja Avbersek, Melanie Bahlo, Mark D. Baker, Ganna Balagura, Simona Balestrini, Carmen Barba, Karen Barboza, Fabrice BartolomeiThomas Bast, Larry Baum, Tobias Baumgartner, Betül Baykan, Nerses Bebek, Albert J. Becker, Felicitas Becker, Caitlin A. Bennett, Bianca Berghuis, Samuel F. Berkovic^*, Ahmad Beydoun, Claudia Bianchini, Francesca Bisulli, Ilan Blatt, Dheeraj R. Bobbili, Ingo Borggraefe, Christian Bosselmann, Vera Braatz, Jonathan P. Bradfield, Knut Brockmann, Lawrence C. Brody, Russell J. Buono, Robyn M. Busch, Hande Caglayan, Ellen Campbell, Laura Canafoglia, Christina Canavati, Gregory D. Cascino, Barbara Castellotti, Zied Landoulsi, International League Against Epilepsy Consortium on Complex Epilepsies

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

25 Citations (Scopus)

Abstract

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Original language	English
Pages (from-to)	1471-1482
Number of pages	12
Journal	Nature Genetics
Volume	55
Issue number	9
DOIs	https://doi.org/10.1038/s41588-023-01485-w
Publication status	Published - Sept 2023
Externally published	Yes

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Stevelink, R., Campbell, C., Chen, S., Abou-Khalil, B., Adesoji, O. M., Afawi, Z., Amadori, E., Anderson, A., Anderson, J., Andrade, D. M., Annesi, G., Auce, P., Avbersek, A., Bahlo, M., Baker, M. D., Balagura, G., Balestrini, S., Barba, C., Barboza, K., ... International League Against Epilepsy Consortium on Complex Epilepsies (2023). GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nature Genetics, 55(9), 1471-1482. https://doi.org/10.1038/s41588-023-01485-w

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title = "GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture",

abstract = "Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.",

author = "Remi Stevelink and Ciar{\'a}n Campbell and Siwei Chen and Bassel Abou-Khalil and Adesoji, {Oluyomi M.} and Zaid Afawi and Elisabetta Amadori and Alison Anderson and Joseph Anderson and Andrade, {Danielle M.} and Grazia Annesi and Pauls Auce and Andreja Avbersek and Melanie Bahlo and Baker, {Mark D.} and Ganna Balagura and Simona Balestrini and Carmen Barba and Karen Barboza and Fabrice Bartolomei and Thomas Bast and Larry Baum and Tobias Baumgartner and Bet{\"u}l Baykan and Nerses Bebek and Becker, {Albert J.} and Felicitas Becker and Bennett, {Caitlin A.} and Bianca Berghuis and Berkovic, {Samuel F.} and Ahmad Beydoun and Claudia Bianchini and Francesca Bisulli and Ilan Blatt and Bobbili, {Dheeraj R.} and Ingo Borggraefe and Christian Bosselmann and Vera Braatz and Bradfield, {Jonathan P.} and Knut Brockmann and Brody, {Lawrence C.} and Buono, {Russell J.} and Busch, {Robyn M.} and Hande Caglayan and Ellen Campbell and Laura Canafoglia and Christina Canavati and Cascino, {Gregory D.} and Barbara Castellotti and Zied Landoulsi and {International League Against Epilepsy Consortium on Complex Epilepsies}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = sep,

doi = "10.1038/s41588-023-01485-w",

language = "English",

volume = "55",

pages = "1471--1482",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

}

Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Landoulsi, Z & International League Against Epilepsy Consortium on Complex Epilepsies 2023, 'GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture', Nature Genetics, vol. 55, no. 9, pp. 1471-1482. https://doi.org/10.1038/s41588-023-01485-w

TY - JOUR

T1 - GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

AU - Stevelink, Remi

AU - Campbell, Ciarán

AU - Chen, Siwei

AU - Abou-Khalil, Bassel

AU - Adesoji, Oluyomi M.

AU - Afawi, Zaid

AU - Amadori, Elisabetta

AU - Anderson, Alison

AU - Anderson, Joseph

AU - Andrade, Danielle M.

AU - Annesi, Grazia

AU - Auce, Pauls

AU - Avbersek, Andreja

AU - Bahlo, Melanie

AU - Baker, Mark D.

AU - Balagura, Ganna

AU - Balestrini, Simona

AU - Barba, Carmen

AU - Barboza, Karen

AU - Bartolomei, Fabrice

AU - Bast, Thomas

AU - Baum, Larry

AU - Baumgartner, Tobias

AU - Baykan, Betül

AU - Bebek, Nerses

AU - Becker, Albert J.

AU - Becker, Felicitas

AU - Bennett, Caitlin A.

AU - Berghuis, Bianca

AU - Berkovic, Samuel F.

AU - Beydoun, Ahmad

AU - Bianchini, Claudia

AU - Bisulli, Francesca

AU - Blatt, Ilan

AU - Bobbili, Dheeraj R.

AU - Borggraefe, Ingo

AU - Bosselmann, Christian

AU - Braatz, Vera

AU - Bradfield, Jonathan P.

AU - Brockmann, Knut

AU - Brody, Lawrence C.

AU - Buono, Russell J.

AU - Busch, Robyn M.

AU - Caglayan, Hande

AU - Campbell, Ellen

AU - Canafoglia, Laura

AU - Canavati, Christina

AU - Cascino, Gregory D.

AU - Castellotti, Barbara

AU - Landoulsi, Zied

AU - International League Against Epilepsy Consortium on Complex Epilepsies

PY - 2023/9

Y1 - 2023/9

N2 - Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

AB - Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

UR - http://www.scopus.com/inward/record.url?scp=85169457451&partnerID=8YFLogxK

U2 - 10.1038/s41588-023-01485-w

DO - 10.1038/s41588-023-01485-w

M3 - Article

C2 - 37653029

AN - SCOPUS:85169457451

SN - 1061-4036

VL - 55

SP - 1471

EP - 1482

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

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