Clinical Implications of SCN10A Loss-of-Function Variants in 169 610 Exomes Representing the General Population

HomeCirculation: Genomic and Precision MedicineVol. 15, No. 1Clinical Implications of SCN10A Loss-of-Function Variants in 169 610 Exomes Representing the General Population Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toSupplementary MaterialsFree AccessLetterPDF/EPUBClinical Implications of SCN10A Loss-of-Function Variants in 169 610 Exomes Representing the General Population Christian Paludan-Müller, MD, Simon Larsen, BSc, Gustav Ahlberg, MSc, PhD, Laura Andreasen, MD, Laia M. Monfort, MSc, Jesper H. Svendsen, MD, DMSc, Thomas Jespersen, MSc, PhD, DMSc, Henning Bundgaard, MD, DMSc, Jørgen K. Kanters, MD and Morten S. Olesen, MSc, PhD Christian Paludan-MüllerChristian Paludan-Müller https://orcid.org/0000-0002-7724-544X Laboratory for Molecular Cardiology (C.P.-M., S.L., G.A., L.A., L.M.M., J.H.S., M.S.O.), Department of Cardiology, The Heart Centre, Copenhagen University Hospital - Rigshospitalet, Denmark. Department of Biomedical Sciences (C.P.-M., S.L., G.A., L.A., L.M.M., T.J., M.S.O.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Department of Clinical Medicine (C.P.-M., G.A., L.M.M., J.H.S., H.B.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author , Simon LarsenSimon Larsen https://orcid.org/0000-0003-0924-483X Laboratory for Molecular Cardiology (C.P.-M., S.L., G.A., L.A., L.M.M., J.H.S., M.S.O.), Department of Cardiology, The Heart Centre, Copenhagen University Hospital - Rigshospitalet, Denmark. Department of Biomedical Sciences (C.P.-M., S.L., G.A., L.A., L.M.M., T.J., M.S.O.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author , Gustav AhlbergGustav Ahlberg https://orcid.org/0000-0003-0066-2779 Laboratory for Molecular Cardiology (C.P.-M., S.L., G.A., L.A., L.M.M., J.H.S., M.S.O.), Department of Cardiology, The Heart Centre, Copenhagen University Hospital - Rigshospitalet, Denmark. Department of Biomedical Sciences (C.P.-M., S.L., G.A., L.A., L.M.M., T.J., M.S.O.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Department of Clinical Medicine (C.P.-M., G.A., L.M.M., J.H.S., H.B.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author , Laura AndreasenLaura Andreasen https://orcid.org/0000-0002-4732-4921 Laboratory for Molecular Cardiology (C.P.-M., S.L., G.A., L.A., L.M.M., J.H.S., M.S.O.), Department of Cardiology, The Heart Centre, Copenhagen University Hospital - Rigshospitalet, Denmark. Department of Biomedical Sciences (C.P.-M., S.L., G.A., L.A., L.M.M., T.J., M.S.O.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author , Laia M. MonfortLaia M. Monfort Laboratory for Molecular Cardiology (C.P.-M., S.L., G.A., L.A., L.M.M., J.H.S., M.S.O.), Department of Cardiology, The Heart Centre, Copenhagen University Hospital - Rigshospitalet, Denmark. Department of Biomedical Sciences (C.P.-M., S.L., G.A., L.A., L.M.M., T.J., M.S.O.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Department of Clinical Medicine (C.P.-M., G.A., L.M.M., J.H.S., H.B.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author , Jesper H. SvendsenJesper H. Svendsen https://orcid.org/0000-0001-8466-8515 Laboratory for Molecular Cardiology (C.P.-M., S.L., G.A., L.A., L.M.M., J.H.S., M.S.O.), Department of Cardiology, The Heart Centre, Copenhagen University Hospital - Rigshospitalet, Denmark. Department of Clinical Medicine (C.P.-M., G.A., L.M.M., J.H.S., H.B.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author , Thomas JespersenThomas Jespersen Department of Biomedical Sciences (C.P.-M., S.L., G.A., L.A., L.M.M., T.J., M.S.O.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author , Henning BundgaardHenning Bundgaard https://orcid.org/0000-0002-0563-7049 The Unit for Inherited Cardiac Diseases (H.B.), Department of Cardiology, The Heart Centre, Copenhagen University Hospital - Rigshospitalet, Denmark. Department of Clinical Medicine (C.P.-M., G.A., L.M.M., J.H.S., H.B.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author , Jørgen K. KantersJørgen K. Kanters https://orcid.org/0000-0002-3267-4910 Laboratory of Experimental Cardiology, Department of Biomedical Sciences (J.