Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk: Mendelian Randomization and Colocalization Study

被引：17

作者：

Bakker, Mark K. ^{[1
]}

van Straten, Tijmen ^{[1
]}

Chong, Michael ^{[2
,3
,4
]}

Pare, Guillaume ^{[2
,3
,4
]}

Gill, Dipender ^{[5
]}

Ruigrok, Ynte M. ^{[1
]}

机构：

[1] Univ Utrecht, Univ Med Ctr Utrecht, Dept Neurol & Neurosurg, Brain Ctr, Utrecht, Netherlands

[2] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada

[3] McMaster Univ, Thrombosis & Atherosclerosis Res Inst, Hamilton, ON, Canada

[4] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada

[5] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

来源：

STROKE | 2023年 / 54卷 / 01期

基金：

欧洲研究理事会;

关键词：

aneurysm; genetics; hypertension; risk factors; stroke; GENOME-WIDE ASSOCIATION; CONSEQUENCES; GENETICS; LOCI; SEX; AGE;

D O I：

10.1161/STROKEAHA.122.040598

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

BACKGROUND: In a genome-wide association study of intracranial aneurysms (IA), enrichment was found between genes associated with IA and genes encoding targets of effective anti-epileptic drugs. Our aim was to assess if this pleiotropy is driven by shared disease mechanisms that could potentially highlight a treatment strategy for IA. METHODS: Using 2-sample inverse-variance weighted Mendelian randomization and genetic colocalization analyses we assessed: (1) if epilepsy liability in general affects IA risk, and (2) whether changes in gene- and protein-expression levels of anti-epileptic drug targets in blood and arterial tissue may causally affect IA risk. RESULTS: We found no overall effect of epilepsy liability on IA. Expression of 21 genes and 13 proteins corresponding to anti-epileptic drug targets supported a causal effect (P<0.05) on IA risk. Of those genes and proteins, genetic variants affecting CNNM2 levels showed strong evidence for colocalization with IA risk (posterior probability>70%). Higher CNNM2 levels in arterial tissue were associated with increased IA risk (odds ratio, 3.02; [95% CI, 2.32-3.94]; P=3.39x10(-16)). CNNM2 expression was best proxied by rs11191580. The magnitude of the effect of this variant was greater than would be expected if systemic blood pressure was the sole IA-causing mechanism in this locus. CONCLUSIONS: CNNM2 is a driver of the pleiotropy between IA and anti-epileptic drug targets. Administration of the anti-epileptic drugs phenytoin, valproic acid, or carbamazepine may be expected to decrease CNNM2 levels and therefore subsequently decrease IA risk. CNNM2 is therefore an important target to investigate further for its role in the pathogenesis of IA.

引用

页码：208 / 216

页数：9

共 53 条

[1] Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies [J].

Abou-Khalil, Bassel ;

Auce, Pauls ;

Avbersek, Andreja ;

Bahlo, Melanie ;

Balding, David J. ;

Bast, Thomas ;

Baum, Larry ;

Becker, Albert J. ;

Becker, Felicitas ;

Berghuis, Bianca ;

Berkovic, Samuel F. ;

Boysen, Katja E. ;

Bradfield, Jonathan P. ;

Brody, Lawrence C. ;

Buono, Russell J. ;

Campbell, Ellen ;

Cascino, Gregory D. ;

Catarino, Claudia B. ;

Cavalleri, Gianpiero L. ;

Cherny, Stacey S. ;

Chinthapalli, Krishna ;

Coffey, Alison J. ;

Compston, Alastair ;

Coppola, Antonietta ;

Cossette, Patrick ;

Craig, John J. ;

de Haan, Gerrit-Jan ;

De Jonghe, Peter ;

de Kovel, Carolien G. F. ;

Delanty, Norman ;

Depondt, Chantal ;

Devinsky, Orrin ;

Dlugos, Dennis J. ;

Doherty, Colin P. ;

Elger, Christian E. ;

Eriksson, Johan G. ;

Ferraro, Thomas N. ;

Feucht, Martha ;

Francis, Ben ;

Franke, Andre ;

French, Jacqueline A. ;

Freytag, Saskia ;

Gaus, Verena ;

Geller, Eric B. ;

Gieger, Christian ;

Glauser, Tracy ;

Glynn, Simon ;

Goldstein, David B. ;

Gui, Hongsheng ;

Guo, Youling .

