HMG-CoA reductase is a potential therapeutic target for migraine: a mendelian randomization study

Kang Qu; Ming Xi Li; Peng Yu; Bai Hua Wu; Miao Shi; Ming Dong; Aarno Palotie; Alice Pressman; Andrea C. Belin; Anna Bjornsdottir; Arn M.J.M. van den Maagdenberg; Aster V.E. Harder; Bendik S. Winsvold; Bertram Müller-Myhsok; Bru Cormand; Caroline Ran; Carrie Northover; Christian Kubisch; Cornelia van Duijn; Dale R. Nyholt; Daniel I. Chasman; Danielle Posthuma; Davor Lessel; Dorret I. Boomsma; Eija Hämäläinen; Espen S. Kristoffersen; Ester Cuenca-Leon; George Davey-Smith; Gisela M. Terwindt; Gudrun R. Sigurdardottir; Gyda Bjornsdottir; Heidi Hautakangas; Hreinn Stefansson; Irene de Boer; Jaakko Kaprio; Jes Olesen; John Anker Zwart; Kari Stefansson; Lannie Ligthart; Lenore Launer; Linda M. Pedersen; Lisette J.A. Kogelman; Lyn R. Griffiths; M. Arfan Ikram; Maija Wessman; Mari Kaunisto; Maria G. Hrafnsdottir; Marjo Hiekkala; Marjo Riitta Järvelin; Martin Dichgans; Matti Pirinen; Mikko Kallela; Mitja Kurki; Mona A. Chalmer; Nancy Pedersen; Olafur A. Sveinsson; Olli Raitakari; Padhraig Gormley; Patricia Pozo-Rosich; Priit Palta; Rainer Malik; Risto Kajanne; Sigrid Børte; Sigurdur H. Magnusson; Terho Lehtimäki; Thomas F. Hansen; Thorgeir E. Thorgeirsson; Tobias Freilinger; Tobias Kurth; Tonu Esko; Verneri Anttila; Ville Artto

doi:10.1038/s41598-024-61628-9

HMG-CoA reductase is a potential therapeutic target for migraine: a mendelian randomization study

Kang Qu, Ming Xi Li, Peng Yu, Bai Hua Wu, Miao Shi, Ming Dong^*, Aarno Palotie, Alice Pressman, Andrea C. Belin, Anna Bjornsdottir, Arn M.J.M. van den Maagdenberg, Aster V.E. Harder, Bendik S. Winsvold, Bertram Müller-Myhsok, Bru Cormand, Caroline Ran, Carrie Northover, Christian Kubisch, Cornelia van Duijn, Dale R. NyholtDaniel I. Chasman, Danielle Posthuma, Davor Lessel, Dorret I. Boomsma, Eija Hämäläinen, Espen S. Kristoffersen, Ester Cuenca-Leon, George Davey-Smith, Gisela M. Terwindt, Gudrun R. Sigurdardottir, Gyda Bjornsdottir, Heidi Hautakangas, Hreinn Stefansson, Irene de Boer, Jaakko Kaprio, Jes Olesen, John Anker Zwart, Kari Stefansson, Lannie Ligthart, Lenore Launer, Linda M. Pedersen, Lisette J.A. Kogelman, Lyn R. Griffiths, M. Arfan Ikram, Maija Wessman, Mari Kaunisto, Maria G. Hrafnsdottir, Marjo Hiekkala, Marjo Riitta Järvelin, Martin Dichgans, Matti Pirinen, Mikko Kallela, Mitja Kurki, Mona A. Chalmer, Nancy Pedersen, Olafur A. Sveinsson, Olli Raitakari, Padhraig Gormley, Patricia Pozo-Rosich, Priit Palta, Rainer Malik, Risto Kajanne, Sigrid Børte, Sigurdur H. Magnusson, Terho Lehtimäki, Thomas F. Hansen, Thorgeir E. Thorgeirsson, Tobias Freilinger, Tobias Kurth, Tonu Esko, Verneri Anttila, Ville Artto

^*Corresponding author for this work

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

Abstract

Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30–1.84, P = 6.87 × 10⁻⁷). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.

Original language	English
Article number	12094
Pages (from-to)	1-11
Number of pages	11
Journal	Scientific Reports
Volume	14
Early online date	27 May 2024
DOIs	https://doi.org/10.1038/s41598-024-61628-9
Publication status	Published - 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

The authors express their gratitude to the esteemed individuals comprising the International Headache Genetics Consortium, eQTLGen consortium, and FinnGen consortium. They also extend their heartfelt appreciation to the three consortiums for generously contributing pooled data. The dedicated members of the International Headache Genetics Consortium (refer to Supplementary Table 9 for complete details) are acknowledged with utmost respect. This work was supported by a grant from the Natural Science Foundation of Jilin Province of China (Grant No. 20200201606JC), Scientific Research Program of Jilin Health and Family Planning Commission (Grant No. 2016J049) and the National Natural Science Foundation of China (Grant No. 31872772) to Ming Dong.

