Abstract
Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.
Originalsprog | Engelsk |
---|---|
Tidsskrift | Nature Genetics |
Vol/bind | 55 |
Udgave nummer | 11 |
Sider (fra-til) | 1843-1853 |
ISSN | 1061-4036 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:We thank all participants who contributed data and samples used in this study. Their contributions are essential for research such as reported here. We thank all investigators and colleagues who collaborated on the many aspects of this study, including data collection, sample handling, phenotypic characterization of clinical samples, genotyping and analysis of the whole-genome association data. We acknowledge participants and investigators of the FinnGen study and the UK Biobank study. This research has been conducted using the UK Biobank Resource, a major biomedical database (application 42256, https://www.ukbiobank.ac.uk/ ). The financial support from the European Commission to the painFACT project to T.E.T. (H2020-2020-848099) is acknowledged, as is support from the Novo Nordisk Foundation, DBDS Consortium (grants NNF17OC0027594 and NNF14CC0001). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health ( commonfund.nih.gov/GTEx ). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), GTEx Project March 5, 2014 version Page 5 of 8 Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). The Brain Bank was supported supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101825 and MH101820), the University of North Carolina - Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810) and to the University of Pennsylvania (MH101822). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v9.p2 .
Funding Information:
We thank all participants who contributed data and samples used in this study. Their contributions are essential for research such as reported here. We thank all investigators and colleagues who collaborated on the many aspects of this study, including data collection, sample handling, phenotypic characterization of clinical samples, genotyping and analysis of the whole-genome association data. We acknowledge participants and investigators of the FinnGen study20and the UK Biobank study. This research has been conducted using the UK Biobank Resource, a major biomedical database (application 42256, https://www.ukbiobank.ac.uk/ ). The financial support from the European Commission to the painFACT project to T.E.T. (H2020-2020-848099) is acknowledged, as is support from the Novo Nordisk Foundation, DBDS Consortium (grants NNF17OC0027594 and NNF14CC0001). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx ). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), GTEx Project March 5, 2014 version Page 5 of 8 Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). The Brain Bank was supported supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101825 and MH101820), the University of North Carolina - Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810) and to the University of Pennsylvania (MH101822). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v9.p2.
Publisher Copyright:
© 2023, The Author(s).