Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

International Headache Genetics Consortium; HUNT All-in Headache; Danish Blood Donor Study Genomic Cohort

doi:https://doi.org/10.1038/s41588-021-00990-0

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

International Headache Genetics Consortium, HUNT All-in Headache, Danish Blood Donor Study Genomic Cohort

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

81 Citations (Scopus)

Abstract

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

Original language	English
Pages (from-to)	152-160
Number of pages	9
Journal	Nature Genetics
Volume	54
Issue number	2
DOIs	https://doi.org/10.1038/s41588-021-00990-0
Publication status	Published - 1 Feb 2022

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https://doi.org/10.1038/s41588-021-00990-0

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@article{2ce5cf9b763549bf98bb83f5d2ab10e6,

title = "Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles",

abstract = "Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.",

author = "{International Headache Genetics Consortium} and {HUNT All-in Headache} and {Danish Blood Donor Study Genomic Cohort} and Heidi Hautakangas and Winsvold, {Bendik S.} and Ruotsalainen, {Sanni E.} and Gyda Bjornsdottir and Harder, {Aster V. E.} and Kogelman, {Lisette J. A.} and Thomas, {Laurent F.} and Raymond Noordam and Christian Benner and Padhraig Gormley and Ville Artto and Karina Banasik and Anna Bjornsdottir and Boomsma, {Dorret I.} and Brumpton, {Ben M.} and Burgdorf, {Kristoffer S. lvsten} and Buring, {Julie E.} and Chalmer, {Mona Ameri} and {de Boer}, Irene and Martin Dichgans and Christian Erikstrup and Markus F{\"a}rkkil{\"a} and Garbrielsen, {Maiken Elvestad} and Mohsen Ghanbari and Knut Hagen and Paavo H{\"a}pp{\"o}l{\"a} and Jouke-Jan Hottenga and Hrafnsdottir, {Maria G.} and Kristian Hveem and Johnsen, {Marianne Bakke} and Mika K{\"a}h{\"o}nen and Kristoffersen, {Espen S.} and Tobias Kurth and Terho Lehtim{\"a}ki and Lannie Lighart and Magnusson, {Sigurdur H.} and Rainer Malik and Pedersen, {Ole Birger} and Nadine Pelzer and Penninx, {Brenda W. J. H.} and Caroline Ran and Ridker, {Paul M.} and Rosendaal, {Frits R.} and Sigurdardottir, {Gudrun R.} and Skogholt, {Anne Heidi} and Sveinsson, {Olafur A.} and Thorgeirsson, {Thorgeir E.} and Henrik Ullum and Vijfhuizen, {Lisanne S.} and Elisabeth Wid{\'e}n and Lannie Ligthart",

note = "Funding Information: We thank the study participants for their contribution to this research. We also thank the numerous individuals who contributed to sample collection, storage, handling, phenotyping and genotyping for each of the individual cohorts. We acknowledge the participants and investigators of the FinnGen study. This research has been conducted using the UK Biobank Resource under Application Number 22627. We are supported by following grants: the US National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health (NIH) (grant numbers R21NS09296 and R21NS104398 (D.I.C.)), the Finnish innovation fund Sitra and Finska L?kares?llskapet (E.W.), the Academy of Finland (grant nos. 288509, 312076, 336825 (M.P.)), the Sigrid Juselius Foundation (M.P. and S.R.), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant no. 312062 (S.R.)), the Finnish Foundation for Cardiovascular Research (S.R.), University of Helsinki HiLIFE Fellow and Grand Challenge grants (S.R.), The Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594 (T.F.H. and K.B.)), CANDY foundation (CEHEAD) (T.F.H.), and the South-Eastern Norway Regional Health Authority (grant no. 2020034 (B.S.W.)). A list of study-specific acknowledgements and funding information can be found in the Supplementary Note. Funding Information: We thank the study participants for their contribution to this research. We also thank the numerous individuals who contributed to sample collection, storage, handling, phenotyping and genotyping for each of the individual cohorts. We acknowledge the participants and investigators of the FinnGen study. This research has been conducted using the UK Biobank Resource under Application Number 22627. We are supported by following grants: the US National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health (NIH) (grant numbers R21NS09296 and R21NS104398 (D.I.C.)), the Finnish innovation fund Sitra and Finska L{\"a}kares{\"a}llskapet (E.W.), the Academy of Finland (grant nos. 288509, 312076, 336825 (M.P.)), the Sigrid Juselius Foundation (M.P. and S.R.), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant no. 312062 (S.R.)), the Finnish Foundation for Cardiovascular Research (S.R.), University of Helsinki HiLIFE Fellow and Grand Challenge grants (S.R.), The Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594 (T.F.H. and K.B.)), CANDY foundation (CEHEAD) (T.F.H.), and the South-Eastern Norway Regional Health Authority (grant no. 2020034 (B.S.W.)). A list of study-specific acknowledgements and funding information can be found in the . Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = feb,

day = "1",

doi = "https://doi.org/10.1038/s41588-021-00990-0",

language = "English",

volume = "54",

pages = "152--160",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

AU - International Headache Genetics Consortium

AU - HUNT All-in Headache

AU - Danish Blood Donor Study Genomic Cohort

AU - Hautakangas, Heidi

AU - Winsvold, Bendik S.