Funders	Funder number
International Headache Genetics Consortium
Natural Science Foundation of Jilin Province	20200201606JC
Scientific Research Program of Jilin Health and Family Planning Commission	2016J049
National Natural Science Foundation of China	31872772

Keywords

HMG-CoA reductase
Mendelian randomization
Migraine
Statins

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Qu, K., Li, M. X., Yu, P., Wu, B. H., Shi, M., Dong, M., Palotie, A., Pressman, A., Belin, A. C., Bjornsdottir, A., van den Maagdenberg, A. M. J. M., Harder, A. V. E., Winsvold, B. S., Müller-Myhsok, B., Cormand, B., Ran, C., Northover, C., Kubisch, C., van Duijn, C., ... Artto, V. (2024). HMG-CoA reductase is a potential therapeutic target for migraine: a mendelian randomization study. Scientific Reports, 14, 1-11. Article 12094. https://doi.org/10.1038/s41598-024-61628-9

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title = "HMG-CoA reductase is a potential therapeutic target for migraine: a mendelian randomization study",

abstract = "Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95\% CI 1.30–1.84, P = 6.87 × 10−7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.",

keywords = "HMG-CoA reductase, Mendelian randomization, Migraine, Statins",

author = "Kang Qu and Li, \{Ming Xi\} and Peng Yu and Wu, \{Bai Hua\} and Miao Shi and Ming Dong and Aarno Palotie and Alice Pressman and Belin, \{Andrea C.\} and Anna Bjornsdottir and \{van den Maagdenberg\}, \{Arn M.J.M.\} and Harder, \{Aster V.E.\} and Winsvold, \{Bendik S.\} and Bertram M{\"u}ller-Myhsok and Bru Cormand and Caroline Ran and Carrie Northover and Christian Kubisch and \{van Duijn\}, Cornelia and Nyholt, \{Dale R.\} and Chasman, \{Daniel I.\} and Danielle Posthuma and Davor Lessel and Boomsma, \{Dorret I.\} and Eija H{\"a}m{\"a}l{\"a}inen and Kristoffersen, \{Espen S.\} and Ester Cuenca-Leon and George Davey-Smith and Terwindt, \{Gisela M.\} and Sigurdardottir, \{Gudrun R.\} and Gyda Bjornsdottir and Heidi Hautakangas and Hreinn Stefansson and \{de Boer\}, Irene and Jaakko Kaprio and Jes Olesen and Zwart, \{John Anker\} and Kari Stefansson and Lannie Ligthart and Lenore Launer and Pedersen, \{Linda M.\} and Kogelman, \{Lisette J.A.\} and Griffiths, \{Lyn R.\} and Ikram, \{M. Arfan\} and Maija Wessman and Mari Kaunisto and Hrafnsdottir, \{Maria G.\} and Marjo Hiekkala and J{\"a}rvelin, \{Marjo Riitta\} and Martin Dichgans and Matti Pirinen and Mikko Kallela and Mitja Kurki and Chalmer, \{Mona A.\} and Nancy Pedersen and Sveinsson, \{Olafur A.\} and Olli Raitakari and Padhraig Gormley and Patricia Pozo-Rosich and Priit Palta and Rainer Malik and Risto Kajanne and Sigrid B{\o}rte and Magnusson, \{Sigurdur H.\} and Terho Lehtim{\"a}ki and Hansen, \{Thomas F.\} and Thorgeirsson, \{Thorgeir E.\} and Tobias Freilinger and Tobias Kurth and Tonu Esko and Verneri Anttila and Ville Artto",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1038/s41598-024-61628-9",