NATURE COMMUNICATIONS, 2018, 9

[2] CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations [J].

Accogli, Andrea ;

Scala, Marcello ;

Calcagno, Annalisa ;

Napoli, Flavia ;

Di Iorgi, Natascia ;

Arrigo, Serena ;

Mancardi, Maria Margherita ;

Prato, Giulia ;

Pisciotta, Livia ;

Nagel, Mato ;

Severino, Mariasavina ;

Capra, Valeria .

EUROPEAN JOURNAL OF MEDICAL GENETICS, 2019, 62 (03) :198-203

[3] The GTEx Consortium atlas of genetic regulatory effects across human tissues [J].

Aguet, Francois ;

Barbeira, Alvaro N. ;

Bonazzola, Rodrigo ;

Brown, Andrew ;

Castel, Stephane E. ;

Jo, Brian ;

Kasela, Silva ;

Kim-Hellmuth, Sarah ;

Liang, Yanyu ;

Parsana, Princy ;

Flynn, Elise ;

Fresard, Laure ;

Gamazon, Eric R. ;

Hamel, Andrew R. ;

He, Yuan ;

Hormozdiari, Farhad ;

Mohammadi, Pejman ;

Munoz-Aguirre, Manuel ;

Ardlie, Kristin G. ;

Battle, Alexis ;

Bonazzola, Rodrigo ;

Brown, Christopher D. ;

Cox, Nancy ;

Dermitzakis, Emmanouil T. ;

Engelhardt, Barbara E. ;

Garrido-Martin, Diego ;

Gay, Nicole R. ;

Getz, Gad ;

Guigo, Roderic ;

Hamel, Andrew R. ;

Handsaker, Robert E. ;

He, Yuan ;

Hoffman, Paul J. ;

Hormozdiari, Farhad ;

Im, Hae Kyung ;

Jo, Brian ;

Kasela, Silva ;

Kashin, Seva ;

Kim-Hellmuth, Sarah ;

Kwong, Alan ;

Lappalainen, Tuuli ;

Li, Xiao ;

Liang, Yanyu ;

MacArthur, Daniel G. ;

Mohammadi, Pejman ;

Montgomery, Stephen B. ;

Munoz-Aguirre, Manuel ;

Rouhana, John M. ;

Hormozdiari, Farhad ;

Im, Hae Kyung .

SCIENCE, 2020, 369 (6509) :1318-1330

[4] Genetic effects on gene expression across human tissues [J].

Aguet, Francois ;

Brown, Andrew A. ;

Castel, Stephane E. ;

Davis, Joe R. ;

He, Yuan ;

Jo, Brian ;

Mohammadi, Pejman ;

Park, Yoson ;

Parsana, Princy ;

Segre, Ayellet V. ;

Strober, Benjamin J. ;

Zappala, Zachary ;

Cummings, Beryl B. ;

Gelfand, Ellen T. ;

Hadley, Kane ;

Huang, Katherine H. ;

Lek, Monkol ;

Li, Xiao ;

Nedzel, Jared L. ;

Nguyen, Duyen Y. ;

Noble, Michael S. ;

Sullivan, Timothy J. ;

Tukiainen, Taru ;

MacArthur, Daniel G. ;

Getz, Gad ;

Management, Nih Program ;

Addington, Anjene ;

Guan, Ping ;

Koester, Susan ;

Little, A. Roger ;

Lockhart, Nicole C. ;

Moore, Helen M. ;

Rao, Abhi ;

Struewing, Jeffery P. ;

Volpi, Simona ;

Collection, Biospecimen ;

Brigham, Lori E. ;

Hasz, Richard ;

Hunter, Marcus ;

Johns, Christopher ;

Johnson, Mark ;

Kopen, Gene ;

Leinweber, William F. ;

Lonsdale, John T. ;

McDonald, Alisa ;

Mestichelli, Bernadette ;

Myer, Kevin ;

Roe, Bryan ;

Salvatore, Michael ;

Shad, Saboor .

