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

Jaeyoon Chung, Graham Hamilton, Minsup Kim, Sandro Marini, Bailey E. Montgomery, Jonathan Quincy Andrew Henry, Art E Cho, Devin L. Brown, Bradford B Worrall, James F Meschia, Scott L. Silliman, Magdy Selim, David L. Tirschwell, Chelsea S. Kidwell, Brett M. Kissela, Steven M Greenberg, Anand Viswanathan, Joshua N Goldstein, Carl D Langefeld, Kristiina RannikmaeCathie L M Sudlow, Neshika Samarasekera, Mark Rodrigues, Rustam Al-Shahi Salman, James Prendergast, Sarah Harris, Ian J Deary, Daniel Woo , Jonathan Rosand, Tom Van Agtmael, Christopher D. Anderson

Research output: Contribution to journalArticlepeer-review


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.

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.
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).
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.
Original languageEnglish
Publication statusPublished - 24 May 2021


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