Sudlow, Catherine

Davies, Gail

Salman, Rustam Al-Shahi

Rannikmäe, Kristiina

other

2017-09-22T14:35:12Z

2017-09-22T14:35:12Z

2017-07-08

Background: Cerebral small vessel disease (SVD) causes substantial cognitive, psychiatric and physical disabilities. Despite its common nature, SVD pathogenesis and molecular mechanisms remain poorly understood, and prevention and treatment are probably suboptimal. Identifying the genetic determinants of SVD will improve understanding and may help identify novel treatment targets. The aim of this thesis is to better understand genetic associations with SVD through investigating its pathological, radiological and clinical phenotypes. Methods: To unravel the genetic associations with SVD, I used three complementary approaches. First, I performed a systematic review looking at existing intracerebral haemorrhage (ICH) classification systems and their reliability, to help inform future studies of ICH genetics. Second, I performed a series of systematic reviews and meta-analyses, investigating associations between genetic polymorphisms and histopathologically confirmed cerebral amyloid angiopathy (CAA). Third, I performed meta-analyses of existing genome-wide datasets to determine associations of >1000 common single nucleotide polymorphisms (SNP) in the COL4A1/COL4A2 genomic region with clinico-radiological SVD phenotypes: ICH and its subtypes, ischaemic stroke and its subtypes, and white matter hyperintensities. Results: The reliability of existing ICH classification systems appeared excellent in eight studies conducted in specialist centres with experienced raters, although these existing systems have several limitations. In my systematic evaluation of CAA genetics, meta-analyses of 24 studies including 3520 participants showed robust evidence for a dose-dependent association between APOE ɛ4 and histopathological CAA. There was, however, no convincing association between APOE ɛ2 and presence of CAA in a meta-analysis of 11 studies including 1640 participants. Meta-analyses of five studies including 497 participants showed, contrary to an existing popular hypothesis, that while APOE 4 may increase the risk of developing severe CAA vasculopathy, there is no clear evidence to support a role of ɛ2. There were few data about the role of APOE in hereditary CAA, but in the three studies that had looked at this, there was no evidence for an association between APOE ɛ4 and CAA severity. There were too few studies and participants to draw firm conclusions about the effect of non-APOE ε2/ε3/ε4 genetic polymorphisms on CAA, but there were positive associations with TGF-β1, TOMM40 and CR1 genes in four studies. Finally, in my meta-analyses of the COL4A1/COL4A2 genomic region, three intronic SNPs in COL4A2 were associated with SVD phenotypes: significantly with deep ICH, and suggestively with lacunar ischaemic stroke and WMH. Conclusions: I have shown that while existing ICH classification systems appear to have very good reliability, further research is needed to determine their performance in different settings. For large population-based prospective studies of ICH genetics, anatomical systems are likely to be more feasible, scalable and appropriate, although they have limitations and will need to be further developed. Using systematic reviews and meta-analyses, I have confirmed a dose-related association between APOE ɛ4 and histopathological CAA, but also demonstrated that, despite popular acceptance, there is insufficient data to draw firm conclusions about the association with APOE ɛ2. I found some positive associations with CAA in other genes, which merit replication in further larger studies, and showed that there is currently insufficient data about the role of APOE in hereditary CAA. Finally, I identified a novel association between a locus in a known hereditary SVD gene – COL4A2 – and sporadic SVD. This highlights a new and successful approach for selecting candidate genes and can be expanded in future studies to include other known hereditary SVD genes.

http://hdl.handle.net/1842/23585

en

The University of Edinburgh

Rannikmäe K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, Traylor M, Anderson CD, Battey TW, Radmanesh F, Deka R, Woo JG, Martin LJ, Jimenez-Conde J, Selim M, Brown DL, Silliman SL, Kidwell CS, Montaner J, Langefeld CD, Slowik A, Hansen BM, Lindgren AG, Meschia JF, Fornage M, Bis JC, Debette S, Ikram MA, Longstreth WT, Schmidt R, Zhang CR, Yang Q, Sharma P, Kittner SJ, Mitchell BD, Holliday EG, Levi CR, Attia J, Rothwell PM, Poole DL, Boncoraglio GB, Psaty BM, Malik R, Rost N, Worrall BB, Dichgans M, Van Agtmael T, Woo D, Markus HS, Seshadri S, Rosand J, Sudlow CLM, METASTROKE Consortium, CHARGE WMH Group, ISGC ICH GWAS Study Collaboration, WMH in Ischemic Stroke GWAS Study Collaboration, International Stroke Genetics Consortium. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology 2015;84(9)918-926.

Rannikmäe K, Woodfield R, Anderson CS, Charidimou A, Chiewvit P, Greenberg SM, Jeng J-S, Meretoja A, Palm F, Putaala J, Rinkel GJE, Rosand J, Rost NS, Strbian D, Tatlisumak T, Tsai C-F, Wermer MJH, Werring D, Yeh S-J, Al-Shahi Salman R, Sudlow CLM. Reliability of intracerebral hemorrhage classification systems: a systematic review. International Journal of Stroke 2016.

Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samarasekera N, Al-Shahi Salman R, Sudlow CLM. APOE associations with severe CAAassociated vasculopathic changes – collaborative meta-analysis. Journal of Neurology, Neurosurgery and Psychiatry 2014;85(3):300-305.