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author and Morten S. OlesenMorten S. Olesen Correspondence to: Morten S. Olesen, MSc, PhD, Mærsk Tower 7.9, Bldg 48, Blegdamsvej 3, 2200 Copenhagen N, Denmark. Email E-mail Address: [email protected] https://orcid.org/0000-0001-9477-5322 Laboratory for Molecular Cardiology (C.P.-M., S.L., G.A., L.A., L.M.M., J.H.S., M.S.O.), Department of Cardiology, The Heart Centre, Copenhagen University Hospital - Rigshospitalet, Denmark. Department of Biomedical Sciences (C.P.-M., S.L., G.A., L.A., L.M.M., T.J., M.S.O.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Search for more papers by this author Originally published1 Feb 2022https://doi.org/10.1161/CIRCGEN.121.003574Circulation: Genomic and Precision Medicine. 2022;15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 1, 2022: Ahead of Print Genetic variations in the genes SCN5A (sodium voltage-gated channel α subunit 5) and SCN10A (sodium voltage-gated channel α subunit 10) have previously been associated with cardiac disease including conduction abnormalities and arrhythmias through genome-wide association studies and rare variant analyses.1,2 The 2 neighboring genes constitute the SCN5A-SCN10A locus on chromosome 3, where SCN5A encodes the cardiac voltage-gated sodium channel NaV1.5 and SCN10A encodes the neuronal voltage-gated sodium channel NaV1.8. The function of NaV1.5 is well established, whereas the role of NaV1.8 in cardiac conduction and arrhythmia remains disputed. Recently, a study proposed that only the last seven exons of SCN10A are expressed in mouse and human hearts and that this short isoform associates with cardiac conduction and arrhythmia.3 We searched for rare putative loss-of-function (LOF) variants in SCN10A in ≈170 000 exomes from the general population and examined whether these variants were associated with atrioventricular and left bundle-branch block (AVB), atrial fibrillation (AF), and electrocardiographic (ECG) characteristics.We accessed genomic information, health records, and ECGs from the UK Biobank database, which contains data on >500 000 individuals. The recent data release provides whole-exome sequencing data on >200 000 individuals, whereof 169 610 are unrelated individuals of European ancestry. Resting ECGs in sinus rhythm were available for 17 774 participants. We studied the associations between putative rare LOF variants in SCN10A, AVB (International Classification of Diseases, Tenth Revision code I44), AF (International Classification of Diseases, Tenth Revision code I48), including early onset of the traits, and ECG characteristics. Early-onset of disease was defined as age at diagnosis ≤60 years. A logistic regression analysis was applied when investigating disease association, whereas comparison of ECG parameters was performed using a linear regression model. Models were adjusted for gender, age, and the 10 principal components (UK Biobank database data field no. 22009). The UK Biobank database received ethical approval from the Research Ethics Committee (REC reference 11/NW/0382) and participants gave informed consent.Our study identified 543 unrelated individuals of European ancestry harboring putative LOF variants (leading to early stop codon, frameshift, or splice-site disruption) in SCN10A with a minor allele frequency <1%. All these individuals carried one variant each except a single person, who carried 2 SCN10A LOF variants. We identified 88 different variants and obtained ECGs from 55 variant carriers. A logistic regression burden test of LOF variants did not establish association between SCN10A and AVB (odds ratio [OR], 1.53 [95% CI, 0.90–2.4]; P=0.090) or AF (OR, 1.19 [95% CI, 0.85–1.62]; P=0.28; Table). Supplementary analyses were performed focusing exclusively at LOF variants in the last 7 exons of SCN10A, showing similar results. No association between any ECG parameter and SCN10A LOF variants was identified (Table). For comparisons, we included 125 SCN5A LOF variant carriers (37 unique variants and 14 available ECGs) and found an association with AVB (OR, 3.11 [95% CI, 1.38–6.06]; P=2.3×10-3) and