Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes
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Description
<p>Hemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel α1A subunit gene CACNA1A have been identified in a subset of HM patients, we investigated whether HM patients without a mutation have an increased burden of such variants in the “CACNA1x gene family”. Whole exome sequencing data of an Australian cohort of unrelated HM patients (n = 184), along with public data from gnomAD, as controls, was used to assess the burden of missense variants in CACNA1x genes. We performed both a variant and a subject burden test. We found a significant burden for the number of variants in CACNA1E (p = 1.3 × 10<sup>−4</sup>), CACNA1H (p < 2.2 × 10<sup>−16</sup>) and CACNA1I (p < 2.2 × 10<sup>−16</sup>). There was also a significant burden of subjects with missense variants in CACNA1E (p = 6.2 × 10<sup>−3</sup>), CACNA1H (p < 2.2 × 10<sup>−16</sup>) and CACNA1I (p < 2.2 × 10<sup>−16</sup>). Both the number of variants and number of subjects were replicated for CACNA1H (p = 3.5 × 10<sup>−8</sup>; p = 0.012) and CACNA1I (p = 0.019, p = 0.044), respectively, in a Dutch clinical HM cohort (n = 32), albeit that CACNA1I did not remain significant after multiple testing correction. Our data suggest that HM, in the absence of a single causal mutation, is a complex trait, in which an increased burden of missense variants in CACNA1H and CACNA1I may contribute to the risk of disease.</p>
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ID Code: | 246303 | ||||||||
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Item Type: | Contribution to Journal (Journal Article) | ||||||||
Refereed: | Yes | ||||||||
ORCID iD: |
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Additional Information: | Funding: Open Access funding enabled and organized by CAUL and its Member Institutions. The authors disclose receipt of the following financial support for the research, authorship, and/or publication of this article. This work was supported by the Australian National Health and Medical Research Council (NHMRC-APP1122387) (LRG); a Migraine Research Foundation grant (2016), NY, USA (LRG); an Australian International Science Linkages grant (LRG); by infrastructure purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia – Queensland Node project (LRG); the Centre of Medical System Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) 050–060-409 (AMJMvdM); and the European Community (EC) FP7-EUROHEADPAIN (no. 602633; AMJMvdM). | ||||||||
Measurements or Duration: | 10 pages | ||||||||
Keywords: | Burden-testing, CACNA1x, Headache, Hemiplegic migraine | ||||||||
DOI: | 10.1007/s12035-023-03255-5 | ||||||||
ISSN: | 0893-7648 | ||||||||
Pure ID: | 157243032 | ||||||||
Divisions: | Current > Research Centres > Centre for Genomics and Personalised Health Current > QUT Faculties and Divisions > Academic Division Current > QUT Faculties and Divisions > Faculty of Health Current > Schools > School of Biomedical Sciences |
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Funding Information: | GMT reports consultancy support from Novartis, Allergan/Abbvie, Lilly, and Teva, Lundbeck and independent support from Dutch Research Council, the Dutch Heart & Brain Foundations, IRRF and Dioraphte. AMJMvdM reports research support from Praxis Precision Medicine and Schedule 1 Therapeutics and consultancy support from AbbVie. LRG reports recent consultancy support from Teva and research support from the Australian National Health and Medical Research Council and the US Migraine Research Foundation. IdB reports independent support from the International Retinal Research Foundation and Dutch Heart Foundation. AVEH, LSV, OI, NP, NM, HS and RAL declare no conflict of interest. The authors disclose receipt of the following financial support for the research, authorship, and/or publication of this article. This work was supported by the Australian National Health and Medical Research Council (NHMRC-APP1122387) (LRG); a Migraine Research Foundation grant (2016), NY, USA (LRG); an Australian International Science Linkages grant (LRG); by infrastructure purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia – Queensland Node project (LRG); the Centre of Medical System Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) 050–060-409 (AMJMvdM); and the European Community (EC) FP7-EUROHEADPAIN (no. 602633; AMJMvdM). | ||||||||
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Copyright Owner: | 2023 The Authors | ||||||||
Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au | ||||||||
Deposited On: | 07 Feb 2024 07:39 | ||||||||
Last Modified: | 01 Jun 2024 07:36 |
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