AU - Ruotsalainen, Sanni E.

AU - Bjornsdottir, Gyda

AU - Harder, Aster V. E.

AU - Kogelman, Lisette J. A.

AU - Thomas, Laurent F.

AU - Noordam, Raymond

AU - Benner, Christian

AU - Gormley, Padhraig

AU - Artto, Ville

AU - Banasik, Karina

AU - Bjornsdottir, Anna

AU - Boomsma, Dorret I.

AU - Brumpton, Ben M.

AU - Burgdorf, Kristoffer S. lvsten

AU - Buring, Julie E.

AU - Chalmer, Mona Ameri

AU - de Boer, Irene

AU - Dichgans, Martin

AU - Erikstrup, Christian

AU - Färkkilä, Markus

AU - Garbrielsen, Maiken Elvestad

AU - Ghanbari, Mohsen

AU - Hagen, Knut

AU - Häppölä, Paavo

AU - Hottenga, Jouke-Jan

AU - Hrafnsdottir, Maria G.

AU - Hveem, Kristian

AU - Johnsen, Marianne Bakke

AU - Kähönen, Mika

AU - Kristoffersen, Espen S.

AU - Kurth, Tobias

AU - Lehtimäki, Terho

AU - Lighart, Lannie

AU - Magnusson, Sigurdur H.

AU - Malik, Rainer

AU - Pedersen, Ole Birger

AU - Pelzer, Nadine

AU - Penninx, Brenda W. J. H.

AU - Ran, Caroline

AU - Ridker, Paul M.

AU - Rosendaal, Frits R.

AU - Sigurdardottir, Gudrun R.

AU - Skogholt, Anne Heidi

AU - Sveinsson, Olafur A.

AU - Thorgeirsson, Thorgeir E.

AU - Ullum, Henrik

AU - Vijfhuizen, Lisanne S.

AU - Widén, Elisabeth

AU - Ligthart, Lannie

N1 - Funding Information: We thank the study participants for their contribution to this research. We also thank the numerous individuals who contributed to sample collection, storage, handling, phenotyping and genotyping for each of the individual cohorts. We acknowledge the participants and investigators of the FinnGen study. This research has been conducted using the UK Biobank Resource under Application Number 22627. We are supported by following grants: the US National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health (NIH) (grant numbers R21NS09296 and R21NS104398 (D.I.C.)), the Finnish innovation fund Sitra and Finska L?kares?llskapet (E.W.), the Academy of Finland (grant nos. 288509, 312076, 336825 (M.P.)), the Sigrid Juselius Foundation (M.P. and S.R.), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant no. 312062 (S.R.)), the Finnish Foundation for Cardiovascular Research (S.R.), University of Helsinki HiLIFE Fellow and Grand Challenge grants (S.R.), The Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594 (T.F.H. and K.B.)), CANDY foundation (CEHEAD) (T.F.H.), and the South-Eastern Norway Regional Health Authority (grant no. 2020034 (B.S.W.)). A list of study-specific acknowledgements and funding information can be found in the Supplementary Note. Funding Information: We thank the study participants for their contribution to this research. We also thank the numerous individuals who contributed to sample collection, storage, handling, phenotyping and genotyping for each of the individual cohorts. We acknowledge the participants and investigators of the FinnGen study. This research has been conducted using the UK Biobank Resource under Application Number 22627. We are supported by following grants: the US National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health (NIH) (grant numbers R21NS09296 and R21NS104398 (D.I.C.)), the Finnish innovation fund Sitra and Finska Läkaresällskapet (E.W.), the Academy of Finland (grant nos. 288509, 312076, 336825 (M.P.)), the Sigrid Juselius Foundation (M.P. and S.R.), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant no. 312062 (S.R.)), the Finnish Foundation for Cardiovascular Research (S.R.), University of Helsinki HiLIFE Fellow and Grand Challenge grants (S.R.), The Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594 (T.F.H. and K.B.)), CANDY foundation (CEHEAD) (T.F.H.), and the South-Eastern Norway Regional Health Authority (grant no. 2020034 (B.S.W.)). A list of study-specific acknowledgements and funding information can be found in the . Publisher Copyright: © 2022, The Author(s).

PY - 2022/2/1

Y1 - 2022/2/1

N2 - Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

AB - Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

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U2 - https://doi.org/10.1038/s41588-021-00990-0

DO - https://doi.org/10.1038/s41588-021-00990-0

M3 - Article

C2 - 35115687

SN - 1061-4036

VL - 54

SP - 152

EP - 160

JO - Nature genetics

JF - Nature genetics

IS - 2

ER -

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

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