increased PR interval for carriers as compared to noncarriers (P=1.1×10-3; Table). This supports previous findings associating SCN5A with AVB and PR interval and identifying PR interval to be the main ECG parameter differentiating SCN5A variant carriers and noncarriers.4Table 1. Associations Between SCN5A and SCN10A Loss-of-Function Variants, Cardiac Disease, and ECG CharacteristicsSCN5ASCN10ASCN10A first 21 exonsSCN10A last 7 exonsDiseasesNo. of subjectsOR (95% CI)P valueNo. of subjectsOR (95% CI)P valueNo. of subjectsOR (95% CI)P valueNo. of subjectsOR (95% CI)P valueCarrierNoncarrierCarrierNoncarrierCarrierNoncarrierCarrierNoncarrierAVB835813.11(1.38–6.06)2.3×10-3*1735721.53(0.90–2.41)0.0901035791.84(0.91–3.31)0.062735821.23(0.52–2.42)0.60AF1111 9541.22(0.61–2.21)0.534411 9211.19(0.85–1.62)0.282211 9431.21(0.75–1.86)0.402211 9431.17(0.73–1.79)0.50Early-onset AVB45829.84(3.00–23.58)8.0×10-6*35831.61(0.40–4.21)0.4125842.11(0.35–6.61)0.2915851.09(0.06–4.84)0.93Early-onset AF427101.91(0.58–4.56)0.211027041.17(0.58–2.07)0.63627081.39(0.55–2.87)0.42427100.94(0.29–2.22)0.91ECG parametersBaseline estimate (SE)Coefficient for carrying a LOF variant (SE)P valueBaseline estimate (SE)Coefficient for carrying a LOF variant (SE)P valueBaseline estimate (SE)Coefficient for carrying a LOF variant (SE)P valueBaseline estimate (SE)Coefficient for carrying a LOF variant (SE)P valueP-wave duration, lead V1, ms87 (1.1)1.2 (4.4)0.7987 (1.1)−1.3 (2.2)0.5587 (1.1)1.61 (3.35)0.6387 (1.1)−3.6 (3.0)0.22PR interval, ms123 (1.67)22.7 (7.00)1.1×10-3*123 (1.67)4.48 (3.51)0.20123 (1.67)5.90 (5.32)0.27123 (1.67)3.36 (4.68)0.47P-wave amplitude, lead V1, μV11 (4.0)13 (16)0.4411 (4.0)2.2 (8.4)0.8011 (4.0)14 (13)0.2911 (4.0)−6.8 (11)0.55QRS duration, ms78 (0.82)6.1 (3.4)0.07578 (0.82)0.13 (1.7)0.9478 (0.82)0.84 (2.62)0.7578 (0.82)−0.42 (2.3)0.86QTc interval, ms402 (1.33)−2.95 (5.56)0.60402 (1.33)0.984 (2.81)0.73402 (1.33)4.06 (4.24)0.34402 (1.33)−1.40 (3.73)0.71J-point amplitude, lead V1, μV−11 (5.4)13 (23)0.58−11 (5.4)5.2 (11)0.65−11 (5.4)8.7 (17)0.61−11 (5.4)2.4 (15)0.88RR interval, ms1066 (10.4)21.4 (43.5)0.621066 (10.4)−7.73 (22.0)0.731066 (10.4)−44.3 (33.3)0.181066 (10.4)20.6 (29.3)0.48AVB (ICD-10 code I44) and AF (ICD-10 code I48) are defined from UKBB data field 131 343 and 131 351, respectively. These outcomes were assigned to ICD-10 codes by mapping in-patient hospital records (ICD-9 and ICD-10), death records (ICD-10), primary care records (Read v2 and Read CTV3), and self-reports from interview at UKBB assessment with qualified nurses, described in detail in UKBB resource 593. There were 55 and 14 available ECGs for SCN10A and SCN5A variant carriers, respectively. The total number of ECGs, including controls was 17,774. Carriers and noncarriers refer to individuals carrying a LOF variant or not. Early-onset of disease is defined as age at diagnosis ≤ 60 y. P-values for ECG parameters and disease associations represent analyses of variance. AF indicates atrial fibrillation; AVB, atrioventricular and left bundle-branch block; ICD-10, International Classification of Diseases, Tenth Revision; ICD-9, International Classification of Diseases, Ninth Revision; LOF, loss-of function; OR, odds ratio; QTc, corrected QT interval; and UKBB, UK Biobank database.* Statistically significant associations by a false discovery rate cutoff <10%.Thus, no significant effect on ECG parameters or presence of AVB and AF were identified in SCN10A variant carriers. Increased PR interval and AVB were confirmed in SCN5A variant carriers, emphasizing the importance of NaV1.5 in cardiac conduction and questioning the significance of both NaV1.8 isoforms. Previous studies have associated SCN10A variants with conduction velocity, heart block, and AF and suggested it to be a major causal gene in Brugada syndrome although this has been challenged.3 Man et al3 recently showed that altered expression of the short SCN10A isoform associates with cardiac conduction velocity and proarrhythmogenic characteristics through NaV1.8-modulation of the NaV1.5 current in mice. Although previous publications have provided insightful contributions to