Rannikmäe K, Samarasekera N, Salman R, Martînez-Gonzâlez N, Sudlow CLM. Genetic associations of cerebral amyloid angiopathy – a systematic review and meta-analysis. Journal of Neurology, Neurosurgery and Psychiatry 2013;84(8):901-908.

NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC). Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. Lancet Neurology 2015; doi:10.1016/S1474-4422(15)00338-5.

Malik R, Freilinger T, Winsvold BS, Anttila V, Vander Heiden J, Traylor M, de Vries B, Holliday EG, Terwindt GM, Sturm J, Bis JC, Hopewell JC, Ferrari MD, Rannikmäe K, Wessman M, Kallela M, Kubisch C, Fornage M, Meschia JF, Lehtimäki T, Sudlow C, Clarke R, Chasman DI, Mitchell BD, Maguire J, Kaprio J, Farrall M, Raitakari OT, Kurth T, Ikram MA, Reiner AP, Longstreth WT Jr, Rothwell PM, Strachan DP, Sharma P, Seshadri S, Quaye L, Cherkas L, Schürks M, Rosand J, Ligthart L, Boncoraglio GB, Davey Smith G, van Duijn CM, Stefansson K, Worrall BB, Nyholt DR, Markus HS, van den Maagdenberg AM, Cotsapas C, Zwart JA, Palotie A, International Headache Genetics Consortium, Dichgans M, METASTROKE Collaboration of the International Stroke Genetics Consortium. Shared genetic basis for migraine and ischemic stroke: A genomewide analysis of common variants. Neurology 2015;84(21):2132-2145.

Ay H, Arsava EM, Andsberg G, Benner T, Brown RD Jr, Chapman SN, Cole JW, Delavaran H, Dichgans M, Engström G, Giralt-Steinhauer E, Grewal RP, Gwinn K, Jern C, Jimenez-Conde J, Jood K, Katsnelson M, Kissela B, Kittner SJ, Kleindorfer DO, Labovitz DL, Lanfranconi S, Lee JM, Lehm M, Lemmens R, Levi C, Li L, Lindgren A, Markus HS, McArdle PF, Melander O, Norrving B, Peddareddygari LR, Pedersén A, Pera J, Rannikmäe K, Rexrode KM, Rhodes D, Rich SS, Roquer J, Rosand J, Rothwell PM, Rundek T, Sacco RL, Schmidt R, Schürks M, Seiler S, Sharma P, Slowik A, Sudlow C, Thijs V, Woodfield R, Worrall BB, Meschia JF. Pathogenic ischemic stroke phenotypes in the NINDSstroke genetics network. Stroke 2014;45(12):3589-3596.

Rannikmäe K, Sudlow C. Book chapter “Genetics of Sporadic Cerebral Amyloid Angiopathy” in “Intracerebral Haemorrhage” by InTech. 2014; Chapter 5:51-72.

Rannikmäe K, Woodfield R, Al-Shahi Salman R, Sudlow CLM on behalf of the ICH Classification Collaboration. Reliability of spontaneous intracerebral haemorrhage classification systems: a systematic review. Poster at the European Stroke Organisation Conference in Glasgow in 2015. (Published in International Journal of Stroke, 2015:10 Supplement 2:295.)

Rannikmäe K, Davies G, Thomson P, Devan W, Bevan S, Traylor M, Falcone GJ, Anderson C, Rost N, Woo D, Markus H, Seshadri S, Rosand J, Van Agtmael T, Sudlow CLM. The contribution of variants in collagen IV genes to common cerebrovascular phenotypes. Platform presentation at the European Stroke Conference in Nice in 2014. (Published in Cerebrovascular Diseases, 2014:37 Supplement 1:1–2.)

Rannikmäe K, Davies G, Devan W, Bevan S, Traylor M, Falcone G, Anderson C, Rost N, Markus H, Rosand J, Van Agtmael T, Sudlow CLM on behalf of the METASTROKE Consortium, CHARGE Consortium, and ISGC. The contribution of variants in collagen IV genes to common cerebrovascular phenotypes. Poster at the UK Stroke Forum in Harrogate in 2013. (Published in International Journal of Stroke, 2013:8 Supplement 3:56.)

Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samarasekera N, Al-Shahi Salman R, Sudlow CLM. APOE allele-specific associations with severe CAA-associated vasculopathic changes – collaborative meta-analysis. International Journal of Stroke, 2013:8 Supplement 3:56.)

Woodfield R, Rannikmäe K, Grant I, Sudlow C. Reliability and feasibility of ischemic stroke classification systems for large epidemiological studies. Cerebrovascular Diseases, 2013: 35:159.)

Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Sudlow CLM. Association between APOE genotype and cerebral amyloid angiopathy (CAA)-related vasculopathic changes: Collaborative metaanalysis. Journal of Neurology, 2013:260:S40-S41.)

Attribution-NonCommercial-ShareAlike 4.0 International

http://creativecommons.org/licenses/by-nc-sa/4.0/

genetics

CAA

small vessel disease

COL4A1

COL4A2

ICH

intracerebral haemorrhage

Genetic associations with sporadic cerebral small vessel disease

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy