Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Hyun Hor; Zoltán Kutalik; Yves Dauvilliers; Armand Valsesia; Gert J Lammers; Claire E H M Donjacour; Alex Iranzo; Joan Santamaria; Rosa Peraita Adrados; José L Vicario; Sebastiaan Overeem; Isabelle Arnulf; Ioannis Theodorou; Poul Jennum; Stine Knudsen; Claudio Bassetti; Johannes Mathis; Michel Lecendreux; Geert Mayer; Peter Geisler; Antonio Benetó; Brice Petit; Corinne Pfister; Julie Vienne Bürki; Gérard Didelot; Michel Billiard; Guadalupe Ercilla; Willem Verduijn; Frans H J Claas; Peter Vollenweider; Peter Vollenwider; Gerard Waeber; Dawn M Waterworth; Vincent Mooser; Raphaël Heinzer; Jacques S Beckmann; Sven Bergmann; Mehdi Tafti

doi:10.1038/ng.647

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Hyun Hor, Zoltán Kutalik, Yves Dauvilliers, Armand Valsesia, Gert J Lammers, Claire E H M Donjacour, Alex Iranzo, Joan Santamaria, Rosa Peraita Adrados, José L Vicario, Sebastiaan Overeem, Isabelle Arnulf, Ioannis Theodorou, Poul Jennum, Stine Knudsen, Claudio Bassetti, Johannes Mathis, Michel Lecendreux, Geert Mayer, Peter GeislerAntonio Benetó, Brice Petit, Corinne Pfister, Julie Vienne Bürki, Gérard Didelot, Michel Billiard, Guadalupe Ercilla, Willem Verduijn, Frans H J Claas, Peter Vollenweider, Peter Vollenwider, Gerard Waeber, Dawn M Waterworth, Vincent Mooser, Raphaël Heinzer, Jacques S Beckmann, Sven Bergmann, Mehdi Tafti

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127 Citations (Scopus)

Abstract

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10^-8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10^-43) and DRB1*1301-DQB1*0603 (P < 3 x 10^-7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10^-14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

Original language	English
Journal	Nature Genetics
Volume	42
Issue number	9
Pages (from-to)	786-9
Number of pages	4
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.647
Publication status	Published - 1 Sept 2010

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Hor, H., Kutalik, Z., Dauvilliers, Y., Valsesia, A., Lammers, G. J., Donjacour, C. E. H. M., Iranzo, A., Santamaria, J., Peraita Adrados, R., Vicario, J. L., Overeem, S., Arnulf, I., Theodorou, I., Jennum, P., Knudsen, S., Bassetti, C., Mathis, J., Lecendreux, M., Mayer, G., ... Tafti, M. (2010). Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nature Genetics, 42(9), 786-9. https://doi.org/10.1038/ng.647

Hor, H, Kutalik, Z, Dauvilliers, Y, Valsesia, A, Lammers, GJ, Donjacour, CEHM, Iranzo, A, Santamaria, J, Peraita Adrados, R, Vicario, JL, Overeem, S, Arnulf, I, Theodorou, I, Jennum, P, Knudsen, S, Bassetti, C, Mathis, J, Lecendreux, M, Mayer, G, Geisler, P, Benetó, A, Petit, B, Pfister, C, Bürki, JV, Didelot, G, Billiard, M, Ercilla, G, Verduijn, W, Claas, FHJ, Vollenweider, P, Vollenwider, P, Waeber, G, Waterworth, DM, Mooser, V, Heinzer, R, Beckmann, JS, Bergmann, S & Tafti, M 2010, 'Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy', Nature Genetics, vol. 42, no. 9, pp. 786-9. https://doi.org/10.1038/ng.647

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title = "Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy",

abstract = "Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10-8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10-43) and DRB1*1301-DQB1*0603 (P < 3 x 10-7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10-14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.",

author = "Hyun Hor and Zolt{\'a}n Kutalik and Yves Dauvilliers and Armand Valsesia and Lammers, {Gert J} and Donjacour, {Claire E H M} and Alex Iranzo and Joan Santamaria and {Peraita Adrados}, Rosa and Vicario, {Jos{\'e} L} and Sebastiaan Overeem and Isabelle Arnulf and Ioannis Theodorou and Poul Jennum and Stine Knudsen and Claudio Bassetti and Johannes Mathis and Michel Lecendreux and Geert Mayer and Peter Geisler and Antonio Benet{\'o} and Brice Petit and Corinne Pfister and B{\"u}rki, {Julie Vienne} and G{\'e}rard Didelot and Michel Billiard and Guadalupe Ercilla and Willem Verduijn and Claas, {Frans H J} and Peter Vollenweider and Peter Vollenwider and Gerard Waeber and Waterworth, {Dawn M} and Vincent Mooser and Rapha{\"e}l Heinzer and Beckmann, {Jacques S} and Sven Bergmann and Mehdi Tafti",

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T1 - Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

AU - Hor, Hyun

AU - Kutalik, Zoltán

AU - Dauvilliers, Yves

AU - Valsesia, Armand

AU - Lammers, Gert J

AU - Donjacour, Claire E H M

AU - Iranzo, Alex

AU - Santamaria, Joan

AU - Peraita Adrados, Rosa

AU - Vicario, José L

AU - Overeem, Sebastiaan

AU - Arnulf, Isabelle

AU - Theodorou, Ioannis

AU - Jennum, Poul

AU - Knudsen, Stine

AU - Bassetti, Claudio

AU - Mathis, Johannes

AU - Lecendreux, Michel

AU - Mayer, Geert

AU - Geisler, Peter

AU - Benetó, Antonio

AU - Petit, Brice

AU - Pfister, Corinne

AU - Bürki, Julie Vienne

AU - Didelot, Gérard

AU - Billiard, Michel

AU - Ercilla, Guadalupe

AU - Verduijn, Willem

AU - Claas, Frans H J

AU - Vollenweider, Peter

AU - Vollenwider, Peter

AU - Waeber, Gerard

AU - Waterworth, Dawn M

AU - Mooser, Vincent

AU - Heinzer, Raphaël

AU - Beckmann, Jacques S

AU - Bergmann, Sven

AU - Tafti, Mehdi

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10-8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10-43) and DRB1*1301-DQB1*0603 (P < 3 x 10-7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10-14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

AB - Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10-8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10-43) and DRB1*1301-DQB1*0603 (P < 3 x 10-7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10-14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

U2 - 10.1038/ng.647

DO - 10.1038/ng.647

M3 - Journal article

SN - 1061-4036

VL - 42

SP - 786

EP - 789

JO - Nature: New biology

JF - Nature: New biology

IS - 9

ER -

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Abstract

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