the knowledge of SCN10A, the gene requires further characterization in humans. The associations of SCN10A with cardiac conduction and disease in humans have mainly been established through genome-wide association studies, and as these studies primarily identify variants in noncoding regions, it has been challenging to determine the pathophysiological consequences of the identified variants. Multiple intergenic and intronic regulatory elements reside in the SCN5A-SCN10A locus and previous results5 in combination with our findings indicate that genetic variation in the SCN10A region affects the expression of SCN5A, thus modulating cardiac conduction through impaired NaV1.5 function.We then determined the ORs for which we have 80% power to detect statistically significant differences (P≤0.05). The calculations resulted in an OR >1.6 for AF and an OR >2.25 for AVB. These results demonstrate that the statistical power of the study is adequate to identify variants with effect sizes of clinical relevance and indicate that SCN10A LOF variants are not of major importance in development of atrial arrhythmia.The findings presented in this study confirm the role of NaV1.5 in cardiac conduction. However, the clinical relevance of NaV1.8 in human cardiac conduction and atrial arrhythmia remains in question, since no significant enrichment of SCN10A LOF variants was observed.Researchers can access data from the UK Biobank database by applying on https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access.Article InformationAcknowledgmentsThis research has been conducted using the UK Biobank database (UKBB) resource under application number 43247.Sources of FundingThis work was supported by The Research Foundation at Rigshospitalet, The Research Foundation of the Heart Centre Rigshospitalet, The John and Birthe Meyer Foundation, Villadsen Family Foundation, The Arvid Nilsson Foundation, and The Hallas-Møller Emerging Investigator Novo Nordisk (NNF17OC0031204). Dr Ahlberg has received grant from the Novo Nordisk Foundation, BRIDGE - Translational Excellence Programme, Ref No. NNF18SA0034956.Nonstandard Abbreviations and AcronymsAFatrial fibrillationAVBatrioventricular and left bundle-branch blockLOFloss-of-functionORodds ratioDisclosures None.FootnotesFor Sources of Funding and Disclosures, see page 84.Correspondence to: Morten S. Olesen, MSc, PhD, Mærsk Tower 7.9, Bldg 48, Blegdamsvej 3, 2200 Copenhagen N, Denmark. Email morten.salling.[email protected]comReferences1. Wilde AAM, Amin AS. Clinical spectrum of SCN5A mutations: long QT syndrome, brugada syndrome, and cardiomyopathy.JACC Clin Electrophysiol. 2018; 4:569–579. doi: 10.1016/j.jacep.2018.03.006CrossrefMedlineGoogle Scholar2. Pfeufer A, van Noord C, Marciante KD, Arking DE, Larson MG, Smith AV, Tarasov KV, Müller M, Sotoodehnia N, Sinner MF, et al.. Genome-wide association study of PR interval.Nat Genet. 2010; 42:153–159. doi: 10.1038/ng.517CrossrefMedlineGoogle Scholar3. Man JCK, Bosada FM, Scholman KT, Offerhaus JA, Walsh R, van Duijvenboden K, van Eif VWW, Bezzina CR, Verkerk AO, Boukens BJ, et al.. Variant intronic enhancer controls SCN10A-short expression and heart conduction.Circulation. 2021; 144:229–242. doi: 10.1161/CIRCULATIONAHA.121.054083LinkGoogle Scholar4. Meregalli PG, Tan HL, Probst V, Koopmann TT, Tanck MW, Bhuiyan ZA, Sacher F, Kyndt F, Schott JJ, Albuisson J, et al.. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies.Heart Rhythm. 2009; 6:341–348. doi: 10.1016/j.hrthm.2008.11.009CrossrefMedlineGoogle Scholar5. Man JCK, Mohan RA, Boogaard MVD, Hilvering CRE, Jenkins C, Wakker V, Bianchi V, Laat W, Barnett P, Boukens BJ, et al.. An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo.Nat Commun. 2019; 10:4943. doi: 10.1038/s41467-019-12856-5CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails February 2022Vol 15, Issue 1Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.121.003574PMID: 35103494 Originally publishedFebruary 1, 2022 Keywordsexonatrial fibrillationexomegenetic variationbundle-branch blockPDF download Advertisement SubjectsArrhythmiasAtrial FibrillationGenetic, Association StudiesGeneticsOmics