NATURE, 2017, 550 (7675) :204-+

[5] Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors [J].

Ahola-Olli, Ari V. ;

Wurtz, Peter ;

Havulinna, Aki S. ;

Aalto, Kristiina ;

Pitkanen, Niina ;

Lehtimaki, Terho ;

Kahonen, Mika ;

Lyytikainen, Leo-Pekka ;

Raitoharju, Emma ;

Seppala, Ilkka ;

Sarin, Antti-Pekka ;

Ripatti, Samuli ;

Palotie, Aarne ;

Perola, Markus ;

Viikari, Jorma S. ;

Jalkanen, Sirpa ;

Maksimow, Mikael ;

Salomaa, Veikko ;

Salmi, Marko ;

Kettunen, Johannes ;

Raitakari, Olli T. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2017, 100 (01) :40-50

[6] CNNM2 Mutations Cause Impaired Brain Development and Seizures in Patients with [J].

Arjona, Francisco J. ;

de Baaij, Jeroen H. F. ;

Schlingmann, Karl P. ;

Lameris, Anke L. L. ;

van Wijk, Erwin ;

Flik, Gert ;

Regele, Sabrina ;

Korenke, G. Christoph ;

Neophytou, Birgit ;

Rust, Stephan ;

Reintjes, Nadine ;

Konrad, Martin ;

Bindels, Rene J. M. ;

Hoenderop, Joost G. J. .

PLOS GENETICS, 2014, 10 (04)

[7] Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors [J].

Bakker, Mark K. ;

van der Spek, Rick A. A. ;

van Rheenen, Wouter ;

Morel, Sandrine ;

Bourcier, Romain ;

Hostettler, Isabel C. ;

Alg, Varinder S. ;

van Eijk, Kristel R. ;

Koido, Masaru ;

Akiyama, Masato ;

Terao, Chikashi ;

Matsuda, Koichi ;

Walters, Robin G. ;

Lin, Kuang ;

Li, Liming ;

Millwood, Iona Y. ;

Chen, Zhengming ;

Rouleau, Guy A. ;

Zhou, Sirui ;

Rannikmae, Kristiina ;

Sudlow, Cathie L. M. ;

Houlden, Henry ;

van den Berg, Leonard H. ;

Dina, Christian ;

Naggara, Olivier ;

Gentric, Jean-Christophe ;

Shotar, Eimad ;

Eugene, Francois ;

Desal, Hubert ;

Winsvold, Bendik S. ;

Borte, Sigrid ;

Johnsen, Marianne Bakke ;

Brumpton, Ben M. ;

Sandvei, Marie Softeland ;

Willer, Cristen J. ;

Hveem, Kristian ;

Zwart, John-Anker ;

Verschuren, W. M. Monique ;

Friedrich, Christoph M. ;

Hirsch, Sven ;

Schilling, Sabine ;

Dauvillier, Jerome ;

Martin, Olivier ;

Winsvold, Bendik S. ;

Borte, Sigrid ;

Johnsen, Marianne Bakke ;

Brumpton, Ben M. ;

Sandvei, Marie Softeland ;

Willer, Cristen J. .

NATURE GENETICS, 2020, 52 (12) :1303-1313

[8] Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption [J].

Bowden, Jack ;

Del Greco, Fabiola M. ;

Minelli, Cosetta ;

Zhao, Qingyuan ;

Lawlor, Debbie A. ;

Sheehan, Nuala A. ;

Thompson, John ;

Smith, George Davey .

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2019, 48 (03) :728-742

[9] A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization [J].

Bowden, Jack ;

Del Greco, Fabiola M. ;

Minelli, Cosetta ;

Smith, George Davey ;

Sheehan, Nuala ;

Thompson, John .

STATISTICS IN MEDICINE, 2017, 36 (11) :1783-1802

[10] Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator [J].

Bowden, Jack ;

Smith, George Davey ;

Haycock, Philip C. ;

Burgess, Stephen .

GENETIC EPIDEMIOLOGY, 2016, 40 (04) :304-314

← 1 2 3 4 5 6 →