Rare missense functional variants at COL4A1 and COL4A2 in sporadic intracerebral hemorrhage

Chung, J. et al. (2021) Rare missense functional variants at COL4A1 and COL4A2 in sporadic intracerebral hemorrhage. Neurology, 97(3), e236-e247. (doi: 10.1212/WNL.0000000000012227) (PMID:34031201)

Abstract

Objective: To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH. Methods: We performed sequencing across 559Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling. Results: We identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P>0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in EUR), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen). Conclusions: We identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Hamilton, Dr Graham and Van Agtmael, Professor Tom
• Authors: Chung, J., Hamilton, G., Kim, M., Marini, S., Montgomery, B., Henry, J., Cho, A. E., Brown, D. L., Worrall, B. B., Meschia, J. F., Silliman, S. L., Selim, M., Tirschwell, D. L., Kidwell, C. S., Kissela, B., Greenberg, S. M., Viswanathan, A., Goldstein, J. N., Langefeld, C. D., Rannikmae, K., Sudlow, C. L.M., Samarasekera, N., Rodrigues, M., Al-Shahi Salman, R., Prendergast, J. G.D., Harris, S. E., Deary, I., Woo, D., Rosand, J., Van Agtmael, T., and Anderson, C. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Neurology
• Publisher: American Academy of Neurology
• ISSN: 0028-3878
• ISSN (Online): 1526-632X
• Published Online: 24 May 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Neurology 97(3): e236-e247
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
302164		Collagen IV variants and their role in intracerebral haemorrhage in the general population	Tom Van Agtmael	Medical Research Council (MRC)	MR/R005567/1	CAMS - Cardiovascular Science
300478		Elucidation of molecular pathways underlying cardiac disease caused by Col4a1 mutations	Tom Van Agtmael	Heart Research UK (HEARTRES)	RG 2664/17/20	CAMS - Cardiovascular Science