language = "English",

volume = "14",

pages = "1--11",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Research",

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Qu, K, Li, MX, Yu, P, Wu, BH, Shi, M, Dong, M, Palotie, A, Pressman, A, Belin, AC, Bjornsdottir, A, van den Maagdenberg, AMJM, Harder, AVE, Winsvold, BS, Müller-Myhsok, B, Cormand, B, Ran, C, Northover, C, Kubisch, C, van Duijn, C, Nyholt, DR, Chasman, DI, Posthuma, D, Lessel, D, Boomsma, DI, Hämäläinen, E, Kristoffersen, ES, Cuenca-Leon, E, Davey-Smith, G, Terwindt, GM, Sigurdardottir, GR, Bjornsdottir, G, Hautakangas, H, Stefansson, H, de Boer, I, Kaprio, J, Olesen, J, Zwart, JA, Stefansson, K, Ligthart, L, Launer, L, Pedersen, LM, Kogelman, LJA, Griffiths, LR, Ikram, MA, Wessman, M, Kaunisto, M, Hrafnsdottir, MG, Hiekkala, M, Järvelin, MR, Dichgans, M, Pirinen, M, Kallela, M, Kurki, M, Chalmer, MA, Pedersen, N, Sveinsson, OA, Raitakari, O, Gormley, P, Pozo-Rosich, P, Palta, P, Malik, R, Kajanne, R, Børte, S, Magnusson, SH, Lehtimäki, T, Hansen, TF, Thorgeirsson, TE, Freilinger, T, Kurth, T, Esko, T, Anttila, V & Artto, V 2024, 'HMG-CoA reductase is a potential therapeutic target for migraine: a mendelian randomization study', Scientific Reports, vol. 14, 12094, pp. 1-11. https://doi.org/10.1038/s41598-024-61628-9

TY - JOUR

T1 - HMG-CoA reductase is a potential therapeutic target for migraine

T2 - a mendelian randomization study

AU - Qu, Kang

AU - Li, Ming Xi

AU - Yu, Peng

AU - Wu, Bai Hua

AU - Shi, Miao

AU - Dong, Ming

AU - Palotie, Aarno

AU - Pressman, Alice

AU - Belin, Andrea C.

AU - Bjornsdottir, Anna

AU - van den Maagdenberg, Arn M.J.M.

AU - Harder, Aster V.E.

AU - Winsvold, Bendik S.

AU - Müller-Myhsok, Bertram

AU - Cormand, Bru

AU - Ran, Caroline

AU - Northover, Carrie

AU - Kubisch, Christian

AU - van Duijn, Cornelia

AU - Nyholt, Dale R.

AU - Chasman, Daniel I.

AU - Posthuma, Danielle

AU - Lessel, Davor

AU - Boomsma, Dorret I.

AU - Hämäläinen, Eija

AU - Kristoffersen, Espen S.

AU - Cuenca-Leon, Ester

AU - Davey-Smith, George

AU - Terwindt, Gisela M.

AU - Sigurdardottir, Gudrun R.

AU - Bjornsdottir, Gyda

AU - Hautakangas, Heidi

AU - Stefansson, Hreinn

AU - de Boer, Irene

AU - Kaprio, Jaakko

AU - Olesen, Jes

AU - Zwart, John Anker

AU - Stefansson, Kari

AU - Ligthart, Lannie

AU - Launer, Lenore

AU - Pedersen, Linda M.

AU - Kogelman, Lisette J.A.

AU - Griffiths, Lyn R.

AU - Ikram, M. Arfan

AU - Wessman, Maija

AU - Kaunisto, Mari

AU - Hrafnsdottir, Maria G.

AU - Hiekkala, Marjo

AU - Järvelin, Marjo Riitta

AU - Dichgans, Martin

AU - Pirinen, Matti

AU - Kallela, Mikko

AU - Kurki, Mitja

AU - Chalmer, Mona A.

AU - Pedersen, Nancy

AU - Sveinsson, Olafur A.

AU - Raitakari, Olli

AU - Gormley, Padhraig

AU - Pozo-Rosich, Patricia

AU - Palta, Priit

AU - Malik, Rainer

AU - Kajanne, Risto

AU - Børte, Sigrid

AU - Magnusson, Sigurdur H.

AU - Lehtimäki, Terho

AU - Hansen, Thomas F.

AU - Thorgeirsson, Thorgeir E.

AU - Freilinger, Tobias

AU - Kurth, Tobias

AU - Esko, Tonu

AU - Anttila, Verneri

AU - Artto, Ville

PY - 2024

Y1 - 2024

N2 - Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30–1.84, P = 6.87 × 10−7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.

AB - Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30–1.84, P = 6.87 × 10−7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.

KW - HMG-CoA reductase

KW - Mendelian randomization

KW - Migraine

KW - Statins

UR - https://www.scopus.com/pages/publications/85194900020

UR - https://www.scopus.com/inward/citedby.url?scp=85194900020&partnerID=8YFLogxK

U2 - 10.1038/s41598-024-61628-9

DO - 10.1038/s41598-024-61628-9

M3 - Article

AN - SCOPUS:85194900020

SN - 2045-2322

VL - 14

SP - 1

EP - 11

JO - Scientific Reports

JF - Scientific Reports

M1 - 12094

ER -

HMG-CoA reductase is a potential therapeutic target for migraine: a mendelian randomization study

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